Liam Davenport

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.

The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.

Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).

PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.

These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”

Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
 

Nivolumab in adjuvant setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.

This article first appeared on Medscape.com.

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.

The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.

Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).

PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.

These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”

Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
 

Nivolumab in adjuvant setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.

This article first appeared on Medscape.com.

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.

The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.

Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).

PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.

These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”

Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
 

Nivolumab in adjuvant setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.

This article first appeared on Medscape.com.

Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”

Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was “quite impressive for this patient population.”

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”

“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.

Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
 

Response rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.

However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”

The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
 

LEAP presents challenges

Dr. Chmielowski would like to see treatment in this setting individualized somehow.

“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.

Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.  

This article first appeared on Medscape.com.

Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”

Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was “quite impressive for this patient population.”

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”

“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.

Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
 

Response rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.

However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”

The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
 

LEAP presents challenges

Dr. Chmielowski would like to see treatment in this setting individualized somehow.

“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.

Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.  

This article first appeared on Medscape.com.

Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”

Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was “quite impressive for this patient population.”

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”

“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.

Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
 

Response rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.

However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”

The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
 

LEAP presents challenges

Dr. Chmielowski would like to see treatment in this setting individualized somehow.

“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.

Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.  

This article first appeared on Medscape.com.

Adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy significantly reduces the risk of early recurrence in high-risk hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative breast cancer, suggests a preplanned interim analysis of a phase 3 trial.

The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)

At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.

“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.

He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”

He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”

According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”

Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?

Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.

But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
 

Study details

Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.

The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.

MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.

They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.

The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.

The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.

This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.

The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.

The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.

Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.

Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.

Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.

The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.

The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.

Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.

Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.

“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.

Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.
 

Questions remain

George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.

He said that “positive trials raise as many questions as they answer, and monarchE is no exception.”

For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer and was also presented at the ESMO meeting.

Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”

“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but health care systems and patients care deeply about the answer to this question.”

Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”

He also asked what the optimum duration of therapy would be: “Is it more than we need, or not enough?”

Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”

Finally, Sledge said, “These drugs are expensive. ... 2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”

And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”

The study was funded by Eli Lilly. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
 

This article first appeared on Medscape.com.

Adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy significantly reduces the risk of early recurrence in high-risk hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative breast cancer, suggests a preplanned interim analysis of a phase 3 trial.

The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)

At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.

“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.

He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”

He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”

According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”

Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?

Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.

But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
 

Study details

Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.

The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.

MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.

They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.

The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.

The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.

This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.

The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.

The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.

Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.

Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.

Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.

The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.

The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.

Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.

Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.

“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.

Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.
 

Questions remain

George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.

He said that “positive trials raise as many questions as they answer, and monarchE is no exception.”

For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer and was also presented at the ESMO meeting.

Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”

“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but health care systems and patients care deeply about the answer to this question.”

Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”

He also asked what the optimum duration of therapy would be: “Is it more than we need, or not enough?”

Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”

Finally, Sledge said, “These drugs are expensive. ... 2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”

And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”

The study was funded by Eli Lilly. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
 

This article first appeared on Medscape.com.

Adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy significantly reduces the risk of early recurrence in high-risk hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative breast cancer, suggests a preplanned interim analysis of a phase 3 trial.

The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)

At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.

“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.

He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”

He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”

According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”

Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?

Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.

But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
 

Study details

Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.

The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.

MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.

They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.

The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.

The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.

This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.

The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.

The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.

Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.

Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.

Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.

The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.

The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.

Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.

Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.

“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.

Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.
 

Questions remain

George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.

He said that “positive trials raise as many questions as they answer, and monarchE is no exception.”

For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer and was also presented at the ESMO meeting.

Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”

“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but health care systems and patients care deeply about the answer to this question.”

Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”

He also asked what the optimum duration of therapy would be: “Is it more than we need, or not enough?”

Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”

Finally, Sledge said, “These drugs are expensive. ... 2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”

And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”

The study was funded by Eli Lilly. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
 

This article first appeared on Medscape.com.

The antibody-drug conjugate sacituzumab govitecan (SG, Trodelvy) significantly extends both progression-free survival and overall survival for patients with metastatic triple-negative breast cancer (TNBC) that has progressed after multiple lines of therapy, according to phase 3 trial data.

The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the European Society for Medical Oncology Virtual Congress 2020.

ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician’s choice of chemotherapy. SG significantly improved median progression-free survival (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median overall survival (12.1 vs 6.7 months; HR, 0.48; P < .0001).

The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).

The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.

He said that because the safety profile of SG is consistent with previous reports and the treatment discontinuation rate was low, the clinical benefit “confirms the use of sacituzumab govitecan” in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.

Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.

Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said the treatment algorithm for the management of TNBC will need to be updated in light of these results.

“In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy,” she said.

She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.
 

Objections to study design and execution

Discussant Cardoso said the choice of progression-free survival as the primary endpoint for the trial was not ideal.

“In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival,” she commented.

“Luckily, we saw some results, but we could have missed it,” Cardoso said. She made “a plea to make sure that overall survival is at least the co–primary endpoint” in the future.

Cardoso also said it was not clear to her why the trial had to be stopped. “For the current patients, if there is no crossover, there is no benefit in stopping the trial,” she said.

She went on: “For future patients, it’s better to have the final results sufficiently powered.” She noted that the benefit seen in ASCENT was “moderate” and “so not a substantial breakthrough.” She added that it was “important not to stop trials too early.”

On the positive side, Cardoso said the median number of previous lines of therapy was “quite remarkable for this subtype, and it is important then for us to discuss sequencing,” particularly given that so many patients received checkpoint inhibitors before entering the trial.
 

Safety and a focus on diarrhea

Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.

The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.

Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.

On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.

ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.

Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.

The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”

In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.

The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.

All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.

By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).

Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.

With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).

Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.

Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”

The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.

This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.

“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.

He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”

The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
 

This article first appeared on Medscape.com.

The antibody-drug conjugate sacituzumab govitecan (SG, Trodelvy) significantly extends both progression-free survival and overall survival for patients with metastatic triple-negative breast cancer (TNBC) that has progressed after multiple lines of therapy, according to phase 3 trial data.

The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the European Society for Medical Oncology Virtual Congress 2020.

ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician’s choice of chemotherapy. SG significantly improved median progression-free survival (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median overall survival (12.1 vs 6.7 months; HR, 0.48; P < .0001).

The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).

The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.

He said that because the safety profile of SG is consistent with previous reports and the treatment discontinuation rate was low, the clinical benefit “confirms the use of sacituzumab govitecan” in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.

Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.

Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said the treatment algorithm for the management of TNBC will need to be updated in light of these results.

“In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy,” she said.

She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.
 

Objections to study design and execution

Discussant Cardoso said the choice of progression-free survival as the primary endpoint for the trial was not ideal.

“In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival,” she commented.

“Luckily, we saw some results, but we could have missed it,” Cardoso said. She made “a plea to make sure that overall survival is at least the co–primary endpoint” in the future.

Cardoso also said it was not clear to her why the trial had to be stopped. “For the current patients, if there is no crossover, there is no benefit in stopping the trial,” she said.

She went on: “For future patients, it’s better to have the final results sufficiently powered.” She noted that the benefit seen in ASCENT was “moderate” and “so not a substantial breakthrough.” She added that it was “important not to stop trials too early.”

On the positive side, Cardoso said the median number of previous lines of therapy was “quite remarkable for this subtype, and it is important then for us to discuss sequencing,” particularly given that so many patients received checkpoint inhibitors before entering the trial.
 

Safety and a focus on diarrhea

Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.

The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.

Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.

On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.

ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.

Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.

The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”

In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.

The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.

All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.

By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).

Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.

With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).

Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.

Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”

The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.

This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.

“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.

He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”

The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
 

This article first appeared on Medscape.com.

The antibody-drug conjugate sacituzumab govitecan (SG, Trodelvy) significantly extends both progression-free survival and overall survival for patients with metastatic triple-negative breast cancer (TNBC) that has progressed after multiple lines of therapy, according to phase 3 trial data.

The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the European Society for Medical Oncology Virtual Congress 2020.

ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician’s choice of chemotherapy. SG significantly improved median progression-free survival (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median overall survival (12.1 vs 6.7 months; HR, 0.48; P < .0001).

The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).

The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.

He said that because the safety profile of SG is consistent with previous reports and the treatment discontinuation rate was low, the clinical benefit “confirms the use of sacituzumab govitecan” in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.

Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.

Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said the treatment algorithm for the management of TNBC will need to be updated in light of these results.

“In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy,” she said.

She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.
 

Objections to study design and execution

Discussant Cardoso said the choice of progression-free survival as the primary endpoint for the trial was not ideal.

“In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival,” she commented.

“Luckily, we saw some results, but we could have missed it,” Cardoso said. She made “a plea to make sure that overall survival is at least the co–primary endpoint” in the future.

Cardoso also said it was not clear to her why the trial had to be stopped. “For the current patients, if there is no crossover, there is no benefit in stopping the trial,” she said.

She went on: “For future patients, it’s better to have the final results sufficiently powered.” She noted that the benefit seen in ASCENT was “moderate” and “so not a substantial breakthrough.” She added that it was “important not to stop trials too early.”

On the positive side, Cardoso said the median number of previous lines of therapy was “quite remarkable for this subtype, and it is important then for us to discuss sequencing,” particularly given that so many patients received checkpoint inhibitors before entering the trial.
 

Safety and a focus on diarrhea

Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.

The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.

Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.

On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.

ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.

Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.

The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”

In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.

The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.

All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.

By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).

Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.

With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).

Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.

Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”

The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.

This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.

“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.

He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”

The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
 

This article first appeared on Medscape.com.

Individuals with major depressive disorder (MDD) have an increased heart rate – a finding that may have the potential to identify individuals at risk for the disorder and predict treatment response, early research suggests.

enot-poloskun/Getty Images

Using the rapid-action of the novel antidepressant ketamine and the latest wearable 24-hour electrocardiogram (ECG) technology, investigators found that heart rate could distinguish MDD patients from healthy individuals.

They also found that patients with MDD with the highest resting heart rate had a greater treatment response. In fact, on average, depressed patients had a heart rate that was roughly 10-15 beats per minute higher than healthy controls.

The innovative design of the proof-of-concept study “allowed us to see that average resting heart rate may change quite suddenly to reflect the change in mood,” lead investigator Carmen Schiweck, PhD, Goethe University, Frankfurt am Main, Germany, said in an interview.

These results could have “exciting implications for treatment selection,” and the researchers plan to assess the potential for heart rate to act as an early warning system for depression, they noted.

The findings were presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.

Identifying trait markers

There have been recent attempts to assess heart rate or heart rate variability (HRV) in patients with MDD to identify trait markers, which are present regardless of the disease phase, or state markers, which are present only during a depressive phase.

However, heart rate and HRV are “highly variable” over a 24-hour cycle, a fact that has been ignored by recent classification efforts, the researchers noted. Moreover, most commonly used antidepressants have a long onset of action, which makes studying their impact on the heart rate challenging.

The researchers’ goal was to determine whether heart rate and HRV could be used as trait markers to distinguish MDD patients from healthy individuals and, through the use of ketamine, whether they can also act as state markers for depression.

For the study, 16 treatment-resistant patients with MDD and 16 age- and sex-matched healthy controls wore a portable ECG device for 4 consecutive days and 3 nights. Heart rate and HRV data were subsequently averaged to obtain a 24-hour ECG.

Participants then received a single infusion of intravenous ketamine for 40 minutes. After waiting for 1 hour, the patients resumed ECG recording for an additional 4 days, with changes in mood assessed using the Hamilton Rating Scale for Depression (HAM-D).

Results showed that, compared with the control group, patients with MDD had a significantly higher 24-hour heart rate (P < .001) and a significantly lower HRV, as measured by the root mean square of successive differences (P < .001).

The investigators also found a reduction in heart rate amplitude, which indicates “significant blunting of circadian rhythm variation throughout the day and less recovery at night.”
 

Ninety percent accuracy

Harmonic and binary regression showed that heart rate was able to identify those with MDD versus those in the control group, particularly using nighttime readings, with 90.6% accuracy. The data correctly identified 14 (87.5%) patients and 15 (93.8%) members of the control group.

Following treatment, heart rate decreased significantly among the MDD group (P < .001), but there was no significant change in HRV (P = .295).

There was a significant positive association between baseline heart rate and response to treatment on the HAM-D (r = .55; P = .046), which suggested better outcomes in patients with a higher heart rate.

Interestingly, while heart rate was positively correlated with depression severity before treatment (r = .59; P = .03), this relationship disappeared following treatment (r = –0.04; P = .90), suggesting heart rate changes were not linked to depression states.

While heart rate levels may be useful as a trait marker and, potentially, for predicting response to antidepressant treatment, they did not show potential as a state marker, the investigators noted.

They suggested that, while the results need to be confirmed in longitudinal studies, approval of a ketamine nasal spray “may open up new avenues to conceive treatment paradigms, as explored in this study.”

However, “this is a small proof-of-concept study,” the investigators acknowledged. They also point out that only six of the patients with MDD had a reduction in HAM-D scores of at least 30% in response to treatment.

Future research plans

Dr. Schiweck said in an interview that her team was able to identify differences in heart rate and HRV in MDD patients that were not observed in other studies because portable at-home devices allowed them to monitor heart rate continuously over days.

The use of ketamine may also have been advantageous because the Netherlands Study of Depression and Anxiety (NESDA), which was published in 2010, clearly showed that “traditional antidepressants,” in particular tricyclic antidepressants, have a strong influence on heart rate and HRV, Dr. Schiweck said.

The team next wants to replicate their study in patients who take nonketamine antidepressants and then remit, because most of the recent studies “just assess patients who are remitted and patients who are currently depressed, but it’s a cross-sectional study design,” said Schiweck.

“If we can follow up the same patients over time then we might really know if it is possible to use heart rate as a state marker for depression,” she added. “That’s what we tried to do with ketamine, but our study was very, very small.”

She noted that the investigators would also like to assess individuals who are “very stressed” and may show some depressive symptoms but don’t yet have a diagnosis of depression.

Mind-body link

Commenting on the findings, Brenda W.J.H. Penninx, MD, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam, said the concept of higher heart rate and lower HRV in depression “is indicative of more sympathetic drive and less parasympathetic drive of the autonomic nervous system.”

“That fits with the overall thought that depression is a state with more continuous exposure to stress overactivation of the body, which can be reflected in the [hypothalamic-pituitary-adrenal] axis, leading to higher levels of cortisol stress hormone. But it can also be reflected in the parasympathetic and sympathetic activation of the autonomic nervous system,” she said.

Dr. Penninx, who was also the principal investigator of the NESDA study, was not involved with the current research.

She noted that the NESDA study showed that, when patients with depressive disorder are compared with a healthy controls group, they have a higher heart rate and lower HRV. “But if we then divide people into medicated and nonmedicated people ... then we see that these deviations are only seen in people using medication,” she added.

“Our findings indicate that at least the use of antidepressants is having quite a large impact on autonomic nervous system dysregulation,” Dr. Penninx said. The difference with the current study, she pointed out, is that “it examines the problem over a completely different time scale.”

Although this offers advantages, the current study did not have the large patient numbers that were included in the NESDA study and “they were not clearly able to distinguish the effect of disease from medication,” noted Dr. Penninx.

In addition, this is not an easy area to investigate because there are multiple factors that can mitigate results, including the psychiatric state of the patient, use of medications for both mental illness and cardiometabolic disease, and a patient’s age and gender.

Still, the study clearly illustrates the importance of the interplay between mental health and somatic health and that there is “a very clear indication that we don’t need to separate those,” Dr. Penninx said.

The study was funded by a TGO-IWT Grant from Belgium. The study authors and Dr. Penninx have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Individuals with major depressive disorder (MDD) have an increased heart rate – a finding that may have the potential to identify individuals at risk for the disorder and predict treatment response, early research suggests.

enot-poloskun/Getty Images

Using the rapid-action of the novel antidepressant ketamine and the latest wearable 24-hour electrocardiogram (ECG) technology, investigators found that heart rate could distinguish MDD patients from healthy individuals.

They also found that patients with MDD with the highest resting heart rate had a greater treatment response. In fact, on average, depressed patients had a heart rate that was roughly 10-15 beats per minute higher than healthy controls.

The innovative design of the proof-of-concept study “allowed us to see that average resting heart rate may change quite suddenly to reflect the change in mood,” lead investigator Carmen Schiweck, PhD, Goethe University, Frankfurt am Main, Germany, said in an interview.

These results could have “exciting implications for treatment selection,” and the researchers plan to assess the potential for heart rate to act as an early warning system for depression, they noted.

The findings were presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.

Identifying trait markers

There have been recent attempts to assess heart rate or heart rate variability (HRV) in patients with MDD to identify trait markers, which are present regardless of the disease phase, or state markers, which are present only during a depressive phase.

However, heart rate and HRV are “highly variable” over a 24-hour cycle, a fact that has been ignored by recent classification efforts, the researchers noted. Moreover, most commonly used antidepressants have a long onset of action, which makes studying their impact on the heart rate challenging.

The researchers’ goal was to determine whether heart rate and HRV could be used as trait markers to distinguish MDD patients from healthy individuals and, through the use of ketamine, whether they can also act as state markers for depression.

For the study, 16 treatment-resistant patients with MDD and 16 age- and sex-matched healthy controls wore a portable ECG device for 4 consecutive days and 3 nights. Heart rate and HRV data were subsequently averaged to obtain a 24-hour ECG.

Participants then received a single infusion of intravenous ketamine for 40 minutes. After waiting for 1 hour, the patients resumed ECG recording for an additional 4 days, with changes in mood assessed using the Hamilton Rating Scale for Depression (HAM-D).

Results showed that, compared with the control group, patients with MDD had a significantly higher 24-hour heart rate (P < .001) and a significantly lower HRV, as measured by the root mean square of successive differences (P < .001).

The investigators also found a reduction in heart rate amplitude, which indicates “significant blunting of circadian rhythm variation throughout the day and less recovery at night.”
 

Ninety percent accuracy

Harmonic and binary regression showed that heart rate was able to identify those with MDD versus those in the control group, particularly using nighttime readings, with 90.6% accuracy. The data correctly identified 14 (87.5%) patients and 15 (93.8%) members of the control group.

Following treatment, heart rate decreased significantly among the MDD group (P < .001), but there was no significant change in HRV (P = .295).

There was a significant positive association between baseline heart rate and response to treatment on the HAM-D (r = .55; P = .046), which suggested better outcomes in patients with a higher heart rate.

Interestingly, while heart rate was positively correlated with depression severity before treatment (r = .59; P = .03), this relationship disappeared following treatment (r = –0.04; P = .90), suggesting heart rate changes were not linked to depression states.

While heart rate levels may be useful as a trait marker and, potentially, for predicting response to antidepressant treatment, they did not show potential as a state marker, the investigators noted.

They suggested that, while the results need to be confirmed in longitudinal studies, approval of a ketamine nasal spray “may open up new avenues to conceive treatment paradigms, as explored in this study.”

However, “this is a small proof-of-concept study,” the investigators acknowledged. They also point out that only six of the patients with MDD had a reduction in HAM-D scores of at least 30% in response to treatment.

Future research plans

Dr. Schiweck said in an interview that her team was able to identify differences in heart rate and HRV in MDD patients that were not observed in other studies because portable at-home devices allowed them to monitor heart rate continuously over days.

The use of ketamine may also have been advantageous because the Netherlands Study of Depression and Anxiety (NESDA), which was published in 2010, clearly showed that “traditional antidepressants,” in particular tricyclic antidepressants, have a strong influence on heart rate and HRV, Dr. Schiweck said.

The team next wants to replicate their study in patients who take nonketamine antidepressants and then remit, because most of the recent studies “just assess patients who are remitted and patients who are currently depressed, but it’s a cross-sectional study design,” said Schiweck.

“If we can follow up the same patients over time then we might really know if it is possible to use heart rate as a state marker for depression,” she added. “That’s what we tried to do with ketamine, but our study was very, very small.”

She noted that the investigators would also like to assess individuals who are “very stressed” and may show some depressive symptoms but don’t yet have a diagnosis of depression.

Mind-body link

Commenting on the findings, Brenda W.J.H. Penninx, MD, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam, said the concept of higher heart rate and lower HRV in depression “is indicative of more sympathetic drive and less parasympathetic drive of the autonomic nervous system.”

“That fits with the overall thought that depression is a state with more continuous exposure to stress overactivation of the body, which can be reflected in the [hypothalamic-pituitary-adrenal] axis, leading to higher levels of cortisol stress hormone. But it can also be reflected in the parasympathetic and sympathetic activation of the autonomic nervous system,” she said.

Dr. Penninx, who was also the principal investigator of the NESDA study, was not involved with the current research.

She noted that the NESDA study showed that, when patients with depressive disorder are compared with a healthy controls group, they have a higher heart rate and lower HRV. “But if we then divide people into medicated and nonmedicated people ... then we see that these deviations are only seen in people using medication,” she added.

“Our findings indicate that at least the use of antidepressants is having quite a large impact on autonomic nervous system dysregulation,” Dr. Penninx said. The difference with the current study, she pointed out, is that “it examines the problem over a completely different time scale.”

Although this offers advantages, the current study did not have the large patient numbers that were included in the NESDA study and “they were not clearly able to distinguish the effect of disease from medication,” noted Dr. Penninx.

In addition, this is not an easy area to investigate because there are multiple factors that can mitigate results, including the psychiatric state of the patient, use of medications for both mental illness and cardiometabolic disease, and a patient’s age and gender.

Still, the study clearly illustrates the importance of the interplay between mental health and somatic health and that there is “a very clear indication that we don’t need to separate those,” Dr. Penninx said.

The study was funded by a TGO-IWT Grant from Belgium. The study authors and Dr. Penninx have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Individuals with major depressive disorder (MDD) have an increased heart rate – a finding that may have the potential to identify individuals at risk for the disorder and predict treatment response, early research suggests.

enot-poloskun/Getty Images

Using the rapid-action of the novel antidepressant ketamine and the latest wearable 24-hour electrocardiogram (ECG) technology, investigators found that heart rate could distinguish MDD patients from healthy individuals.

They also found that patients with MDD with the highest resting heart rate had a greater treatment response. In fact, on average, depressed patients had a heart rate that was roughly 10-15 beats per minute higher than healthy controls.

The innovative design of the proof-of-concept study “allowed us to see that average resting heart rate may change quite suddenly to reflect the change in mood,” lead investigator Carmen Schiweck, PhD, Goethe University, Frankfurt am Main, Germany, said in an interview.

These results could have “exciting implications for treatment selection,” and the researchers plan to assess the potential for heart rate to act as an early warning system for depression, they noted.

The findings were presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.

Identifying trait markers

There have been recent attempts to assess heart rate or heart rate variability (HRV) in patients with MDD to identify trait markers, which are present regardless of the disease phase, or state markers, which are present only during a depressive phase.

However, heart rate and HRV are “highly variable” over a 24-hour cycle, a fact that has been ignored by recent classification efforts, the researchers noted. Moreover, most commonly used antidepressants have a long onset of action, which makes studying their impact on the heart rate challenging.

The researchers’ goal was to determine whether heart rate and HRV could be used as trait markers to distinguish MDD patients from healthy individuals and, through the use of ketamine, whether they can also act as state markers for depression.

For the study, 16 treatment-resistant patients with MDD and 16 age- and sex-matched healthy controls wore a portable ECG device for 4 consecutive days and 3 nights. Heart rate and HRV data were subsequently averaged to obtain a 24-hour ECG.

Participants then received a single infusion of intravenous ketamine for 40 minutes. After waiting for 1 hour, the patients resumed ECG recording for an additional 4 days, with changes in mood assessed using the Hamilton Rating Scale for Depression (HAM-D).

Results showed that, compared with the control group, patients with MDD had a significantly higher 24-hour heart rate (P < .001) and a significantly lower HRV, as measured by the root mean square of successive differences (P < .001).

The investigators also found a reduction in heart rate amplitude, which indicates “significant blunting of circadian rhythm variation throughout the day and less recovery at night.”
 

Ninety percent accuracy

Harmonic and binary regression showed that heart rate was able to identify those with MDD versus those in the control group, particularly using nighttime readings, with 90.6% accuracy. The data correctly identified 14 (87.5%) patients and 15 (93.8%) members of the control group.

Following treatment, heart rate decreased significantly among the MDD group (P < .001), but there was no significant change in HRV (P = .295).

There was a significant positive association between baseline heart rate and response to treatment on the HAM-D (r = .55; P = .046), which suggested better outcomes in patients with a higher heart rate.

Interestingly, while heart rate was positively correlated with depression severity before treatment (r = .59; P = .03), this relationship disappeared following treatment (r = –0.04; P = .90), suggesting heart rate changes were not linked to depression states.

While heart rate levels may be useful as a trait marker and, potentially, for predicting response to antidepressant treatment, they did not show potential as a state marker, the investigators noted.

They suggested that, while the results need to be confirmed in longitudinal studies, approval of a ketamine nasal spray “may open up new avenues to conceive treatment paradigms, as explored in this study.”

However, “this is a small proof-of-concept study,” the investigators acknowledged. They also point out that only six of the patients with MDD had a reduction in HAM-D scores of at least 30% in response to treatment.

Future research plans

Dr. Schiweck said in an interview that her team was able to identify differences in heart rate and HRV in MDD patients that were not observed in other studies because portable at-home devices allowed them to monitor heart rate continuously over days.

The use of ketamine may also have been advantageous because the Netherlands Study of Depression and Anxiety (NESDA), which was published in 2010, clearly showed that “traditional antidepressants,” in particular tricyclic antidepressants, have a strong influence on heart rate and HRV, Dr. Schiweck said.

The team next wants to replicate their study in patients who take nonketamine antidepressants and then remit, because most of the recent studies “just assess patients who are remitted and patients who are currently depressed, but it’s a cross-sectional study design,” said Schiweck.

“If we can follow up the same patients over time then we might really know if it is possible to use heart rate as a state marker for depression,” she added. “That’s what we tried to do with ketamine, but our study was very, very small.”

She noted that the investigators would also like to assess individuals who are “very stressed” and may show some depressive symptoms but don’t yet have a diagnosis of depression.

Mind-body link

Commenting on the findings, Brenda W.J.H. Penninx, MD, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam, said the concept of higher heart rate and lower HRV in depression “is indicative of more sympathetic drive and less parasympathetic drive of the autonomic nervous system.”

“That fits with the overall thought that depression is a state with more continuous exposure to stress overactivation of the body, which can be reflected in the [hypothalamic-pituitary-adrenal] axis, leading to higher levels of cortisol stress hormone. But it can also be reflected in the parasympathetic and sympathetic activation of the autonomic nervous system,” she said.

Dr. Penninx, who was also the principal investigator of the NESDA study, was not involved with the current research.

She noted that the NESDA study showed that, when patients with depressive disorder are compared with a healthy controls group, they have a higher heart rate and lower HRV. “But if we then divide people into medicated and nonmedicated people ... then we see that these deviations are only seen in people using medication,” she added.

“Our findings indicate that at least the use of antidepressants is having quite a large impact on autonomic nervous system dysregulation,” Dr. Penninx said. The difference with the current study, she pointed out, is that “it examines the problem over a completely different time scale.”

Although this offers advantages, the current study did not have the large patient numbers that were included in the NESDA study and “they were not clearly able to distinguish the effect of disease from medication,” noted Dr. Penninx.

In addition, this is not an easy area to investigate because there are multiple factors that can mitigate results, including the psychiatric state of the patient, use of medications for both mental illness and cardiometabolic disease, and a patient’s age and gender.

Still, the study clearly illustrates the importance of the interplay between mental health and somatic health and that there is “a very clear indication that we don’t need to separate those,” Dr. Penninx said.

The study was funded by a TGO-IWT Grant from Belgium. The study authors and Dr. Penninx have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

The gut microbiota differs significantly between patients with major depressive disorder (MDD) and healthy individuals and may be modifiable with a probiotic diet to improve stress and depression scores, two new studies suggest.

ChrisChrisW/iStock/Getty Images

In one study, investigators compared stool samples between patients with MDD and healthy controls. They found significant differences in bacterial profiles between the two groups, as well as between patients who responded vs those who were resistant to treatment.

“This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD and suggests a role in response to antidepressants,” coinvestigator Andrea Fontana, MSc, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, said in an interview.

Results from the second study showed significant improvements in self-reported stress, anxiety, and depression scores in healthy individuals following a “psychobiotic” diet (using probiotics or prebiotics to manipulate the microbiota to improve mental health) that was rich in fruit, vegetables, and fermented foods vs. those who received dietary advice alone.

The investigators, led by Kirsten Berding, PhD, APC Microbiome Ireland, University College Cork, Ireland, now plan on testing their psychobiotic diet in patients with MDD and hope the findings could be helpful in “the development of adjuvant therapeutic opportunities” where pharmacologic treatment is not effective.

Both studies were presented at the virtual congress of the European College of Neuropsychopharmacology, held online this year because of the COVID-19 pandemic.
 

A “hallmark” of major depression

Mr. Fontana and colleagues note that the mostly suboptimal response to pharmacologic treatments among patients with MDD is one of the factors that “contributes to the large socioeconomic burden” of the disease.

Previous research shows patients with MDD have gut dysbiosis, or an imbalance in the natural flora; that antidepressants have antimicrobial properties; and that probiotics have an antibiotic effect. However, the correlation between the composition of the gut microbiota and antidepressant response is poorly understood.

The investigators recruited 34 patients with MDD (aged 18-70 years) who were in a euthymic phase and who did not have comorbid conditions that could affect the gut microbiota.

Eight patients were treatment resistant, defined as a poor response to at least two adequate trials of different antidepressant classes, while 19 were treatment responsive and seven were treatment naive.

The researchers also recruited 20 healthy individuals via word of mouth to act as the control group. There were no significant differences between patients and the control group in terms of baseline characteristics.

Genomic sequencing of bacteria obtained from stool samples showed that it was possible to distinguish between patients with MDD and the healthy individuals, especially at the family, genus, and species levels.

In particular, there were significant differences in the Paenibacillaceae and Flavobacteriaceaea families, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis, among others.

Results also showed that the phyla Proteobacteria, Tenericutes, and the family Peptostreptococcaceae were more common in patients with treatment-resistant MDD, whereas the phylum Actinobacteria was more abundant in treatment responders.

Moreover, several bacteria were found only in the microbiota of patients with treatment-resistant MDD, while others were seen only in treatment-responsive patients. This made it possible to discriminate not only between treatment-resistant and -responsive patients but also between those two patient groups and healthy controls.

“The results of our study confirm that gut dysbiosis is a hallmark of MDD, and suggests that the gut microbiota of patients with treatment-resistant MDD significantly differs from responders to antidepressants,” Mr. Fontana said.
 

Psychobiotic diet

For the second study, Dr. Berding and colleagues note that “psychobiotics” has previously achieved “promising results.”

In addition, diet is both “one of the most influential modifying factors” for the gut microbiota and an easily accessible strategy, they wrote. However, there is also a paucity of studies in this area, they added.

The researchers randomly assigned healthy volunteers with relatively poor dietary habits to either a 4-week psychobiotic diet group (n = 21) or a control group (n = 19).

Courtesy National Cancer Institute

Individuals in the psychobiotic group were told to eat a diet rich in prebiotics, such as fruit and vegetables, fiber including whole grains and legumes, and fermented foods. The control group was educated on Irish healthy-eating guidelines.

Stool and saliva samples were collected and the participants completed several self-reported mental health questionnaires, as well as a 7-day food diary. They also took the socially evaluated cold-pressor test (SECPT) to measure acute stress responses.

Results showed that total daily energy intake decreased significantly in both the diet and control groups over the study period (P = .04 for both) but did not differ significantly between the groups.

In contrast, dietary fiber intake increased significantly in the diet group (P < .001) and was significantly higher than in the control group at the end of the intervention (P = .03).

Individuals in the diet group showed significant decreases in scores on the Perceived Stress Scale (P = .002) and the Beck Depression Inventory (P = .007) during the study, an effect that was not found in the control group.
 

Dietary intervention

There were no significant effects of diet on the acute stress response, but both groups showed improvements in self-concept, or perceived ability to cope, on the Primary Appraisal, Secondary Appraisal index (P = .03 for the diet group, P = .04 for the control group).

The results show that a dietary intervention targeted at the microbiota “can improve subjective feelings of stress and depression in a healthy population,” the investigators wrote.

However, elucidating the “contribution of the microbiota-gut-brain axis on the signaling response to dietary interventions” will require further studies on microbiota sequencing and biological measures of stress, they added.

This will “contribute to the understanding of the benefits of a psychobiotic diet on stress and anxiety,” wrote the researchers.

Dr. Berding said in an interview that while the consumption of dietary fiber changed the most in the diet group, “it would not be the only nutrient” that had an impact on the results, with fermented foods a likely candidate.

She said the next step is to test the dietary intervention in patients with MDD; however, “doing nutritional interventions in diseased populations is always difficult.”

Dr. Berding suggested that the best approach would be to study inpatients in a clinic, as “we would be able to provide every meal and only provide foods that are part of the dietary intervention.”

Although another option would be to conduct the study in outpatients, she noted that assessing inpatients “would give us the best control over compliance.”
 

“Brilliant ideas”

Commenting on the findings, Sergueï Fetissov, MD, PhD, professor of physiology at Rouen University, Mont-Saint-Aignan, France, said that although both studies bring attention to a possible role for the gut microbiota in MDD, neither “provide any experimental evidence of a causative nature.”

Dr. Fetissov, who was not involved in either study, noted that this topic has been the subject of clinical nutritional research for many years.

However, “we still need some strong evidence to prove that some bacteria can influence the regulation of mood and anxiety and stress,” he said.

In addition, researchers currently do not know what actually causes MDD. “How we can say the gut bacteria regulates something if we don’t know what really causes the altered mood?” said Dr. Fetissov.

He noted that over the last 50 years, there have been great advances in the development of drugs that alleviate depression and anxiety by regulating dopamine, serotonin, and other neurotransmitters. However, it is still unknown whether these reflect primary or secondary aspects of mood disorders.

Furthermore, it is not clear “how probiotics to bacteria can influence these neuronal pathways,” he said.

“The ideas are brilliant and I support them ... but we have to provide proof,” Dr. Fetissov concluded.

The research by Dr. Berding and colleagues is funded by a postdoctoral fellowship grant from the Irish Research Council. The study authors and Dr. Fetissov have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The gut microbiota differs significantly between patients with major depressive disorder (MDD) and healthy individuals and may be modifiable with a probiotic diet to improve stress and depression scores, two new studies suggest.

ChrisChrisW/iStock/Getty Images

In one study, investigators compared stool samples between patients with MDD and healthy controls. They found significant differences in bacterial profiles between the two groups, as well as between patients who responded vs those who were resistant to treatment.

“This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD and suggests a role in response to antidepressants,” coinvestigator Andrea Fontana, MSc, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, said in an interview.

Results from the second study showed significant improvements in self-reported stress, anxiety, and depression scores in healthy individuals following a “psychobiotic” diet (using probiotics or prebiotics to manipulate the microbiota to improve mental health) that was rich in fruit, vegetables, and fermented foods vs. those who received dietary advice alone.

The investigators, led by Kirsten Berding, PhD, APC Microbiome Ireland, University College Cork, Ireland, now plan on testing their psychobiotic diet in patients with MDD and hope the findings could be helpful in “the development of adjuvant therapeutic opportunities” where pharmacologic treatment is not effective.

Both studies were presented at the virtual congress of the European College of Neuropsychopharmacology, held online this year because of the COVID-19 pandemic.
 

A “hallmark” of major depression

Mr. Fontana and colleagues note that the mostly suboptimal response to pharmacologic treatments among patients with MDD is one of the factors that “contributes to the large socioeconomic burden” of the disease.

Previous research shows patients with MDD have gut dysbiosis, or an imbalance in the natural flora; that antidepressants have antimicrobial properties; and that probiotics have an antibiotic effect. However, the correlation between the composition of the gut microbiota and antidepressant response is poorly understood.

The investigators recruited 34 patients with MDD (aged 18-70 years) who were in a euthymic phase and who did not have comorbid conditions that could affect the gut microbiota.

Eight patients were treatment resistant, defined as a poor response to at least two adequate trials of different antidepressant classes, while 19 were treatment responsive and seven were treatment naive.

The researchers also recruited 20 healthy individuals via word of mouth to act as the control group. There were no significant differences between patients and the control group in terms of baseline characteristics.

Genomic sequencing of bacteria obtained from stool samples showed that it was possible to distinguish between patients with MDD and the healthy individuals, especially at the family, genus, and species levels.

In particular, there were significant differences in the Paenibacillaceae and Flavobacteriaceaea families, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis, among others.

Results also showed that the phyla Proteobacteria, Tenericutes, and the family Peptostreptococcaceae were more common in patients with treatment-resistant MDD, whereas the phylum Actinobacteria was more abundant in treatment responders.

Moreover, several bacteria were found only in the microbiota of patients with treatment-resistant MDD, while others were seen only in treatment-responsive patients. This made it possible to discriminate not only between treatment-resistant and -responsive patients but also between those two patient groups and healthy controls.

“The results of our study confirm that gut dysbiosis is a hallmark of MDD, and suggests that the gut microbiota of patients with treatment-resistant MDD significantly differs from responders to antidepressants,” Mr. Fontana said.
 

Psychobiotic diet

For the second study, Dr. Berding and colleagues note that “psychobiotics” has previously achieved “promising results.”

In addition, diet is both “one of the most influential modifying factors” for the gut microbiota and an easily accessible strategy, they wrote. However, there is also a paucity of studies in this area, they added.

The researchers randomly assigned healthy volunteers with relatively poor dietary habits to either a 4-week psychobiotic diet group (n = 21) or a control group (n = 19).

Courtesy National Cancer Institute

Individuals in the psychobiotic group were told to eat a diet rich in prebiotics, such as fruit and vegetables, fiber including whole grains and legumes, and fermented foods. The control group was educated on Irish healthy-eating guidelines.

Stool and saliva samples were collected and the participants completed several self-reported mental health questionnaires, as well as a 7-day food diary. They also took the socially evaluated cold-pressor test (SECPT) to measure acute stress responses.

Results showed that total daily energy intake decreased significantly in both the diet and control groups over the study period (P = .04 for both) but did not differ significantly between the groups.

In contrast, dietary fiber intake increased significantly in the diet group (P < .001) and was significantly higher than in the control group at the end of the intervention (P = .03).

Individuals in the diet group showed significant decreases in scores on the Perceived Stress Scale (P = .002) and the Beck Depression Inventory (P = .007) during the study, an effect that was not found in the control group.
 

Dietary intervention

There were no significant effects of diet on the acute stress response, but both groups showed improvements in self-concept, or perceived ability to cope, on the Primary Appraisal, Secondary Appraisal index (P = .03 for the diet group, P = .04 for the control group).

The results show that a dietary intervention targeted at the microbiota “can improve subjective feelings of stress and depression in a healthy population,” the investigators wrote.

However, elucidating the “contribution of the microbiota-gut-brain axis on the signaling response to dietary interventions” will require further studies on microbiota sequencing and biological measures of stress, they added.

This will “contribute to the understanding of the benefits of a psychobiotic diet on stress and anxiety,” wrote the researchers.

Dr. Berding said in an interview that while the consumption of dietary fiber changed the most in the diet group, “it would not be the only nutrient” that had an impact on the results, with fermented foods a likely candidate.

She said the next step is to test the dietary intervention in patients with MDD; however, “doing nutritional interventions in diseased populations is always difficult.”

Dr. Berding suggested that the best approach would be to study inpatients in a clinic, as “we would be able to provide every meal and only provide foods that are part of the dietary intervention.”

Although another option would be to conduct the study in outpatients, she noted that assessing inpatients “would give us the best control over compliance.”
 

“Brilliant ideas”

Commenting on the findings, Sergueï Fetissov, MD, PhD, professor of physiology at Rouen University, Mont-Saint-Aignan, France, said that although both studies bring attention to a possible role for the gut microbiota in MDD, neither “provide any experimental evidence of a causative nature.”

Dr. Fetissov, who was not involved in either study, noted that this topic has been the subject of clinical nutritional research for many years.

However, “we still need some strong evidence to prove that some bacteria can influence the regulation of mood and anxiety and stress,” he said.

In addition, researchers currently do not know what actually causes MDD. “How we can say the gut bacteria regulates something if we don’t know what really causes the altered mood?” said Dr. Fetissov.

He noted that over the last 50 years, there have been great advances in the development of drugs that alleviate depression and anxiety by regulating dopamine, serotonin, and other neurotransmitters. However, it is still unknown whether these reflect primary or secondary aspects of mood disorders.

Furthermore, it is not clear “how probiotics to bacteria can influence these neuronal pathways,” he said.

“The ideas are brilliant and I support them ... but we have to provide proof,” Dr. Fetissov concluded.

The research by Dr. Berding and colleagues is funded by a postdoctoral fellowship grant from the Irish Research Council. The study authors and Dr. Fetissov have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The gut microbiota differs significantly between patients with major depressive disorder (MDD) and healthy individuals and may be modifiable with a probiotic diet to improve stress and depression scores, two new studies suggest.

ChrisChrisW/iStock/Getty Images

In one study, investigators compared stool samples between patients with MDD and healthy controls. They found significant differences in bacterial profiles between the two groups, as well as between patients who responded vs those who were resistant to treatment.

“This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD and suggests a role in response to antidepressants,” coinvestigator Andrea Fontana, MSc, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, said in an interview.

Results from the second study showed significant improvements in self-reported stress, anxiety, and depression scores in healthy individuals following a “psychobiotic” diet (using probiotics or prebiotics to manipulate the microbiota to improve mental health) that was rich in fruit, vegetables, and fermented foods vs. those who received dietary advice alone.

The investigators, led by Kirsten Berding, PhD, APC Microbiome Ireland, University College Cork, Ireland, now plan on testing their psychobiotic diet in patients with MDD and hope the findings could be helpful in “the development of adjuvant therapeutic opportunities” where pharmacologic treatment is not effective.

Both studies were presented at the virtual congress of the European College of Neuropsychopharmacology, held online this year because of the COVID-19 pandemic.
 

A “hallmark” of major depression

Mr. Fontana and colleagues note that the mostly suboptimal response to pharmacologic treatments among patients with MDD is one of the factors that “contributes to the large socioeconomic burden” of the disease.

Previous research shows patients with MDD have gut dysbiosis, or an imbalance in the natural flora; that antidepressants have antimicrobial properties; and that probiotics have an antibiotic effect. However, the correlation between the composition of the gut microbiota and antidepressant response is poorly understood.

The investigators recruited 34 patients with MDD (aged 18-70 years) who were in a euthymic phase and who did not have comorbid conditions that could affect the gut microbiota.

Eight patients were treatment resistant, defined as a poor response to at least two adequate trials of different antidepressant classes, while 19 were treatment responsive and seven were treatment naive.

The researchers also recruited 20 healthy individuals via word of mouth to act as the control group. There were no significant differences between patients and the control group in terms of baseline characteristics.

Genomic sequencing of bacteria obtained from stool samples showed that it was possible to distinguish between patients with MDD and the healthy individuals, especially at the family, genus, and species levels.

In particular, there were significant differences in the Paenibacillaceae and Flavobacteriaceaea families, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis, among others.

Results also showed that the phyla Proteobacteria, Tenericutes, and the family Peptostreptococcaceae were more common in patients with treatment-resistant MDD, whereas the phylum Actinobacteria was more abundant in treatment responders.

Moreover, several bacteria were found only in the microbiota of patients with treatment-resistant MDD, while others were seen only in treatment-responsive patients. This made it possible to discriminate not only between treatment-resistant and -responsive patients but also between those two patient groups and healthy controls.

“The results of our study confirm that gut dysbiosis is a hallmark of MDD, and suggests that the gut microbiota of patients with treatment-resistant MDD significantly differs from responders to antidepressants,” Mr. Fontana said.
 

Psychobiotic diet

For the second study, Dr. Berding and colleagues note that “psychobiotics” has previously achieved “promising results.”

In addition, diet is both “one of the most influential modifying factors” for the gut microbiota and an easily accessible strategy, they wrote. However, there is also a paucity of studies in this area, they added.

The researchers randomly assigned healthy volunteers with relatively poor dietary habits to either a 4-week psychobiotic diet group (n = 21) or a control group (n = 19).

Courtesy National Cancer Institute

Individuals in the psychobiotic group were told to eat a diet rich in prebiotics, such as fruit and vegetables, fiber including whole grains and legumes, and fermented foods. The control group was educated on Irish healthy-eating guidelines.

Stool and saliva samples were collected and the participants completed several self-reported mental health questionnaires, as well as a 7-day food diary. They also took the socially evaluated cold-pressor test (SECPT) to measure acute stress responses.

Results showed that total daily energy intake decreased significantly in both the diet and control groups over the study period (P = .04 for both) but did not differ significantly between the groups.

In contrast, dietary fiber intake increased significantly in the diet group (P < .001) and was significantly higher than in the control group at the end of the intervention (P = .03).

Individuals in the diet group showed significant decreases in scores on the Perceived Stress Scale (P = .002) and the Beck Depression Inventory (P = .007) during the study, an effect that was not found in the control group.
 

Dietary intervention

There were no significant effects of diet on the acute stress response, but both groups showed improvements in self-concept, or perceived ability to cope, on the Primary Appraisal, Secondary Appraisal index (P = .03 for the diet group, P = .04 for the control group).

The results show that a dietary intervention targeted at the microbiota “can improve subjective feelings of stress and depression in a healthy population,” the investigators wrote.

However, elucidating the “contribution of the microbiota-gut-brain axis on the signaling response to dietary interventions” will require further studies on microbiota sequencing and biological measures of stress, they added.

This will “contribute to the understanding of the benefits of a psychobiotic diet on stress and anxiety,” wrote the researchers.

Dr. Berding said in an interview that while the consumption of dietary fiber changed the most in the diet group, “it would not be the only nutrient” that had an impact on the results, with fermented foods a likely candidate.

She said the next step is to test the dietary intervention in patients with MDD; however, “doing nutritional interventions in diseased populations is always difficult.”

Dr. Berding suggested that the best approach would be to study inpatients in a clinic, as “we would be able to provide every meal and only provide foods that are part of the dietary intervention.”

Although another option would be to conduct the study in outpatients, she noted that assessing inpatients “would give us the best control over compliance.”
 

“Brilliant ideas”

Commenting on the findings, Sergueï Fetissov, MD, PhD, professor of physiology at Rouen University, Mont-Saint-Aignan, France, said that although both studies bring attention to a possible role for the gut microbiota in MDD, neither “provide any experimental evidence of a causative nature.”

Dr. Fetissov, who was not involved in either study, noted that this topic has been the subject of clinical nutritional research for many years.

However, “we still need some strong evidence to prove that some bacteria can influence the regulation of mood and anxiety and stress,” he said.

In addition, researchers currently do not know what actually causes MDD. “How we can say the gut bacteria regulates something if we don’t know what really causes the altered mood?” said Dr. Fetissov.

He noted that over the last 50 years, there have been great advances in the development of drugs that alleviate depression and anxiety by regulating dopamine, serotonin, and other neurotransmitters. However, it is still unknown whether these reflect primary or secondary aspects of mood disorders.

Furthermore, it is not clear “how probiotics to bacteria can influence these neuronal pathways,” he said.

“The ideas are brilliant and I support them ... but we have to provide proof,” Dr. Fetissov concluded.

The research by Dr. Berding and colleagues is funded by a postdoctoral fellowship grant from the Irish Research Council. The study authors and Dr. Fetissov have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The use of immunotherapy for upper gastrointestinal tumors and renal cancer, ALK- and EGFR-targeted agents in non–small cell lung cancer (NSCLC), and the next step in personalized prostate cancer management will all be subjects of headlining presentations at the ESMO Virtual Congress 2020.

The conference will, like so many other major events, be held online this year because of the COVID-19 pandemic.

John B. Haanen, PhD, ESMO 2020 scientific chair, who is from the Netherlands Cancer Institute, Amsterdam, the Netherlands, told Medscape Medical News that, because the congress is being held online this year, fewer abstracts were submitted; nevertheless, “We were very happy to see ... that the quality was very good.”

The number of submissions was not the only problem the organizing committee had to face in transforming the ESMO Congress into a virtual meeting.

They were unable to fit the scientific and educational programs together and so have had to split them over two consecutive weekends. Moreover, many of the sessions were highly interactive and needed to be either adapted or omitted.

“So the program is somewhat different,” Haanen said. He noted that “the presentations were also made shorter, especially on the educational sessions, because...we can’t expect people to sit behind screens for hours listening to long presentations.”

He added: “That was out of the question.”

Haanen is nevertheless hopeful that the virtual meeting will be “very exciting.”

Solange Peters, MD, PhD, ESMO president, who is also affiliated with the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said in a press conference that it was a “sacrifice” to move ESMO 2020 online and that “there were very sad moments” when deciding on the content.

However, there were some benefits from the change.

She said that all of the ESMO meetings this year have seen “huge” increases in the number of attendees and the geographical span or reach of each of the conferences.

“So suddenly you also realize that, what is one of the missions of ESMO being to convey education globally ... was probably better reached, better achieved with the virtual format,” she commented.
 

Presidential symposia

Turning to the program, Haanen first picked out the third presidential symposium, which will be held on Monday, September 21. This will focus entirely on upper gastrointestinal tumors in both the adjuvant and metastatic setting.

He said that in recent years, “very little progress has been made” in this area, with treatment mostly consisting of chemotherapy and chemoradiotherapy.

However, this year’s presentations will explore the addition of immunotherapy either to chemotherapy or as an adjuvant treatment following completion of standard-of-care treatment for local disease.

Haanen said that the results will be “very interesting ... and may change current practice,” something that “is very important for both doctors and their patients.”

On Saturday, September 19, the first presidential symposium will include two presentations on lung cancer that Haanen said will offer some “exciting new [results] that I am sure will change clinical practice.”

One will be on the CROWN phase 3 trial comparing lorlatinib and crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC.

The other will present results on central nervous system disease recurrence from the ADAURA phase 3 trial of osimertinib adjuvant therapy in patients with resected EGFR-mutated NSCLC.

The same session will also see new data in advanced renal cell carcinoma from CheckMate 9ER, in which the c-Met and VEGFR2 inhibitor cabozantinib (Cabometyx) was combined with nivolumab (Opdivo) and compared to sunitinib (Sutent) in untreated patients.

“Last year, there were already some exciting results of the combination of axitinib [Inlyta], either with pembrolizumab [Keytruda] or with avelumab [Bavencio]...in the first-line setting in metastatic clear cell renal cell cancer,” Hannen said.

“Clearly there was a survival advantage over the standard of care, sunitinib,” he added.

This year, not only will efficacy data from CheckMate 9ER be presented but also quality-of-life results.

“That’s very important, because what everybody is afraid of is that, by adding drugs, you always get more impact on the quality of life, but you will see that the quality-of-life results are very exciting,” he said.

The second presidential symposium will feature studies on prostate cancer, notably the phase 3 IPATential150 trial of abiraterone (Zytiga) plus either ipatasertib or placebo in metastatic castration-resistant prostate cancer.

Ipatasertib targets Akt, and Haanen said that “by adding it to, let’s say, standard-of-care treatment ... the question of course of will be, Does that have a better outcome?”

He believes the results will be a “very nice illustration” that prostate cancer management is heading in the direction of personalized treatment.

Alongside the presidential symposia, there will be a number of proffered paper sessions on the latest results in all aspects of oncology, including results from the ASCENT trial in triple-negative breast cancer, as well as a dedicated COVID-19 track.

Haanen said that the ESMO Virtual Congress 2020, coming after the AACR and ASCO annual meetings, has the “advantage” of being able to present the latest outcomes of patients treated with chemotherapy and immunotherapy against the backdrop of the pandemic.

This will include a study from the ESMO Resilience Task Force on the impact of COVID-19 on oncology professionals both in terms of their personal distress and burnout and their job performance.

“I think that is very important,” Haanen said, “especially because the whole thing with COVID-19 is not yet over, and everybody is preparing for a second wave in the fall and winter.

“It may help us give us clues on how we can protect ourselves or each other to prevent burnout or other problems that we as healthcare caregivers face in this difficult period.”
 

Next year

For next year, Peters remains hopeful that the ESMO 2021 meeting will take place as planned in Paris.

She anticipates that, indeed, ESMO meetings will be able to take place from spring next year.

This will depend on a vaccine for COVID-19 becoming widely available, although oncologists in some countries may still not be able to travel.

This means “starting probably with hybrid formats, with some of the faculty being on site and some not, [and] the same thing for the attendees,” Peters said.

She suggested that, for ESMO Congress 2021 to work as an on-site meeting, it will require at least half or two-thirds of the originally anticipated number of attendees.

“I hope that Paris next year will happen,” Peters said, adding that it “will probably happen with less attendees – that’s fine, but [still] with a large number of faculty and attendees.”

The commentators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The use of immunotherapy for upper gastrointestinal tumors and renal cancer, ALK- and EGFR-targeted agents in non–small cell lung cancer (NSCLC), and the next step in personalized prostate cancer management will all be subjects of headlining presentations at the ESMO Virtual Congress 2020.

The conference will, like so many other major events, be held online this year because of the COVID-19 pandemic.

John B. Haanen, PhD, ESMO 2020 scientific chair, who is from the Netherlands Cancer Institute, Amsterdam, the Netherlands, told Medscape Medical News that, because the congress is being held online this year, fewer abstracts were submitted; nevertheless, “We were very happy to see ... that the quality was very good.”

The number of submissions was not the only problem the organizing committee had to face in transforming the ESMO Congress into a virtual meeting.

They were unable to fit the scientific and educational programs together and so have had to split them over two consecutive weekends. Moreover, many of the sessions were highly interactive and needed to be either adapted or omitted.

“So the program is somewhat different,” Haanen said. He noted that “the presentations were also made shorter, especially on the educational sessions, because...we can’t expect people to sit behind screens for hours listening to long presentations.”

He added: “That was out of the question.”

Haanen is nevertheless hopeful that the virtual meeting will be “very exciting.”

Solange Peters, MD, PhD, ESMO president, who is also affiliated with the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said in a press conference that it was a “sacrifice” to move ESMO 2020 online and that “there were very sad moments” when deciding on the content.

However, there were some benefits from the change.

She said that all of the ESMO meetings this year have seen “huge” increases in the number of attendees and the geographical span or reach of each of the conferences.

“So suddenly you also realize that, what is one of the missions of ESMO being to convey education globally ... was probably better reached, better achieved with the virtual format,” she commented.
 

Presidential symposia

Turning to the program, Haanen first picked out the third presidential symposium, which will be held on Monday, September 21. This will focus entirely on upper gastrointestinal tumors in both the adjuvant and metastatic setting.

He said that in recent years, “very little progress has been made” in this area, with treatment mostly consisting of chemotherapy and chemoradiotherapy.

However, this year’s presentations will explore the addition of immunotherapy either to chemotherapy or as an adjuvant treatment following completion of standard-of-care treatment for local disease.

Haanen said that the results will be “very interesting ... and may change current practice,” something that “is very important for both doctors and their patients.”

On Saturday, September 19, the first presidential symposium will include two presentations on lung cancer that Haanen said will offer some “exciting new [results] that I am sure will change clinical practice.”

One will be on the CROWN phase 3 trial comparing lorlatinib and crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC.

The other will present results on central nervous system disease recurrence from the ADAURA phase 3 trial of osimertinib adjuvant therapy in patients with resected EGFR-mutated NSCLC.

The same session will also see new data in advanced renal cell carcinoma from CheckMate 9ER, in which the c-Met and VEGFR2 inhibitor cabozantinib (Cabometyx) was combined with nivolumab (Opdivo) and compared to sunitinib (Sutent) in untreated patients.

“Last year, there were already some exciting results of the combination of axitinib [Inlyta], either with pembrolizumab [Keytruda] or with avelumab [Bavencio]...in the first-line setting in metastatic clear cell renal cell cancer,” Hannen said.

“Clearly there was a survival advantage over the standard of care, sunitinib,” he added.

This year, not only will efficacy data from CheckMate 9ER be presented but also quality-of-life results.

“That’s very important, because what everybody is afraid of is that, by adding drugs, you always get more impact on the quality of life, but you will see that the quality-of-life results are very exciting,” he said.

The second presidential symposium will feature studies on prostate cancer, notably the phase 3 IPATential150 trial of abiraterone (Zytiga) plus either ipatasertib or placebo in metastatic castration-resistant prostate cancer.

Ipatasertib targets Akt, and Haanen said that “by adding it to, let’s say, standard-of-care treatment ... the question of course of will be, Does that have a better outcome?”

He believes the results will be a “very nice illustration” that prostate cancer management is heading in the direction of personalized treatment.

Alongside the presidential symposia, there will be a number of proffered paper sessions on the latest results in all aspects of oncology, including results from the ASCENT trial in triple-negative breast cancer, as well as a dedicated COVID-19 track.

Haanen said that the ESMO Virtual Congress 2020, coming after the AACR and ASCO annual meetings, has the “advantage” of being able to present the latest outcomes of patients treated with chemotherapy and immunotherapy against the backdrop of the pandemic.

This will include a study from the ESMO Resilience Task Force on the impact of COVID-19 on oncology professionals both in terms of their personal distress and burnout and their job performance.

“I think that is very important,” Haanen said, “especially because the whole thing with COVID-19 is not yet over, and everybody is preparing for a second wave in the fall and winter.

“It may help us give us clues on how we can protect ourselves or each other to prevent burnout or other problems that we as healthcare caregivers face in this difficult period.”
 

Next year

For next year, Peters remains hopeful that the ESMO 2021 meeting will take place as planned in Paris.

She anticipates that, indeed, ESMO meetings will be able to take place from spring next year.

This will depend on a vaccine for COVID-19 becoming widely available, although oncologists in some countries may still not be able to travel.

This means “starting probably with hybrid formats, with some of the faculty being on site and some not, [and] the same thing for the attendees,” Peters said.

She suggested that, for ESMO Congress 2021 to work as an on-site meeting, it will require at least half or two-thirds of the originally anticipated number of attendees.

“I hope that Paris next year will happen,” Peters said, adding that it “will probably happen with less attendees – that’s fine, but [still] with a large number of faculty and attendees.”

The commentators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The use of immunotherapy for upper gastrointestinal tumors and renal cancer, ALK- and EGFR-targeted agents in non–small cell lung cancer (NSCLC), and the next step in personalized prostate cancer management will all be subjects of headlining presentations at the ESMO Virtual Congress 2020.

The conference will, like so many other major events, be held online this year because of the COVID-19 pandemic.

John B. Haanen, PhD, ESMO 2020 scientific chair, who is from the Netherlands Cancer Institute, Amsterdam, the Netherlands, told Medscape Medical News that, because the congress is being held online this year, fewer abstracts were submitted; nevertheless, “We were very happy to see ... that the quality was very good.”

The number of submissions was not the only problem the organizing committee had to face in transforming the ESMO Congress into a virtual meeting.

They were unable to fit the scientific and educational programs together and so have had to split them over two consecutive weekends. Moreover, many of the sessions were highly interactive and needed to be either adapted or omitted.

“So the program is somewhat different,” Haanen said. He noted that “the presentations were also made shorter, especially on the educational sessions, because...we can’t expect people to sit behind screens for hours listening to long presentations.”

He added: “That was out of the question.”

Haanen is nevertheless hopeful that the virtual meeting will be “very exciting.”

Solange Peters, MD, PhD, ESMO president, who is also affiliated with the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said in a press conference that it was a “sacrifice” to move ESMO 2020 online and that “there were very sad moments” when deciding on the content.

However, there were some benefits from the change.

She said that all of the ESMO meetings this year have seen “huge” increases in the number of attendees and the geographical span or reach of each of the conferences.

“So suddenly you also realize that, what is one of the missions of ESMO being to convey education globally ... was probably better reached, better achieved with the virtual format,” she commented.
 

Presidential symposia

Turning to the program, Haanen first picked out the third presidential symposium, which will be held on Monday, September 21. This will focus entirely on upper gastrointestinal tumors in both the adjuvant and metastatic setting.

He said that in recent years, “very little progress has been made” in this area, with treatment mostly consisting of chemotherapy and chemoradiotherapy.

However, this year’s presentations will explore the addition of immunotherapy either to chemotherapy or as an adjuvant treatment following completion of standard-of-care treatment for local disease.

Haanen said that the results will be “very interesting ... and may change current practice,” something that “is very important for both doctors and their patients.”

On Saturday, September 19, the first presidential symposium will include two presentations on lung cancer that Haanen said will offer some “exciting new [results] that I am sure will change clinical practice.”

One will be on the CROWN phase 3 trial comparing lorlatinib and crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC.

The other will present results on central nervous system disease recurrence from the ADAURA phase 3 trial of osimertinib adjuvant therapy in patients with resected EGFR-mutated NSCLC.

The same session will also see new data in advanced renal cell carcinoma from CheckMate 9ER, in which the c-Met and VEGFR2 inhibitor cabozantinib (Cabometyx) was combined with nivolumab (Opdivo) and compared to sunitinib (Sutent) in untreated patients.

“Last year, there were already some exciting results of the combination of axitinib [Inlyta], either with pembrolizumab [Keytruda] or with avelumab [Bavencio]...in the first-line setting in metastatic clear cell renal cell cancer,” Hannen said.

“Clearly there was a survival advantage over the standard of care, sunitinib,” he added.

This year, not only will efficacy data from CheckMate 9ER be presented but also quality-of-life results.

“That’s very important, because what everybody is afraid of is that, by adding drugs, you always get more impact on the quality of life, but you will see that the quality-of-life results are very exciting,” he said.

The second presidential symposium will feature studies on prostate cancer, notably the phase 3 IPATential150 trial of abiraterone (Zytiga) plus either ipatasertib or placebo in metastatic castration-resistant prostate cancer.

Ipatasertib targets Akt, and Haanen said that “by adding it to, let’s say, standard-of-care treatment ... the question of course of will be, Does that have a better outcome?”

He believes the results will be a “very nice illustration” that prostate cancer management is heading in the direction of personalized treatment.

Alongside the presidential symposia, there will be a number of proffered paper sessions on the latest results in all aspects of oncology, including results from the ASCENT trial in triple-negative breast cancer, as well as a dedicated COVID-19 track.

Haanen said that the ESMO Virtual Congress 2020, coming after the AACR and ASCO annual meetings, has the “advantage” of being able to present the latest outcomes of patients treated with chemotherapy and immunotherapy against the backdrop of the pandemic.

This will include a study from the ESMO Resilience Task Force on the impact of COVID-19 on oncology professionals both in terms of their personal distress and burnout and their job performance.

“I think that is very important,” Haanen said, “especially because the whole thing with COVID-19 is not yet over, and everybody is preparing for a second wave in the fall and winter.

“It may help us give us clues on how we can protect ourselves or each other to prevent burnout or other problems that we as healthcare caregivers face in this difficult period.”
 

Next year

For next year, Peters remains hopeful that the ESMO 2021 meeting will take place as planned in Paris.

She anticipates that, indeed, ESMO meetings will be able to take place from spring next year.

This will depend on a vaccine for COVID-19 becoming widely available, although oncologists in some countries may still not be able to travel.

This means “starting probably with hybrid formats, with some of the faculty being on site and some not, [and] the same thing for the attendees,” Peters said.

She suggested that, for ESMO Congress 2021 to work as an on-site meeting, it will require at least half or two-thirds of the originally anticipated number of attendees.

“I hope that Paris next year will happen,” Peters said, adding that it “will probably happen with less attendees – that’s fine, but [still] with a large number of faculty and attendees.”

The commentators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The investigational anti-PD-1 antibody sintilimab (Tyvyt, Innovent Biologics and Eli Lilly) has shown that it improves the efficacy of platinum-based chemotherapy in the first-line treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC) in a phase 3 trial dubbed ORIENT-11.

The study was presented at the World Congress on Lung Cancer 2020 Virtual Presidential Symposium, held virtually due to the COVID-19 pandemic, on August 8. It was also published simultaneously in the Journal of Thoracic Oncology.

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of programmed death (PD)-1 to PD-ligand 1 (PD-L1) or PD-L2 with high affinity, and has received market authorization in China for the treatment of Hodgkin lymphoma.

For ORIENT-11, almost 400 patients with advanced nonsquamous NSCLC were randomly assigned to sintilimab or placebo plus pemetrexed and platinum-based chemotherapy in a 2:1 ratio.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS [progression-free survival], compared to placebo,” reducing progression rates by 52%, noted lead investigator Li Zhang, MD, professor of medical oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Crucially, this benefit “was seen across key clinical subgroups,” he added.

He noted that the overall response rate “was also improved, with a durable response,” while the results, which are not yet mature, suggest the experimental arm was associated with an overall survival (OS) benefit.

Study discussant Misako Nagasaka, MD, a thoracic oncologist and clinical investigator at Karmanos Cancer Institute, Detroit, said that the PFS benefit seen in the study is “certainly encouraging.”

Adding a note of caution, she continued: “But we have seen studies with PFS improvement which did not translate into OS improvement.

“Longer follow-up would allow events to mature and we will ultimately see if there would be a significant OS benefit,” she said.

Dr. Nagasaka also pointed out that the greater benefit with sintilimab seen in patients with high PD-L1 begs the question as to what would be the preferred regimen in those with higher or lower expression.

And, she said, this is not just about what regimen to choose but “more importantly, why?”

“Perhaps you’d like to use something with the best response rate, perhaps you’re sticking to a single agent immunotherapy because the toxicity profile is more favorable, or perhaps you [are] convinced with a certain regimen because of the robust PFS and OS data,” she said.

“Whatever you chose, there was a reason for your choice,” she said, adding that the sintilimab combination would have to “fulfill those reasons for you to consider choosing this regimen.”

Study details

Dr. Zhang began his presentation by noting that previous phase 1b studies have shown that sintilimab plus pemetrexed and platinum-based chemotherapy has a “tolerable safety profile and promising efficacy” in previously untreated non-squamous NSCLC.

They therefore conducted ORIENT-11, a randomized, double-blind, phase 3 study involving 397 patients with untreated stage IIIB/C or IV nonsquamous NSCLC who had neither EGFR nor ALK gene alterations.

The patients were randomly assigned in a 2:1 fashion to sintilimab plus pemetrexed and platinum-based chemotherapy (n = 266) or placebo plus pemetrexed and chemo (n = 131) for four cycles, followed by sintilimab or placebo plus pemetrexed for up to 24 months.

Thirty-five patients in the placebo arm crossed over to sintilimab monotherapy, representing 31.3% of the intention-to-treat population.

At the data cutoff of Nov. 15, 2019, 198 events had occurred, at a median follow-up of 8.9 months.

The team found that median PFS was significantly higher with sintilimab than placebo combination therapy, at 8.9 months vs. 5.0 months, or a hazard ratio of 0.482 (P < .00001).

Dr. Zhang noted that the benefit with sintilimab plus pemetrexed and platinum-based chemotherapy was seen across all subgroups.

However, it was notable that the impact of adding sintilimab on PFS was greater in patients with a tumor proportion score (TPS) ≥50%.

The HR for progression vs. the placebo treatment arm was 0.310, with median PFS not reached, which decreased to 0.503 in patients with a TPS of 1%-49% and 0.664 among those with a TPS <1%.

The results also showed that there was a “nominally significant improvement” in overall survival with sintilimab versus placebo, at a HR of 0.609 (P = 0.01921).

The ORR was markedly different between the sintilimab and placebo groups, at 51.9% vs. 29.8%, with the duration of response not reached in the sintilimab arm compared with 5.5 months in the placebo arm.

The sintilimab arm included three (1.1%) complete responses, which was not observed with pemetrexed and platinum-based chemotherapy alone.

Finally, Dr. Zhang observed that the safety profiles of the sintilimab and placebo arms were similar, with comparable rates of any, grade 3-5, and serious adverse events largely driven by high rates of chemotherapy-related events.

While there were fewer adverse events that led to death with sintilimab, at 2.3% vs. 6.9% with placebo, there were, as expected, more immune-related adverse events, at 43.2% vs. 36.6%, respectively.

Comparison with pembrolizumab

In her discussion, Dr. Nagasaka said that the first question that came to mind when she saw the results was: “How does the ORIENT-11 data compare with KEYNOTE-189?”

For that study, pembrolizumab (Keytruda, Merck) was added to pemetrexed plus carboplatin chemotherapy and compared with standard of care alone in patients with untreated metastatic nonsquamous NSCLC.

As reported by Medscape Medical News, pembrolizumab was associated with a 48% reduced risk of disease progression, as well as improved overall survival.

Dr. Nagasaka said that ORIENT-11 “had patients that tended to be younger, there were more males, more with performance status 1, and those who had never smoked” than those in KEYNOTE-189.

“But most importantly, KEYNOTE-189 had a very small number of patients from East Asia, only 1% in the pembro arm and 2.9% in the placebo arm.”

In contrast, all the patients included in ORIENT-11 were from East Asia, making the study of “high importance.”

She added that, “while across-trial comparisons must be taken with caution, the medium PFS of ORIENT-11 ... appears comparable to those of KEYNOTE-189,” while the HR “appears identical.”

This is despite median follow-up time in ORIENT-11 of “only” 8.9 months vs. a median of 23.1 months in the updated KEYNOTE-189 data.

There are plans to register the sintilimab combination therapy in China for the treatment of nonsquamous NSCLC, where it will go up against pembrolizumab as well as, potentially, tislelizumab (BeiGene).

The study was sponsored by Innovent Biologics and Eli Lilly. Dr. Zhang disclosed research grants from Eli Lilly and Pfizer. Dr. Nagasaka disclosed serving on the advisory boards of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, and EMD Serono; as a consultant for Caris Life Sciences; and receiving travel support from An Hearts Therapeutics.

This article first appeared on Medscape.com.

The investigational anti-PD-1 antibody sintilimab (Tyvyt, Innovent Biologics and Eli Lilly) has shown that it improves the efficacy of platinum-based chemotherapy in the first-line treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC) in a phase 3 trial dubbed ORIENT-11.

The study was presented at the World Congress on Lung Cancer 2020 Virtual Presidential Symposium, held virtually due to the COVID-19 pandemic, on August 8. It was also published simultaneously in the Journal of Thoracic Oncology.

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of programmed death (PD)-1 to PD-ligand 1 (PD-L1) or PD-L2 with high affinity, and has received market authorization in China for the treatment of Hodgkin lymphoma.

For ORIENT-11, almost 400 patients with advanced nonsquamous NSCLC were randomly assigned to sintilimab or placebo plus pemetrexed and platinum-based chemotherapy in a 2:1 ratio.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS [progression-free survival], compared to placebo,” reducing progression rates by 52%, noted lead investigator Li Zhang, MD, professor of medical oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Crucially, this benefit “was seen across key clinical subgroups,” he added.

He noted that the overall response rate “was also improved, with a durable response,” while the results, which are not yet mature, suggest the experimental arm was associated with an overall survival (OS) benefit.

Study discussant Misako Nagasaka, MD, a thoracic oncologist and clinical investigator at Karmanos Cancer Institute, Detroit, said that the PFS benefit seen in the study is “certainly encouraging.”

Adding a note of caution, she continued: “But we have seen studies with PFS improvement which did not translate into OS improvement.

“Longer follow-up would allow events to mature and we will ultimately see if there would be a significant OS benefit,” she said.

Dr. Nagasaka also pointed out that the greater benefit with sintilimab seen in patients with high PD-L1 begs the question as to what would be the preferred regimen in those with higher or lower expression.

And, she said, this is not just about what regimen to choose but “more importantly, why?”

“Perhaps you’d like to use something with the best response rate, perhaps you’re sticking to a single agent immunotherapy because the toxicity profile is more favorable, or perhaps you [are] convinced with a certain regimen because of the robust PFS and OS data,” she said.

“Whatever you chose, there was a reason for your choice,” she said, adding that the sintilimab combination would have to “fulfill those reasons for you to consider choosing this regimen.”

Study details

Dr. Zhang began his presentation by noting that previous phase 1b studies have shown that sintilimab plus pemetrexed and platinum-based chemotherapy has a “tolerable safety profile and promising efficacy” in previously untreated non-squamous NSCLC.

They therefore conducted ORIENT-11, a randomized, double-blind, phase 3 study involving 397 patients with untreated stage IIIB/C or IV nonsquamous NSCLC who had neither EGFR nor ALK gene alterations.

The patients were randomly assigned in a 2:1 fashion to sintilimab plus pemetrexed and platinum-based chemotherapy (n = 266) or placebo plus pemetrexed and chemo (n = 131) for four cycles, followed by sintilimab or placebo plus pemetrexed for up to 24 months.

Thirty-five patients in the placebo arm crossed over to sintilimab monotherapy, representing 31.3% of the intention-to-treat population.

At the data cutoff of Nov. 15, 2019, 198 events had occurred, at a median follow-up of 8.9 months.

The team found that median PFS was significantly higher with sintilimab than placebo combination therapy, at 8.9 months vs. 5.0 months, or a hazard ratio of 0.482 (P < .00001).

Dr. Zhang noted that the benefit with sintilimab plus pemetrexed and platinum-based chemotherapy was seen across all subgroups.

However, it was notable that the impact of adding sintilimab on PFS was greater in patients with a tumor proportion score (TPS) ≥50%.

The HR for progression vs. the placebo treatment arm was 0.310, with median PFS not reached, which decreased to 0.503 in patients with a TPS of 1%-49% and 0.664 among those with a TPS <1%.

The results also showed that there was a “nominally significant improvement” in overall survival with sintilimab versus placebo, at a HR of 0.609 (P = 0.01921).

The ORR was markedly different between the sintilimab and placebo groups, at 51.9% vs. 29.8%, with the duration of response not reached in the sintilimab arm compared with 5.5 months in the placebo arm.

The sintilimab arm included three (1.1%) complete responses, which was not observed with pemetrexed and platinum-based chemotherapy alone.

Finally, Dr. Zhang observed that the safety profiles of the sintilimab and placebo arms were similar, with comparable rates of any, grade 3-5, and serious adverse events largely driven by high rates of chemotherapy-related events.

While there were fewer adverse events that led to death with sintilimab, at 2.3% vs. 6.9% with placebo, there were, as expected, more immune-related adverse events, at 43.2% vs. 36.6%, respectively.

Comparison with pembrolizumab

In her discussion, Dr. Nagasaka said that the first question that came to mind when she saw the results was: “How does the ORIENT-11 data compare with KEYNOTE-189?”

For that study, pembrolizumab (Keytruda, Merck) was added to pemetrexed plus carboplatin chemotherapy and compared with standard of care alone in patients with untreated metastatic nonsquamous NSCLC.

As reported by Medscape Medical News, pembrolizumab was associated with a 48% reduced risk of disease progression, as well as improved overall survival.

Dr. Nagasaka said that ORIENT-11 “had patients that tended to be younger, there were more males, more with performance status 1, and those who had never smoked” than those in KEYNOTE-189.

“But most importantly, KEYNOTE-189 had a very small number of patients from East Asia, only 1% in the pembro arm and 2.9% in the placebo arm.”

In contrast, all the patients included in ORIENT-11 were from East Asia, making the study of “high importance.”

She added that, “while across-trial comparisons must be taken with caution, the medium PFS of ORIENT-11 ... appears comparable to those of KEYNOTE-189,” while the HR “appears identical.”

This is despite median follow-up time in ORIENT-11 of “only” 8.9 months vs. a median of 23.1 months in the updated KEYNOTE-189 data.

There are plans to register the sintilimab combination therapy in China for the treatment of nonsquamous NSCLC, where it will go up against pembrolizumab as well as, potentially, tislelizumab (BeiGene).

The study was sponsored by Innovent Biologics and Eli Lilly. Dr. Zhang disclosed research grants from Eli Lilly and Pfizer. Dr. Nagasaka disclosed serving on the advisory boards of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, and EMD Serono; as a consultant for Caris Life Sciences; and receiving travel support from An Hearts Therapeutics.

This article first appeared on Medscape.com.

The investigational anti-PD-1 antibody sintilimab (Tyvyt, Innovent Biologics and Eli Lilly) has shown that it improves the efficacy of platinum-based chemotherapy in the first-line treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC) in a phase 3 trial dubbed ORIENT-11.

The study was presented at the World Congress on Lung Cancer 2020 Virtual Presidential Symposium, held virtually due to the COVID-19 pandemic, on August 8. It was also published simultaneously in the Journal of Thoracic Oncology.

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of programmed death (PD)-1 to PD-ligand 1 (PD-L1) or PD-L2 with high affinity, and has received market authorization in China for the treatment of Hodgkin lymphoma.

For ORIENT-11, almost 400 patients with advanced nonsquamous NSCLC were randomly assigned to sintilimab or placebo plus pemetrexed and platinum-based chemotherapy in a 2:1 ratio.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS [progression-free survival], compared to placebo,” reducing progression rates by 52%, noted lead investigator Li Zhang, MD, professor of medical oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Crucially, this benefit “was seen across key clinical subgroups,” he added.

He noted that the overall response rate “was also improved, with a durable response,” while the results, which are not yet mature, suggest the experimental arm was associated with an overall survival (OS) benefit.

Study discussant Misako Nagasaka, MD, a thoracic oncologist and clinical investigator at Karmanos Cancer Institute, Detroit, said that the PFS benefit seen in the study is “certainly encouraging.”

Adding a note of caution, she continued: “But we have seen studies with PFS improvement which did not translate into OS improvement.

“Longer follow-up would allow events to mature and we will ultimately see if there would be a significant OS benefit,” she said.

Dr. Nagasaka also pointed out that the greater benefit with sintilimab seen in patients with high PD-L1 begs the question as to what would be the preferred regimen in those with higher or lower expression.

And, she said, this is not just about what regimen to choose but “more importantly, why?”

“Perhaps you’d like to use something with the best response rate, perhaps you’re sticking to a single agent immunotherapy because the toxicity profile is more favorable, or perhaps you [are] convinced with a certain regimen because of the robust PFS and OS data,” she said.

“Whatever you chose, there was a reason for your choice,” she said, adding that the sintilimab combination would have to “fulfill those reasons for you to consider choosing this regimen.”

Study details

Dr. Zhang began his presentation by noting that previous phase 1b studies have shown that sintilimab plus pemetrexed and platinum-based chemotherapy has a “tolerable safety profile and promising efficacy” in previously untreated non-squamous NSCLC.

They therefore conducted ORIENT-11, a randomized, double-blind, phase 3 study involving 397 patients with untreated stage IIIB/C or IV nonsquamous NSCLC who had neither EGFR nor ALK gene alterations.

The patients were randomly assigned in a 2:1 fashion to sintilimab plus pemetrexed and platinum-based chemotherapy (n = 266) or placebo plus pemetrexed and chemo (n = 131) for four cycles, followed by sintilimab or placebo plus pemetrexed for up to 24 months.

Thirty-five patients in the placebo arm crossed over to sintilimab monotherapy, representing 31.3% of the intention-to-treat population.

At the data cutoff of Nov. 15, 2019, 198 events had occurred, at a median follow-up of 8.9 months.

The team found that median PFS was significantly higher with sintilimab than placebo combination therapy, at 8.9 months vs. 5.0 months, or a hazard ratio of 0.482 (P < .00001).

Dr. Zhang noted that the benefit with sintilimab plus pemetrexed and platinum-based chemotherapy was seen across all subgroups.

However, it was notable that the impact of adding sintilimab on PFS was greater in patients with a tumor proportion score (TPS) ≥50%.

The HR for progression vs. the placebo treatment arm was 0.310, with median PFS not reached, which decreased to 0.503 in patients with a TPS of 1%-49% and 0.664 among those with a TPS <1%.

The results also showed that there was a “nominally significant improvement” in overall survival with sintilimab versus placebo, at a HR of 0.609 (P = 0.01921).

The ORR was markedly different between the sintilimab and placebo groups, at 51.9% vs. 29.8%, with the duration of response not reached in the sintilimab arm compared with 5.5 months in the placebo arm.

The sintilimab arm included three (1.1%) complete responses, which was not observed with pemetrexed and platinum-based chemotherapy alone.

Finally, Dr. Zhang observed that the safety profiles of the sintilimab and placebo arms were similar, with comparable rates of any, grade 3-5, and serious adverse events largely driven by high rates of chemotherapy-related events.

While there were fewer adverse events that led to death with sintilimab, at 2.3% vs. 6.9% with placebo, there were, as expected, more immune-related adverse events, at 43.2% vs. 36.6%, respectively.

Comparison with pembrolizumab

In her discussion, Dr. Nagasaka said that the first question that came to mind when she saw the results was: “How does the ORIENT-11 data compare with KEYNOTE-189?”

For that study, pembrolizumab (Keytruda, Merck) was added to pemetrexed plus carboplatin chemotherapy and compared with standard of care alone in patients with untreated metastatic nonsquamous NSCLC.

As reported by Medscape Medical News, pembrolizumab was associated with a 48% reduced risk of disease progression, as well as improved overall survival.

Dr. Nagasaka said that ORIENT-11 “had patients that tended to be younger, there were more males, more with performance status 1, and those who had never smoked” than those in KEYNOTE-189.

“But most importantly, KEYNOTE-189 had a very small number of patients from East Asia, only 1% in the pembro arm and 2.9% in the placebo arm.”

In contrast, all the patients included in ORIENT-11 were from East Asia, making the study of “high importance.”

She added that, “while across-trial comparisons must be taken with caution, the medium PFS of ORIENT-11 ... appears comparable to those of KEYNOTE-189,” while the HR “appears identical.”

This is despite median follow-up time in ORIENT-11 of “only” 8.9 months vs. a median of 23.1 months in the updated KEYNOTE-189 data.

There are plans to register the sintilimab combination therapy in China for the treatment of nonsquamous NSCLC, where it will go up against pembrolizumab as well as, potentially, tislelizumab (BeiGene).

The study was sponsored by Innovent Biologics and Eli Lilly. Dr. Zhang disclosed research grants from Eli Lilly and Pfizer. Dr. Nagasaka disclosed serving on the advisory boards of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, and EMD Serono; as a consultant for Caris Life Sciences; and receiving travel support from An Hearts Therapeutics.

This article first appeared on Medscape.com.

Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.

The trial “met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis,” reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,

The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma,” he said. He suggested that it should therefore “be considered as a new standard of care.”

The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.

A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.

Bass highlighted that the performance of nivo+ipi was “almost the same” in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.

In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.

This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.

For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a “new standard of care” for nivo+ipi should be reserved for nonepithelioid disease.

In this setting, he described the overall survival improvement as “transformative,” considering the “marked chemo resistance” of nonepithelioid tumors, which is “almost certainly” associated with epithelial-to-mesenchymal transition (EMT).

In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma “could further extend the benefit for patients.”
 

Improving survival in mesothelioma

“We have been trying to improve the overall survival of patients with mesothelioma now for many decades,” Bass commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate «is still below 10%,” he noted.

Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.

However, nivolumab and ipilimumab have a “complementary mechanism of action,” and two previous reports have indicated that together, they have clinical activity in the second-line setting.

The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.

The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.

They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.

“Patients could have a subsequent therapy,” Bass noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.

Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.

The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.

Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).

The results indicated that overall survival was similar across key subgroups, which suggests that “no subgroup was harmed” by nivo+ipi, Bass said.
 

Stratification by PD-LI expression

Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was “the same” as that of chemotherapy, Bass said.

“But in cases where there is any expression of PD-L1, the experimental arm performs better,” at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.

There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.

Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.

Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.

Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
 

Choosing immunotherapy vs. chemotherapy

In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. “What’s very clear is the response rate is slightly higher,” as is the disease control rate, he said.

This, he explained, “is perhaps not surprising, given that these two previous trials were in the relapse setting.”

He pointed out, however, that the progression-free survival data from those previous trials were “not a million miles away” from results seen in CheckMate 743, “suggesting that this immunotherapy does have significant activity in the relapse setting.”

For Fennell, the “pivotal data” are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed “poorly” in this setting, whereas it performs “as expected” in epithelioid mesothelioma.

He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.

“What does this mean?” Fennell asked.

“If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.

“This does not appear, however, to impact in any way the efficacy of the immunotherapy,” he noted.

Fennell believes that, with regard to both efficacy and safety, the balance is “very much in favor” of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.

Indeed, the choice is “possible tilting slightly towards chemotherapy” in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.

The study was supported by Bristol-Myers Squibb. Bass has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

This article first appeared on Medscape.com.

Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.

The trial “met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis,” reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,

The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma,” he said. He suggested that it should therefore “be considered as a new standard of care.”

The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.

A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.

Bass highlighted that the performance of nivo+ipi was “almost the same” in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.

In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.

This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.

For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a “new standard of care” for nivo+ipi should be reserved for nonepithelioid disease.

In this setting, he described the overall survival improvement as “transformative,” considering the “marked chemo resistance” of nonepithelioid tumors, which is “almost certainly” associated with epithelial-to-mesenchymal transition (EMT).

In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma “could further extend the benefit for patients.”
 

Improving survival in mesothelioma

“We have been trying to improve the overall survival of patients with mesothelioma now for many decades,” Bass commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate «is still below 10%,” he noted.

Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.

However, nivolumab and ipilimumab have a “complementary mechanism of action,” and two previous reports have indicated that together, they have clinical activity in the second-line setting.

The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.

The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.

They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.

“Patients could have a subsequent therapy,” Bass noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.

Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.

The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.

Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).

The results indicated that overall survival was similar across key subgroups, which suggests that “no subgroup was harmed” by nivo+ipi, Bass said.
 

Stratification by PD-LI expression

Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was “the same” as that of chemotherapy, Bass said.

“But in cases where there is any expression of PD-L1, the experimental arm performs better,” at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.

There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.

Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.

Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.

Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
 

Choosing immunotherapy vs. chemotherapy

In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. “What’s very clear is the response rate is slightly higher,” as is the disease control rate, he said.

This, he explained, “is perhaps not surprising, given that these two previous trials were in the relapse setting.”

He pointed out, however, that the progression-free survival data from those previous trials were “not a million miles away” from results seen in CheckMate 743, “suggesting that this immunotherapy does have significant activity in the relapse setting.”

For Fennell, the “pivotal data” are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed “poorly” in this setting, whereas it performs “as expected” in epithelioid mesothelioma.

He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.

“What does this mean?” Fennell asked.

“If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.

“This does not appear, however, to impact in any way the efficacy of the immunotherapy,” he noted.

Fennell believes that, with regard to both efficacy and safety, the balance is “very much in favor” of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.

Indeed, the choice is “possible tilting slightly towards chemotherapy” in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.

The study was supported by Bristol-Myers Squibb. Bass has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

This article first appeared on Medscape.com.

Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.

The trial “met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis,” reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,

The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma,” he said. He suggested that it should therefore “be considered as a new standard of care.”

The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.

A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.

Bass highlighted that the performance of nivo+ipi was “almost the same” in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.

In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.

This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.

For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a “new standard of care” for nivo+ipi should be reserved for nonepithelioid disease.

In this setting, he described the overall survival improvement as “transformative,” considering the “marked chemo resistance” of nonepithelioid tumors, which is “almost certainly” associated with epithelial-to-mesenchymal transition (EMT).

In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma “could further extend the benefit for patients.”
 

Improving survival in mesothelioma

“We have been trying to improve the overall survival of patients with mesothelioma now for many decades,” Bass commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate «is still below 10%,” he noted.

Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.

However, nivolumab and ipilimumab have a “complementary mechanism of action,” and two previous reports have indicated that together, they have clinical activity in the second-line setting.

The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.

The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.

They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.

“Patients could have a subsequent therapy,” Bass noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.

Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.

The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.

Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).

The results indicated that overall survival was similar across key subgroups, which suggests that “no subgroup was harmed” by nivo+ipi, Bass said.
 

Stratification by PD-LI expression

Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was “the same” as that of chemotherapy, Bass said.

“But in cases where there is any expression of PD-L1, the experimental arm performs better,” at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.

There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.

Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.

Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.

Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
 

Choosing immunotherapy vs. chemotherapy

In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. “What’s very clear is the response rate is slightly higher,” as is the disease control rate, he said.

This, he explained, “is perhaps not surprising, given that these two previous trials were in the relapse setting.”

He pointed out, however, that the progression-free survival data from those previous trials were “not a million miles away” from results seen in CheckMate 743, “suggesting that this immunotherapy does have significant activity in the relapse setting.”

For Fennell, the “pivotal data” are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed “poorly” in this setting, whereas it performs “as expected” in epithelioid mesothelioma.

He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.

“What does this mean?” Fennell asked.

“If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.

“This does not appear, however, to impact in any way the efficacy of the immunotherapy,” he noted.

Fennell believes that, with regard to both efficacy and safety, the balance is “very much in favor” of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.

Indeed, the choice is “possible tilting slightly towards chemotherapy” in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.

The study was supported by Bristol-Myers Squibb. Bass has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

This article first appeared on Medscape.com.

Recent research has shown that social cognition training can benefit patients with schizophrenia, and a new study suggests that adding regular aerobic exercise sessions substantially increases the improvements in a dose-response manner.

kaspiic/thinkstockphotos.com

In a randomized controlled trial (RCT) in 47 patients with schizophrenia, improvement in cognition tripled after adding an aerobic exercise program to cognitive training (CT) compared with CT alone.

Investigators, led by Keith H. Nuechterlein, PhD, professor of psychology, University of California, Los Angeles, note that there is “increasing evidence” to support the use of aerobic exercise to improve cognition and functioning in schizophrenia.

However, the “extent to which these gains are dependent on the amount of aerobic exercise completed remains unclear, although variability in adherence to intended exercise regiments is evident,” they write.

They also point out that strategies to encourage regular exercise in patients with schizophrenia “are only starting to be explored.”

The findings were scheduled to be presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020, but the meeting was canceled because of the coronavirus pandemic.

Body Circuit Training

In the study, 47 patients with first-episode schizophrenia were randomly assigned to receive 6 months of CT alone or 6 months of CT plus exercise (CT+E).

All participants underwent 4 hours per week of computerized CT with BrainHQ and SocialVille programs (PositScience).

Patients in the CT+E group also took part in total body circuit training. Two aerobic exercise sessions per week were held at the clinic and two were to be completed at home. The goal was 150 minutes of exercise per week in total.

Exercise intensity was titrated to the individual, at a target of 60% to 80% of heart rate reserve.

Both the CT and CT+E groups showed cognitive gains on the MATRICS Consensus Cognitive Battery (MCCB) test, as well as work/school functioning gains on the Global Assessment Scale: Role.

However, results showed that the improvements in the CT+E group were three times greater than those shown in the CT group (P < .02 for the MCCB overall composite score).

Cognitive Gain Predictors

Because there were also substantial differences in the magnitude of cognitive improvement between the CT+E patients, the investigators sought to identify predictors of cognitive gain.

They found that patients in the CT+E group completed, on average, 85% of their in-clinic exercise sessions but only 39% of their home exercise sessions.

Those who completed a higher overall proportion of the exercise sessions had the largest cognitive gains (P = .03). This relationship was even stronger for patients who completed home exercise sessions (P = .02).

“Thus, aerobic exercise showed a dose-response relationship to cognitive improvement,” the researchers report.

To improve completion rates for home sessions, the investigators tried paying the patients $5 for each session completed, which was “helpful” but did not iron out the variability in adherence.

They also tried assigning points for completing the most exercise sessions in the desired heart rate. They awarded a monthly winner and divided the patients into two completion groups. However, there were “mixed” results.

“Development of systematic incentive strategies to encourage regular aerobic exercise will be critical to successful dissemination of exercise programs as part of the treatment of schizophrenia,” the researchers write.

They add that “pilot work with smartphone reminder systems is underway.”

Effective, but Intensity Is Key

Commenting on the study for Medscape Medical News, David Kimhy, PhD, program leader for New Interventions in Schizophrenia, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, said the results are consistent with previous research.  

Aerobic exercise is “highly effective in improving neurocognitive functioning” in patients with schizophrenia, said Kimhy, who was not involved in the research.

“Many individuals with schizophrenia tend to have a highly sedentary lifestyle resulting in poor aerobic fitness,” he said. “Thus, aerobic fitness may represent one of the few modifiable risk factors for ameliorating poor neurocognitive functioning.”

He noted that those benefits are in addition to “the many cardiovascular and health benefits aerobic exercise provide, which are nearly nonexistent for cognitive training and pharmacological interventions.”

However, even if patients do take part in exercise sessions, “an important issue is in-session fidelity with training goals, as individuals may attend scheduled sessions but exercise very lightly,” Kimhy noted.

He pointed out that the proportion of time these patients exercise at their designated target training intensity is highly correlated with neurocognitive improvement. Consequently, “exercising with a trainer may increase both attendance and in-session training fidelity.”

Overall, although the current study suggests that in-clinic exercise sessions can be advantageous, “the recent COVID-19 pandemic made such options very challenging,” Kimhy said.

“To address this issue, our research group and others are currently examining employment of aerobic exercise training at home, connected with trainers via live two-way telehealth video calls,” he added.

Plasticity-Based Training

Two recent studies also indicate that remotely administered training programs can improve social cognition.

In the first study, published online July 2 in Schizophrenia Bulletin, 147 outpatients with schizophrenia were randomly assigned to complete 40 sessions of either SocialVille plasticity-based social cognition training or computer-based games such as crossword puzzles and solitaire.

“To develop these social cognition training exercises, we analyzed a tremendous amount of prior research about how the brain processes social information,” lead author Mor Nahum, PhD, School of Occupational Therapy, Hebrew University, Jerusalem, Israel, said in a press release.

“It turns out that social cognition requires fast and accurate brain information processing, so we developed exercises that trained the brain to process social stimuli, like faces and emotions, quickly and accurately,” Nahum added.

The interventions were conducted at home, with 55 participants completing the cognitive training and 53 completing the computer game sessions. (The remaining 39 either dropped out or withdrew.)

An average of 28 hours of social cognition training over 3 months was associated with a significant improvement on social cognitive composite scores compared with computer games (P < .001), but not on the UCSD Performance-Based Skills Assessment.

Further analysis suggested that more time spent on the cognitive training was associated with greater improvements in social cognition and social functioning, as well as on a motivation subscale.

The results “provide support for the efficacy of a remote, plasticity-based social cognitive training program,” the investigators write.

Such programs “may serve as a cost-effective adjunct to existing psychosocial treatments,” they add.

Auditory vs Visual Training

In the other study, published online May 21 in Schizophrenia Research, investigators led by Rogerio Panizzutti, MD, PhD, Instituto de Ciencias Biomedicas, Federal University of Rio de Janeiro, Brazil, randomly assigned 79 patients with schizophrenia to 40 hours of auditory or visual computerized training.

The exercises were dynamically equivalent between the two types of training, and their difficulty increased as the training progressed.

Both groups showed improvements in reasoning, problem-solving, and reported symptoms. However, the group receiving visual training also had greater improvement in global cognition and attention than the group receiving auditory training. 

All studies were supported by Posit Science Corporation. The study authors and Kimhy have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Recent research has shown that social cognition training can benefit patients with schizophrenia, and a new study suggests that adding regular aerobic exercise sessions substantially increases the improvements in a dose-response manner.

kaspiic/thinkstockphotos.com

In a randomized controlled trial (RCT) in 47 patients with schizophrenia, improvement in cognition tripled after adding an aerobic exercise program to cognitive training (CT) compared with CT alone.

Investigators, led by Keith H. Nuechterlein, PhD, professor of psychology, University of California, Los Angeles, note that there is “increasing evidence” to support the use of aerobic exercise to improve cognition and functioning in schizophrenia.

However, the “extent to which these gains are dependent on the amount of aerobic exercise completed remains unclear, although variability in adherence to intended exercise regiments is evident,” they write.

They also point out that strategies to encourage regular exercise in patients with schizophrenia “are only starting to be explored.”

The findings were scheduled to be presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020, but the meeting was canceled because of the coronavirus pandemic.

Body Circuit Training

In the study, 47 patients with first-episode schizophrenia were randomly assigned to receive 6 months of CT alone or 6 months of CT plus exercise (CT+E).

All participants underwent 4 hours per week of computerized CT with BrainHQ and SocialVille programs (PositScience).

Patients in the CT+E group also took part in total body circuit training. Two aerobic exercise sessions per week were held at the clinic and two were to be completed at home. The goal was 150 minutes of exercise per week in total.

Exercise intensity was titrated to the individual, at a target of 60% to 80% of heart rate reserve.

Both the CT and CT+E groups showed cognitive gains on the MATRICS Consensus Cognitive Battery (MCCB) test, as well as work/school functioning gains on the Global Assessment Scale: Role.

However, results showed that the improvements in the CT+E group were three times greater than those shown in the CT group (P < .02 for the MCCB overall composite score).

Cognitive Gain Predictors

Because there were also substantial differences in the magnitude of cognitive improvement between the CT+E patients, the investigators sought to identify predictors of cognitive gain.

They found that patients in the CT+E group completed, on average, 85% of their in-clinic exercise sessions but only 39% of their home exercise sessions.

Those who completed a higher overall proportion of the exercise sessions had the largest cognitive gains (P = .03). This relationship was even stronger for patients who completed home exercise sessions (P = .02).

“Thus, aerobic exercise showed a dose-response relationship to cognitive improvement,” the researchers report.

To improve completion rates for home sessions, the investigators tried paying the patients $5 for each session completed, which was “helpful” but did not iron out the variability in adherence.

They also tried assigning points for completing the most exercise sessions in the desired heart rate. They awarded a monthly winner and divided the patients into two completion groups. However, there were “mixed” results.

“Development of systematic incentive strategies to encourage regular aerobic exercise will be critical to successful dissemination of exercise programs as part of the treatment of schizophrenia,” the researchers write.

They add that “pilot work with smartphone reminder systems is underway.”

Effective, but Intensity Is Key

Commenting on the study for Medscape Medical News, David Kimhy, PhD, program leader for New Interventions in Schizophrenia, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, said the results are consistent with previous research.  

Aerobic exercise is “highly effective in improving neurocognitive functioning” in patients with schizophrenia, said Kimhy, who was not involved in the research.

“Many individuals with schizophrenia tend to have a highly sedentary lifestyle resulting in poor aerobic fitness,” he said. “Thus, aerobic fitness may represent one of the few modifiable risk factors for ameliorating poor neurocognitive functioning.”

He noted that those benefits are in addition to “the many cardiovascular and health benefits aerobic exercise provide, which are nearly nonexistent for cognitive training and pharmacological interventions.”

However, even if patients do take part in exercise sessions, “an important issue is in-session fidelity with training goals, as individuals may attend scheduled sessions but exercise very lightly,” Kimhy noted.

He pointed out that the proportion of time these patients exercise at their designated target training intensity is highly correlated with neurocognitive improvement. Consequently, “exercising with a trainer may increase both attendance and in-session training fidelity.”

Overall, although the current study suggests that in-clinic exercise sessions can be advantageous, “the recent COVID-19 pandemic made such options very challenging,” Kimhy said.

“To address this issue, our research group and others are currently examining employment of aerobic exercise training at home, connected with trainers via live two-way telehealth video calls,” he added.

Plasticity-Based Training

Two recent studies also indicate that remotely administered training programs can improve social cognition.

In the first study, published online July 2 in Schizophrenia Bulletin, 147 outpatients with schizophrenia were randomly assigned to complete 40 sessions of either SocialVille plasticity-based social cognition training or computer-based games such as crossword puzzles and solitaire.

“To develop these social cognition training exercises, we analyzed a tremendous amount of prior research about how the brain processes social information,” lead author Mor Nahum, PhD, School of Occupational Therapy, Hebrew University, Jerusalem, Israel, said in a press release.

“It turns out that social cognition requires fast and accurate brain information processing, so we developed exercises that trained the brain to process social stimuli, like faces and emotions, quickly and accurately,” Nahum added.

The interventions were conducted at home, with 55 participants completing the cognitive training and 53 completing the computer game sessions. (The remaining 39 either dropped out or withdrew.)

An average of 28 hours of social cognition training over 3 months was associated with a significant improvement on social cognitive composite scores compared with computer games (P < .001), but not on the UCSD Performance-Based Skills Assessment.

Further analysis suggested that more time spent on the cognitive training was associated with greater improvements in social cognition and social functioning, as well as on a motivation subscale.

The results “provide support for the efficacy of a remote, plasticity-based social cognitive training program,” the investigators write.

Such programs “may serve as a cost-effective adjunct to existing psychosocial treatments,” they add.

Auditory vs Visual Training

In the other study, published online May 21 in Schizophrenia Research, investigators led by Rogerio Panizzutti, MD, PhD, Instituto de Ciencias Biomedicas, Federal University of Rio de Janeiro, Brazil, randomly assigned 79 patients with schizophrenia to 40 hours of auditory or visual computerized training.

The exercises were dynamically equivalent between the two types of training, and their difficulty increased as the training progressed.

Both groups showed improvements in reasoning, problem-solving, and reported symptoms. However, the group receiving visual training also had greater improvement in global cognition and attention than the group receiving auditory training. 

All studies were supported by Posit Science Corporation. The study authors and Kimhy have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Recent research has shown that social cognition training can benefit patients with schizophrenia, and a new study suggests that adding regular aerobic exercise sessions substantially increases the improvements in a dose-response manner.

kaspiic/thinkstockphotos.com

In a randomized controlled trial (RCT) in 47 patients with schizophrenia, improvement in cognition tripled after adding an aerobic exercise program to cognitive training (CT) compared with CT alone.

Investigators, led by Keith H. Nuechterlein, PhD, professor of psychology, University of California, Los Angeles, note that there is “increasing evidence” to support the use of aerobic exercise to improve cognition and functioning in schizophrenia.

However, the “extent to which these gains are dependent on the amount of aerobic exercise completed remains unclear, although variability in adherence to intended exercise regiments is evident,” they write.

They also point out that strategies to encourage regular exercise in patients with schizophrenia “are only starting to be explored.”

The findings were scheduled to be presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020, but the meeting was canceled because of the coronavirus pandemic.

Body Circuit Training

In the study, 47 patients with first-episode schizophrenia were randomly assigned to receive 6 months of CT alone or 6 months of CT plus exercise (CT+E).

All participants underwent 4 hours per week of computerized CT with BrainHQ and SocialVille programs (PositScience).

Patients in the CT+E group also took part in total body circuit training. Two aerobic exercise sessions per week were held at the clinic and two were to be completed at home. The goal was 150 minutes of exercise per week in total.

Exercise intensity was titrated to the individual, at a target of 60% to 80% of heart rate reserve.

Both the CT and CT+E groups showed cognitive gains on the MATRICS Consensus Cognitive Battery (MCCB) test, as well as work/school functioning gains on the Global Assessment Scale: Role.

However, results showed that the improvements in the CT+E group were three times greater than those shown in the CT group (P < .02 for the MCCB overall composite score).

Cognitive Gain Predictors

Because there were also substantial differences in the magnitude of cognitive improvement between the CT+E patients, the investigators sought to identify predictors of cognitive gain.

They found that patients in the CT+E group completed, on average, 85% of their in-clinic exercise sessions but only 39% of their home exercise sessions.

Those who completed a higher overall proportion of the exercise sessions had the largest cognitive gains (P = .03). This relationship was even stronger for patients who completed home exercise sessions (P = .02).

“Thus, aerobic exercise showed a dose-response relationship to cognitive improvement,” the researchers report.

To improve completion rates for home sessions, the investigators tried paying the patients $5 for each session completed, which was “helpful” but did not iron out the variability in adherence.

They also tried assigning points for completing the most exercise sessions in the desired heart rate. They awarded a monthly winner and divided the patients into two completion groups. However, there were “mixed” results.

“Development of systematic incentive strategies to encourage regular aerobic exercise will be critical to successful dissemination of exercise programs as part of the treatment of schizophrenia,” the researchers write.

They add that “pilot work with smartphone reminder systems is underway.”

Effective, but Intensity Is Key

Commenting on the study for Medscape Medical News, David Kimhy, PhD, program leader for New Interventions in Schizophrenia, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, said the results are consistent with previous research.  

Aerobic exercise is “highly effective in improving neurocognitive functioning” in patients with schizophrenia, said Kimhy, who was not involved in the research.

“Many individuals with schizophrenia tend to have a highly sedentary lifestyle resulting in poor aerobic fitness,” he said. “Thus, aerobic fitness may represent one of the few modifiable risk factors for ameliorating poor neurocognitive functioning.”

He noted that those benefits are in addition to “the many cardiovascular and health benefits aerobic exercise provide, which are nearly nonexistent for cognitive training and pharmacological interventions.”

However, even if patients do take part in exercise sessions, “an important issue is in-session fidelity with training goals, as individuals may attend scheduled sessions but exercise very lightly,” Kimhy noted.

He pointed out that the proportion of time these patients exercise at their designated target training intensity is highly correlated with neurocognitive improvement. Consequently, “exercising with a trainer may increase both attendance and in-session training fidelity.”

Overall, although the current study suggests that in-clinic exercise sessions can be advantageous, “the recent COVID-19 pandemic made such options very challenging,” Kimhy said.

“To address this issue, our research group and others are currently examining employment of aerobic exercise training at home, connected with trainers via live two-way telehealth video calls,” he added.

Plasticity-Based Training

Two recent studies also indicate that remotely administered training programs can improve social cognition.

In the first study, published online July 2 in Schizophrenia Bulletin, 147 outpatients with schizophrenia were randomly assigned to complete 40 sessions of either SocialVille plasticity-based social cognition training or computer-based games such as crossword puzzles and solitaire.

“To develop these social cognition training exercises, we analyzed a tremendous amount of prior research about how the brain processes social information,” lead author Mor Nahum, PhD, School of Occupational Therapy, Hebrew University, Jerusalem, Israel, said in a press release.

“It turns out that social cognition requires fast and accurate brain information processing, so we developed exercises that trained the brain to process social stimuli, like faces and emotions, quickly and accurately,” Nahum added.

The interventions were conducted at home, with 55 participants completing the cognitive training and 53 completing the computer game sessions. (The remaining 39 either dropped out or withdrew.)

An average of 28 hours of social cognition training over 3 months was associated with a significant improvement on social cognitive composite scores compared with computer games (P < .001), but not on the UCSD Performance-Based Skills Assessment.

Further analysis suggested that more time spent on the cognitive training was associated with greater improvements in social cognition and social functioning, as well as on a motivation subscale.

The results “provide support for the efficacy of a remote, plasticity-based social cognitive training program,” the investigators write.

Such programs “may serve as a cost-effective adjunct to existing psychosocial treatments,” they add.

Auditory vs Visual Training

In the other study, published online May 21 in Schizophrenia Research, investigators led by Rogerio Panizzutti, MD, PhD, Instituto de Ciencias Biomedicas, Federal University of Rio de Janeiro, Brazil, randomly assigned 79 patients with schizophrenia to 40 hours of auditory or visual computerized training.

The exercises were dynamically equivalent between the two types of training, and their difficulty increased as the training progressed.

Both groups showed improvements in reasoning, problem-solving, and reported symptoms. However, the group receiving visual training also had greater improvement in global cognition and attention than the group receiving auditory training. 

All studies were supported by Posit Science Corporation. The study authors and Kimhy have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.