User login
Immunotherapy-related toxicities may be more common than reported in trials
SAN DIEGO – Certain immune-related adverse events related to PD1/PD-L1 treatment of patients with non–small cell lung cancer (NSCLC) may be more common than reported in clinical trials, a recent analysis of administrative claims data suggests.
Pneumonitis was seen in 10.9% of patients up to 60 days after the last dose of immunotherapy, according to the analysis of data from a large, U.S. commercial insurance database, presented at the Palliative and Supportive Care in Oncology Symposium.
By comparison, pneumonitis was reported in just 5.8% of NSCLC patients during treatment with the PD-1 (programmed cell death-1) inhibitor pembrolizumab in KEYNOTE-024, a pivotal randomized phase 3 clinical trial, said Elizabeth Jane Cathcart-Rake, MD, senior study author and an oncology fellow at the Mayo Clinic, Rochester, Minn.
Rates of immune-related adverse events in this study were generally higher than in clinical trials, both for common side effects and more rare conditions such as hypophysitis, according to Dr. Cathcart-Rake.
These new claims-based data might be considered complementary to clinical trial data, the researcher said.
“Together, they may give us a better sense of the broader implications of these adverse events,” she said in an interview.
Joe Rotella, MD, a board member of the American Academy for Hospice and Palliative Care Medicine, said results of this insurance database study provide a perspective on the real-world incidence of adverse events associated with immune checkpoint inhibitors.
“We’ve only been using these therapies for a few years, so this new analysis gives us more information on the prevalence of these side effects in patients as the therapies gain wider use,” Dr. Rotella said in a news release.
In the study, Dr. Cathcart-Rake and coinvestigators queried the OptumLabs Data Warehouse to identify 3,164 patients with NSCLC who received PD-1 or PD-L1 (programmed death-ligand 1) inhibitors between 2015 and 2017. They looked at incidence of adverse events both at the time of the last immunotherapy dose and at 60 days after the last dose.
The incidence of pneumonitis, just 4.9% on the last date of immunotherapy, increased to 10.9% at 60 days after the last dose, Dr. Cathcart-Rake reported.
Beyond pneumonitis, the most common immunotherapy-related toxicities at 60 days were hypothyroidism in 7.0%, arrhythmia in 6.1%, and nephritis or acute kidney injury in 5.4%, according to the investigators.
Dr. Cathcart-Rake also highlighted the incidence of some less common immunotherapy-related toxicities such as hypophysitis or hypothalamic-pituitary-adrenal axis toxicity, seen in 2.8% of patients by 60 days.
“That’s a small number, but hypophysitis can be really profound, and frequently leads to hospitalization,” she said. “I think this just gives us enough of a signal that providers really need to be on top of looking for these adverse events and to counsel patients beforehand.”
These data could also be helpful for advising hospitalists, emergency room physicians, and other providers who may not be attuned to the potential risks of cancer immunotherapy as compared with traditional cytotoxic chemotherapy, Dr. Cathcart-Rake said at the meeting cosponsored by AAHPM, ASCO, ASTRO, and MASCC.
“A patient with cancer may be on immunotherapy and their risk for infection is quite low, but they may be at a huge risk for pneumonitis, which is treated completely differently,” she said. “So I think this should just raise alarms that close clinical monitoring for these conditions is really important.”
Dr. Cathcart-Rake disclosed that her institution receives research funding from Novartis. One study coinvestigator reported consulting or advisory roles with Trovagene, Genentech, Bristol-Myers Squibb, and Abbvie.
SOURCE: Cathcart-Rake EJ et al. 2018 Palliative and Supportive Care in Oncology Symposium. Abstract 184.
SAN DIEGO – Certain immune-related adverse events related to PD1/PD-L1 treatment of patients with non–small cell lung cancer (NSCLC) may be more common than reported in clinical trials, a recent analysis of administrative claims data suggests.
Pneumonitis was seen in 10.9% of patients up to 60 days after the last dose of immunotherapy, according to the analysis of data from a large, U.S. commercial insurance database, presented at the Palliative and Supportive Care in Oncology Symposium.
By comparison, pneumonitis was reported in just 5.8% of NSCLC patients during treatment with the PD-1 (programmed cell death-1) inhibitor pembrolizumab in KEYNOTE-024, a pivotal randomized phase 3 clinical trial, said Elizabeth Jane Cathcart-Rake, MD, senior study author and an oncology fellow at the Mayo Clinic, Rochester, Minn.
Rates of immune-related adverse events in this study were generally higher than in clinical trials, both for common side effects and more rare conditions such as hypophysitis, according to Dr. Cathcart-Rake.
These new claims-based data might be considered complementary to clinical trial data, the researcher said.
“Together, they may give us a better sense of the broader implications of these adverse events,” she said in an interview.
Joe Rotella, MD, a board member of the American Academy for Hospice and Palliative Care Medicine, said results of this insurance database study provide a perspective on the real-world incidence of adverse events associated with immune checkpoint inhibitors.
“We’ve only been using these therapies for a few years, so this new analysis gives us more information on the prevalence of these side effects in patients as the therapies gain wider use,” Dr. Rotella said in a news release.
In the study, Dr. Cathcart-Rake and coinvestigators queried the OptumLabs Data Warehouse to identify 3,164 patients with NSCLC who received PD-1 or PD-L1 (programmed death-ligand 1) inhibitors between 2015 and 2017. They looked at incidence of adverse events both at the time of the last immunotherapy dose and at 60 days after the last dose.
The incidence of pneumonitis, just 4.9% on the last date of immunotherapy, increased to 10.9% at 60 days after the last dose, Dr. Cathcart-Rake reported.
Beyond pneumonitis, the most common immunotherapy-related toxicities at 60 days were hypothyroidism in 7.0%, arrhythmia in 6.1%, and nephritis or acute kidney injury in 5.4%, according to the investigators.
Dr. Cathcart-Rake also highlighted the incidence of some less common immunotherapy-related toxicities such as hypophysitis or hypothalamic-pituitary-adrenal axis toxicity, seen in 2.8% of patients by 60 days.
“That’s a small number, but hypophysitis can be really profound, and frequently leads to hospitalization,” she said. “I think this just gives us enough of a signal that providers really need to be on top of looking for these adverse events and to counsel patients beforehand.”
These data could also be helpful for advising hospitalists, emergency room physicians, and other providers who may not be attuned to the potential risks of cancer immunotherapy as compared with traditional cytotoxic chemotherapy, Dr. Cathcart-Rake said at the meeting cosponsored by AAHPM, ASCO, ASTRO, and MASCC.
“A patient with cancer may be on immunotherapy and their risk for infection is quite low, but they may be at a huge risk for pneumonitis, which is treated completely differently,” she said. “So I think this should just raise alarms that close clinical monitoring for these conditions is really important.”
Dr. Cathcart-Rake disclosed that her institution receives research funding from Novartis. One study coinvestigator reported consulting or advisory roles with Trovagene, Genentech, Bristol-Myers Squibb, and Abbvie.
SOURCE: Cathcart-Rake EJ et al. 2018 Palliative and Supportive Care in Oncology Symposium. Abstract 184.
SAN DIEGO – Certain immune-related adverse events related to PD1/PD-L1 treatment of patients with non–small cell lung cancer (NSCLC) may be more common than reported in clinical trials, a recent analysis of administrative claims data suggests.
Pneumonitis was seen in 10.9% of patients up to 60 days after the last dose of immunotherapy, according to the analysis of data from a large, U.S. commercial insurance database, presented at the Palliative and Supportive Care in Oncology Symposium.
By comparison, pneumonitis was reported in just 5.8% of NSCLC patients during treatment with the PD-1 (programmed cell death-1) inhibitor pembrolizumab in KEYNOTE-024, a pivotal randomized phase 3 clinical trial, said Elizabeth Jane Cathcart-Rake, MD, senior study author and an oncology fellow at the Mayo Clinic, Rochester, Minn.
Rates of immune-related adverse events in this study were generally higher than in clinical trials, both for common side effects and more rare conditions such as hypophysitis, according to Dr. Cathcart-Rake.
These new claims-based data might be considered complementary to clinical trial data, the researcher said.
“Together, they may give us a better sense of the broader implications of these adverse events,” she said in an interview.
Joe Rotella, MD, a board member of the American Academy for Hospice and Palliative Care Medicine, said results of this insurance database study provide a perspective on the real-world incidence of adverse events associated with immune checkpoint inhibitors.
“We’ve only been using these therapies for a few years, so this new analysis gives us more information on the prevalence of these side effects in patients as the therapies gain wider use,” Dr. Rotella said in a news release.
In the study, Dr. Cathcart-Rake and coinvestigators queried the OptumLabs Data Warehouse to identify 3,164 patients with NSCLC who received PD-1 or PD-L1 (programmed death-ligand 1) inhibitors between 2015 and 2017. They looked at incidence of adverse events both at the time of the last immunotherapy dose and at 60 days after the last dose.
The incidence of pneumonitis, just 4.9% on the last date of immunotherapy, increased to 10.9% at 60 days after the last dose, Dr. Cathcart-Rake reported.
Beyond pneumonitis, the most common immunotherapy-related toxicities at 60 days were hypothyroidism in 7.0%, arrhythmia in 6.1%, and nephritis or acute kidney injury in 5.4%, according to the investigators.
Dr. Cathcart-Rake also highlighted the incidence of some less common immunotherapy-related toxicities such as hypophysitis or hypothalamic-pituitary-adrenal axis toxicity, seen in 2.8% of patients by 60 days.
“That’s a small number, but hypophysitis can be really profound, and frequently leads to hospitalization,” she said. “I think this just gives us enough of a signal that providers really need to be on top of looking for these adverse events and to counsel patients beforehand.”
These data could also be helpful for advising hospitalists, emergency room physicians, and other providers who may not be attuned to the potential risks of cancer immunotherapy as compared with traditional cytotoxic chemotherapy, Dr. Cathcart-Rake said at the meeting cosponsored by AAHPM, ASCO, ASTRO, and MASCC.
“A patient with cancer may be on immunotherapy and their risk for infection is quite low, but they may be at a huge risk for pneumonitis, which is treated completely differently,” she said. “So I think this should just raise alarms that close clinical monitoring for these conditions is really important.”
Dr. Cathcart-Rake disclosed that her institution receives research funding from Novartis. One study coinvestigator reported consulting or advisory roles with Trovagene, Genentech, Bristol-Myers Squibb, and Abbvie.
SOURCE: Cathcart-Rake EJ et al. 2018 Palliative and Supportive Care in Oncology Symposium. Abstract 184.
REPORTING FROM PALLONC 2018
Key clinical point: In non–small cell lung cancer patients treated with PD-1/PD-L1 inhibitors, immune-related adverse events may occur more frequently than has been suggested by clinical trial data.
Major finding: Pneumonitis was seen in nearly 11% of patients up to 60 days after the last immunotherapy dose, which investigators said was higher than reported in a pivotal phase 3 study.
Study details: Analysis of administrative claims data for 3,164 NSCLC patients treated between 2015 and 2017.
Disclosures: Researchers reported institutional research funding from Novartis. One researcher reported consulting or advisory roles with Trovagene, Genentech, Bristol-Myers Squibb, and Abbvie.
Source: Cathcart-Rake EJ et al. Palliative and Supportive Care in Oncology Symposium. Abstract 184.
PD-L1 correlates with worse sporadic, hereditary ccRCC outcomes
In patients with either sporadic or hereditary clear cell renal cell carcinoma, tumor expression of programmed death–ligand 1 (PD-L1) is associated with aggressive disease, investigators have found.
Analysis of tumor samples from patients with sporadic clear cell renal cell carcinoma (ccRCC) and others with Von Hippel-Lindau (VHL)–associated hereditary ccRCC showed that positive PD-L1 correlated with aggressive clinicopathologic features, reported Baoan Hong, MD, from Peking University First Hospital in Beijing, and colleagues.
“PD-L1 is a promising predictive biomarker for the utilization of PD-1/PD-L1 checkpoint inhibitors in ccRCC patients,” they wrote in Genitourinary Cancer.
The investigators conducted a retrospective analysis of PD-L1 expression and its potential correlation with disease features using samples from 129 patients with sporadic ccRCC and 26 patients with VHL disease who underwent partial or radical nephrectomy at their center from 2010 to 2017.
Sporadic ccRCC
The median age of patients with sporadic ccRCC was 61 years and the median tumor size was 4.3 cm. Of the 129 patients, 56 had pathological stage T1a at diagnosis, 44 had stage T1b, 8 had stage T2, and 21 had stage T3. In all, 25 patients had Fuhrman nuclear grade 3 tumors and 104 had grade 1 or 2 tumors. A total of 7 patients had metastases to lymph nodes, 41 had microvascular invasion, and 16 had tumor necrosis.
In all, 61 of these patients had PD-L1-positive tumors and 68 were PD-L1 negative. Positive PD-L1 was significantly associated with male gender (P = .025) and worse disease features, including higher T stage (P = .0011) and higher Fuhrman nuclear grade (P = .022).
After a median follow-up of 68 months, 9 patients in this group died and 17 others developed distant metastases or recurrent disease. Patients whose tumors were PD-L1 negative had significantly longer disease-free survival than patients with PD-L1-positive tumors, at a median 36 versus 28 months (P = .037).
VHL-associated ccRCC
Of the 26 patients with VHL-associated hereditary ccRCC (13 men and 13 women; median age, 42 years), 13 had pathological stage T1a disease, 7 had T1b, and 2 each has stage T2a, T3a, and T3b tumors. A total of 18 patients had Fuhrman nuclear grade 1 tumors and 8 had grade 2 tumors.
In this cohort, 17 patients had PD-L1-negative tumors, and 9 had PD-L1-positive tumors. PD-L1 expression was more common in patients with Fuhrman nuclear grade 2 tumors (six of eight cases). Patients with Fuhrman nuclear grade 1 tumors were more likely to be PD-L1 negative (15 of 18, P = .008). PD-L1 expression was not significantly correlated with either gender or tumor stage in this cohort.
There were no associations in this population between PD-L1 status and either age, tumor size, microvascular invasion, tumor necrosis, or lymph node metastases.
The investigators also compared the age of onset of all VHL-associated tumors in this cohort in PD-L1-positive versus PD-L1-negative patients, but found no statistically significant differences.
The authors acknowledged that the cohort sizes were small and that follow-up was relatively short, which could have a bearing on the analysis of associations between PD-L1 expression and disease features.
“Whether PD-L1 expression level in ccRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated,” they wrote.
The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.
SOURCE: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.
In patients with either sporadic or hereditary clear cell renal cell carcinoma, tumor expression of programmed death–ligand 1 (PD-L1) is associated with aggressive disease, investigators have found.
Analysis of tumor samples from patients with sporadic clear cell renal cell carcinoma (ccRCC) and others with Von Hippel-Lindau (VHL)–associated hereditary ccRCC showed that positive PD-L1 correlated with aggressive clinicopathologic features, reported Baoan Hong, MD, from Peking University First Hospital in Beijing, and colleagues.
“PD-L1 is a promising predictive biomarker for the utilization of PD-1/PD-L1 checkpoint inhibitors in ccRCC patients,” they wrote in Genitourinary Cancer.
The investigators conducted a retrospective analysis of PD-L1 expression and its potential correlation with disease features using samples from 129 patients with sporadic ccRCC and 26 patients with VHL disease who underwent partial or radical nephrectomy at their center from 2010 to 2017.
Sporadic ccRCC
The median age of patients with sporadic ccRCC was 61 years and the median tumor size was 4.3 cm. Of the 129 patients, 56 had pathological stage T1a at diagnosis, 44 had stage T1b, 8 had stage T2, and 21 had stage T3. In all, 25 patients had Fuhrman nuclear grade 3 tumors and 104 had grade 1 or 2 tumors. A total of 7 patients had metastases to lymph nodes, 41 had microvascular invasion, and 16 had tumor necrosis.
In all, 61 of these patients had PD-L1-positive tumors and 68 were PD-L1 negative. Positive PD-L1 was significantly associated with male gender (P = .025) and worse disease features, including higher T stage (P = .0011) and higher Fuhrman nuclear grade (P = .022).
After a median follow-up of 68 months, 9 patients in this group died and 17 others developed distant metastases or recurrent disease. Patients whose tumors were PD-L1 negative had significantly longer disease-free survival than patients with PD-L1-positive tumors, at a median 36 versus 28 months (P = .037).
VHL-associated ccRCC
Of the 26 patients with VHL-associated hereditary ccRCC (13 men and 13 women; median age, 42 years), 13 had pathological stage T1a disease, 7 had T1b, and 2 each has stage T2a, T3a, and T3b tumors. A total of 18 patients had Fuhrman nuclear grade 1 tumors and 8 had grade 2 tumors.
In this cohort, 17 patients had PD-L1-negative tumors, and 9 had PD-L1-positive tumors. PD-L1 expression was more common in patients with Fuhrman nuclear grade 2 tumors (six of eight cases). Patients with Fuhrman nuclear grade 1 tumors were more likely to be PD-L1 negative (15 of 18, P = .008). PD-L1 expression was not significantly correlated with either gender or tumor stage in this cohort.
There were no associations in this population between PD-L1 status and either age, tumor size, microvascular invasion, tumor necrosis, or lymph node metastases.
The investigators also compared the age of onset of all VHL-associated tumors in this cohort in PD-L1-positive versus PD-L1-negative patients, but found no statistically significant differences.
The authors acknowledged that the cohort sizes were small and that follow-up was relatively short, which could have a bearing on the analysis of associations between PD-L1 expression and disease features.
“Whether PD-L1 expression level in ccRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated,” they wrote.
The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.
SOURCE: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.
In patients with either sporadic or hereditary clear cell renal cell carcinoma, tumor expression of programmed death–ligand 1 (PD-L1) is associated with aggressive disease, investigators have found.
Analysis of tumor samples from patients with sporadic clear cell renal cell carcinoma (ccRCC) and others with Von Hippel-Lindau (VHL)–associated hereditary ccRCC showed that positive PD-L1 correlated with aggressive clinicopathologic features, reported Baoan Hong, MD, from Peking University First Hospital in Beijing, and colleagues.
“PD-L1 is a promising predictive biomarker for the utilization of PD-1/PD-L1 checkpoint inhibitors in ccRCC patients,” they wrote in Genitourinary Cancer.
The investigators conducted a retrospective analysis of PD-L1 expression and its potential correlation with disease features using samples from 129 patients with sporadic ccRCC and 26 patients with VHL disease who underwent partial or radical nephrectomy at their center from 2010 to 2017.
Sporadic ccRCC
The median age of patients with sporadic ccRCC was 61 years and the median tumor size was 4.3 cm. Of the 129 patients, 56 had pathological stage T1a at diagnosis, 44 had stage T1b, 8 had stage T2, and 21 had stage T3. In all, 25 patients had Fuhrman nuclear grade 3 tumors and 104 had grade 1 or 2 tumors. A total of 7 patients had metastases to lymph nodes, 41 had microvascular invasion, and 16 had tumor necrosis.
In all, 61 of these patients had PD-L1-positive tumors and 68 were PD-L1 negative. Positive PD-L1 was significantly associated with male gender (P = .025) and worse disease features, including higher T stage (P = .0011) and higher Fuhrman nuclear grade (P = .022).
After a median follow-up of 68 months, 9 patients in this group died and 17 others developed distant metastases or recurrent disease. Patients whose tumors were PD-L1 negative had significantly longer disease-free survival than patients with PD-L1-positive tumors, at a median 36 versus 28 months (P = .037).
VHL-associated ccRCC
Of the 26 patients with VHL-associated hereditary ccRCC (13 men and 13 women; median age, 42 years), 13 had pathological stage T1a disease, 7 had T1b, and 2 each has stage T2a, T3a, and T3b tumors. A total of 18 patients had Fuhrman nuclear grade 1 tumors and 8 had grade 2 tumors.
In this cohort, 17 patients had PD-L1-negative tumors, and 9 had PD-L1-positive tumors. PD-L1 expression was more common in patients with Fuhrman nuclear grade 2 tumors (six of eight cases). Patients with Fuhrman nuclear grade 1 tumors were more likely to be PD-L1 negative (15 of 18, P = .008). PD-L1 expression was not significantly correlated with either gender or tumor stage in this cohort.
There were no associations in this population between PD-L1 status and either age, tumor size, microvascular invasion, tumor necrosis, or lymph node metastases.
The investigators also compared the age of onset of all VHL-associated tumors in this cohort in PD-L1-positive versus PD-L1-negative patients, but found no statistically significant differences.
The authors acknowledged that the cohort sizes were small and that follow-up was relatively short, which could have a bearing on the analysis of associations between PD-L1 expression and disease features.
“Whether PD-L1 expression level in ccRCC is related to the effectiveness of PD-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated,” they wrote.
The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.
SOURCE: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.
FROM CLINICAL GENITOURINARY CANCER
Key clinical point: Expression of programmed death–ligand 1 (PD-L1) in both sporadic and hereditary clear cell renal cell carcinoma (ccRCC) was associated with worse prognosis.
Major finding: Median disease-free survival of patients with sporadic ccRCC tumors negative for PD-L1 was 36 months, compared with 28 months for patients with PD-L1-positive tumors.
Study details: A retrospective analysis of tissues from 129 patients with sporadic ccRCC and 26 with Von Hippel-Lindau–associated hereditary ccRCC.
Disclosures: The study was supported by the National Natural Science Foundation of China and Special Health Development Research Project of Capital. The authors reported having no relevant disclosures.
Source: Hong B et al. Clin Genitourin Cancer. 2018 Nov 13. doi: 10.1016/j.clgc.2018.11.001.
Adjunctive Promacta approved for first-line SAA
The Food and Drug Administration has approved use of eltrombopag (Promacta) for patients severe aplastic anemia (SAA), Novartis announced Nov. 16.
The agency’s move means that eltrombopag, a synthetic thrombopoietin-receptor agonist, is now approved for use in combination with standard immunosuppressive therapy as first-line treatment for adults, and pediatric patients aged 2 and older with SAA. The drug received breakthrough therapy designation and priority review for this indication, the company said in a press release.
In addition, eltrombopag is FDA-approved for SAA patients who have had an insufficient response to immunosuppressive therapy, those with chronic immune thrombocytopenia who have had an insufficient response to other treatments, and those with thrombocytopenia and with chronic hepatitis C infection.
. The trial included 153 previously untreated SAA patients aged 2 and older. The patients received eltrombopag in combination with horse antithymocyte globulin and cyclosporine.
The starting dose of eltrombopag in the trial was 150 mg once daily for patients aged 12 and older (75 mg for East and Southeast Asians), 75 mg once daily for patients aged 6 to 11 (37.5 mg for East and Southeast Asians), and 2.5 mg/kg once daily for patients aged 2 to 5 (1.25 mg/kg for East and Southeast Asians).
Patients were divided into three cohorts with different dosing schedules. The recommended schedule from the third cohort (n = 92) was eltrombopag from day 1 to month 6, plus horse antithymocyte globulin and cyclosporine. All patients in this cohort were eligible to receive a low dose of cyclosporine for an additional 18 months if they achieved a hematologic response at 6 months.
Among the patients treated at the recommended dosing schedule, the 6-month overall response rate was 79%, and the complete response rate was 44%. The median duration of both overall and complete response was 24.3 months.
The most common adverse events in these patients were increases in ALT (29%), AST (17%), and blood bilirubin (17%). Also, rash (8%), and skin discoloration, including hyperpigmentation (5%), were cited as adverse events.
Updated results from the trial are available in the prescribing information for eltrombopag. In most countries outside of the United States, the drug is marketed as Revolade.
The Food and Drug Administration has approved use of eltrombopag (Promacta) for patients severe aplastic anemia (SAA), Novartis announced Nov. 16.
The agency’s move means that eltrombopag, a synthetic thrombopoietin-receptor agonist, is now approved for use in combination with standard immunosuppressive therapy as first-line treatment for adults, and pediatric patients aged 2 and older with SAA. The drug received breakthrough therapy designation and priority review for this indication, the company said in a press release.
In addition, eltrombopag is FDA-approved for SAA patients who have had an insufficient response to immunosuppressive therapy, those with chronic immune thrombocytopenia who have had an insufficient response to other treatments, and those with thrombocytopenia and with chronic hepatitis C infection.
. The trial included 153 previously untreated SAA patients aged 2 and older. The patients received eltrombopag in combination with horse antithymocyte globulin and cyclosporine.
The starting dose of eltrombopag in the trial was 150 mg once daily for patients aged 12 and older (75 mg for East and Southeast Asians), 75 mg once daily for patients aged 6 to 11 (37.5 mg for East and Southeast Asians), and 2.5 mg/kg once daily for patients aged 2 to 5 (1.25 mg/kg for East and Southeast Asians).
Patients were divided into three cohorts with different dosing schedules. The recommended schedule from the third cohort (n = 92) was eltrombopag from day 1 to month 6, plus horse antithymocyte globulin and cyclosporine. All patients in this cohort were eligible to receive a low dose of cyclosporine for an additional 18 months if they achieved a hematologic response at 6 months.
Among the patients treated at the recommended dosing schedule, the 6-month overall response rate was 79%, and the complete response rate was 44%. The median duration of both overall and complete response was 24.3 months.
The most common adverse events in these patients were increases in ALT (29%), AST (17%), and blood bilirubin (17%). Also, rash (8%), and skin discoloration, including hyperpigmentation (5%), were cited as adverse events.
Updated results from the trial are available in the prescribing information for eltrombopag. In most countries outside of the United States, the drug is marketed as Revolade.
The Food and Drug Administration has approved use of eltrombopag (Promacta) for patients severe aplastic anemia (SAA), Novartis announced Nov. 16.
The agency’s move means that eltrombopag, a synthetic thrombopoietin-receptor agonist, is now approved for use in combination with standard immunosuppressive therapy as first-line treatment for adults, and pediatric patients aged 2 and older with SAA. The drug received breakthrough therapy designation and priority review for this indication, the company said in a press release.
In addition, eltrombopag is FDA-approved for SAA patients who have had an insufficient response to immunosuppressive therapy, those with chronic immune thrombocytopenia who have had an insufficient response to other treatments, and those with thrombocytopenia and with chronic hepatitis C infection.
. The trial included 153 previously untreated SAA patients aged 2 and older. The patients received eltrombopag in combination with horse antithymocyte globulin and cyclosporine.
The starting dose of eltrombopag in the trial was 150 mg once daily for patients aged 12 and older (75 mg for East and Southeast Asians), 75 mg once daily for patients aged 6 to 11 (37.5 mg for East and Southeast Asians), and 2.5 mg/kg once daily for patients aged 2 to 5 (1.25 mg/kg for East and Southeast Asians).
Patients were divided into three cohorts with different dosing schedules. The recommended schedule from the third cohort (n = 92) was eltrombopag from day 1 to month 6, plus horse antithymocyte globulin and cyclosporine. All patients in this cohort were eligible to receive a low dose of cyclosporine for an additional 18 months if they achieved a hematologic response at 6 months.
Among the patients treated at the recommended dosing schedule, the 6-month overall response rate was 79%, and the complete response rate was 44%. The median duration of both overall and complete response was 24.3 months.
The most common adverse events in these patients were increases in ALT (29%), AST (17%), and blood bilirubin (17%). Also, rash (8%), and skin discoloration, including hyperpigmentation (5%), were cited as adverse events.
Updated results from the trial are available in the prescribing information for eltrombopag. In most countries outside of the United States, the drug is marketed as Revolade.
Early phase 2 data: Mocetinostat/durvalumab combo shows promise in mNSCLC
WASHINGTON, D.C. – (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.
Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.
Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.
Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.
Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.
“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.
Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.
“So I think this is likely to be related to mocetinostat,” Dr. Patel said.
Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.
For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.
“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.
In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.
Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.
The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.
Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
SOURCE: Patel M et al. SITC 2018, Abstract 027.
WASHINGTON, D.C. – (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.
Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.
Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.
Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.
Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.
“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.
Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.
“So I think this is likely to be related to mocetinostat,” Dr. Patel said.
Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.
For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.
“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.
In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.
Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.
The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.
Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
SOURCE: Patel M et al. SITC 2018, Abstract 027.
WASHINGTON, D.C. – (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.
Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.
Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.
Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.
Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.
“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.
Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.
“So I think this is likely to be related to mocetinostat,” Dr. Patel said.
Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.
For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.
“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.
In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.
Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.
The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.
Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
SOURCE: Patel M et al. SITC 2018, Abstract 027.
REPORTING FROM SITC 2018
Key clinical point: Mocetinostat/durvalumab shows clinical activity and manageable side effects in metastatic NSCLC.
Major finding: Five patients achieved a confirmed partial response.
Study details: A phase 2 study including 29 NSCLC patients.
Disclosures: Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
Source: Patel M et al. SITC 2018, Abstract 027.
Azacitidine-nivolumab combo 'encouraging' in AML
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
FROM CANCER DISCOVERY
Key clinical point:
Major finding: The overall response rate was 33%.
Study details: This phase 2 trial included 70 patients with relapsed/refractory acute myeloid leukemia.
Disclosures: The research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Researchers reported financial relationships with Bristol-Myers Squibb.
Source: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
FDA approves pembrolizumab for sorafenib-intolerant HCC patients
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.
Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.
The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.
Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.
Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.
The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.
Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.
Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.
The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.
Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.
Adding pembrolizumab to cisplatin-based CRT shows promise in HPV+ head and neck cancers
WASHINGTON – according to Steven F. Powell, MD.
Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.
About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.
“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.
Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.
Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.
Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.
It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.
“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.
As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”
The patient who progressed developed distant metastases and died from their disease, he said.
Treatment in this study included 40 mg/m2 of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).
“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.
Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.
“So adding CRT did not impact the safety of giving standard therapy,” he said.
Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.
The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.
“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.
“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.
The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
WASHINGTON – according to Steven F. Powell, MD.
Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.
About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.
“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.
Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.
Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.
Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.
It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.
“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.
As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”
The patient who progressed developed distant metastases and died from their disease, he said.
Treatment in this study included 40 mg/m2 of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).
“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.
Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.
“So adding CRT did not impact the safety of giving standard therapy,” he said.
Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.
The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.
“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.
“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.
The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
WASHINGTON – according to Steven F. Powell, MD.
Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.
About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.
“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.
Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.
Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.
Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.
It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.
“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.
As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”
The patient who progressed developed distant metastases and died from their disease, he said.
Treatment in this study included 40 mg/m2 of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).
“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.
Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.
“So adding CRT did not impact the safety of giving standard therapy,” he said.
Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.
The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.
“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.
“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.
The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
REPORTING FROM SITC 2018
Key clinical point: Adding pembrolizumab to weekly low-dose cisplatin-based chemoradiotherapy shows promise in human papillomavirus–associated head and neck squamous cell carcinoma.
Major finding: A total of 85% of patients had a complete response at the 21-month follow-up; progression-free survival was 97.1%.
Study details: An expansion cohort of 34 patients.
Disclosures: The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
Refractory immune-mediated colitis: Fecal transplant may be the answer
WASHINGTON – , according to Yinghong Wang, MD.
In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.
Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.
A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.
Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.
“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.
Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.
However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.
“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.
Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.
“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”
Dr. Wang reported having no disclosures.
SOURCE: Wang Y et al. SITC 2018, Abstract P194.
WASHINGTON – , according to Yinghong Wang, MD.
In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.
Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.
A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.
Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.
“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.
Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.
However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.
“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.
Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.
“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”
Dr. Wang reported having no disclosures.
SOURCE: Wang Y et al. SITC 2018, Abstract P194.
WASHINGTON – , according to Yinghong Wang, MD.
In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.
Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.
A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.
Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.
“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.
Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.
However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.
“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.
Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.
“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”
Dr. Wang reported having no disclosures.
SOURCE: Wang Y et al. SITC 2018, Abstract P194.
REPORTING FROM SITC 2018
Key clinical point: FMT lead to recovery in two patients with refractory IMC.
Major finding: FMT was effective for the treatment of IMC in two patients.
Study details: Two case reports.
Disclosures: Dr. Wang reported having no disclosures.
Source: Wang Y et al. SITC 2018, Abstract P194.
Pembrolizumab extends survival of head and neck cancer
MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial. 
Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.
A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.
There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.
“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.
The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.
A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m2 plus 5-FU 1000 mg/m2 per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
Pembrolizumab monotherapy vs. EXTREME
For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).
The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).
There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.
Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.
Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
Pembrolizumab plus chemo vs. EXTREME
The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.
In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.
There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.
“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.
“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.
He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”
The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.
Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.
A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.
There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.
“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.
The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.
A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m2 plus 5-FU 1000 mg/m2 per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
Pembrolizumab monotherapy vs. EXTREME
For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).
The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).
There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.
Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.
Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
Pembrolizumab plus chemo vs. EXTREME
The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.
In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.
There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.
“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.
“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.
He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”
The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.
Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.
A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.
There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.
“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.
The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.
A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m2 plus 5-FU 1000 mg/m2 per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
Pembrolizumab monotherapy vs. EXTREME
For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).
The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).
There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.
Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.
Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
Pembrolizumab plus chemo vs. EXTREME
The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.
In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.
There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.
“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.
“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.
He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”
The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
REPORTING FROM ESMO 2018
Key clinical point: Pembrolizumab alone or in combination with chemotherapy was associated with better overall survival of squamous cell head and neck cancer, compared with the EXTREME chemotherapy regimen.
Major finding: Overall survival among patients with a PD-L1 combined positive score of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 compared with 10.7 months for patients treated with the EXTREME regimen.
Study details: Randomized phase 3 trial of 882 patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Disclosures: The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
Source: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
Nivo + ipi shows durable activity against metastatic melanoma
MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.
Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.
“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.
The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.
As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.
Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).
At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.
Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.
Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).
The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.
Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.
The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).
The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.
The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.
Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.
The investigators did not report on serious adverse events in the current analysis.
Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.
“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.
He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.
Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.
SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.
MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.
Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.
“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.
The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.
As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.
Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).
At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.
Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.
Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).
The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.
Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.
The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).
The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.
The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.
Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.
The investigators did not report on serious adverse events in the current analysis.
Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.
“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.
He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.
Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.
SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.
MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.
Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.
“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.
The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.
As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.
Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).
At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.
Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.
Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).
The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.
Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.
The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).
The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.
The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.
Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.
The investigators did not report on serious adverse events in the current analysis.
Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.
“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.
He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.
Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.
SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.
REPORTING FROM ESMO 2018
Key clinical point: Nivolumab and ipilimumab combined provide superior progression-free and overall survival compared with nivolumab or ipilimumab alone.
Major finding: At 4-year minimum follow-up the median overall survival with the combination had not be reached, vs. 36.9 months for nivolumab and 19.9 months for ipilimumab.
Study details: Randomized phase 3 trial of 945 patients with previously untreated stage III or IV malignant melanoma.
Disclosures: Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.
Source: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.