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The personal cancer vaccine NEO-PV-01 shows promise in metastatic cancers
WASHINGTON – according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.
No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.
Most adverse events that occurred were mild and related to the local injection, she noted.
Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.
All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.
“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.
The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.
As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.
“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.
Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.
An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.
The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.
“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.
Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
WASHINGTON – according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.
No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.
Most adverse events that occurred were mild and related to the local injection, she noted.
Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.
All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.
“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.
The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.
As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.
“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.
Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.
An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.
The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.
“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.
Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
WASHINGTON – according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.
No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.
Most adverse events that occurred were mild and related to the local injection, she noted.
Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.
All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.
“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.
The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.
As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.
“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.
Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.
An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.
The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.
“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.
Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
REPORTING FROM SITC 2018
Key clinical point: The NEO-PV-01 personalized cancer vaccine shows good tolerability and safety and appears to have clinical efficacy.
Major finding: There were no vaccine-related serious adverse events, and all patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T-cell responses.
Study details: A study of the NEO-PV-01 personalized cancer vaccine in 34 patients.
Disclosures: Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
Source: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
Cancer vaccine fails in CRC but trial yields lessons
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Tecemotide did not improve outcomes among patients with resected liver-only metastases of CRC.
Major finding: Tecemotide was not superior to placebo with respect to median recurrence-free survival (6.1 vs. 11.4 months; P = .1754) or overall survival (62.8 months vs. not reached; P = .2141).
Study details: A phase 2 randomized controlled trial among 121 patients having had R0/R1 resection of isolated liver CRC metastases (LICC trial).
Disclosures: Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
Source: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
Novel bispecific CAR shows promise in B-cell malignancies
SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.
Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.
Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.
“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.
“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.
“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.
The dose assessed in the current analysis was 1 x 106 CAR T cells/kg; other planned doses include 3 x 106 CAR T cells/kg and 1 x 107 CAR T cells/kg, he said.
All patients underwent lymphodepletion with cyclophosphamide (500 mg/m2 daily x 3 doses) and fludarabine (30 mg/m2 daily x 3 doses) followed by CAR T-cell infusion 2 days later.
The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.
Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.
“But questions remain about determining the durability of response and the causes of therapy failure,” he said.
One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.
“We have now escalated the dose to 3 x 106 CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.
A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.
Dr. Hossain reported having no financial disclosures.
SOURCE: Hossain N et al. ASH 2018, Abstract 490.
SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.
Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.
Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.
“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.
“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.
“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.
The dose assessed in the current analysis was 1 x 106 CAR T cells/kg; other planned doses include 3 x 106 CAR T cells/kg and 1 x 107 CAR T cells/kg, he said.
All patients underwent lymphodepletion with cyclophosphamide (500 mg/m2 daily x 3 doses) and fludarabine (30 mg/m2 daily x 3 doses) followed by CAR T-cell infusion 2 days later.
The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.
Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.
“But questions remain about determining the durability of response and the causes of therapy failure,” he said.
One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.
“We have now escalated the dose to 3 x 106 CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.
A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.
Dr. Hossain reported having no financial disclosures.
SOURCE: Hossain N et al. ASH 2018, Abstract 490.
SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.
Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.
Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.
“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.
“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.
“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.
The dose assessed in the current analysis was 1 x 106 CAR T cells/kg; other planned doses include 3 x 106 CAR T cells/kg and 1 x 107 CAR T cells/kg, he said.
All patients underwent lymphodepletion with cyclophosphamide (500 mg/m2 daily x 3 doses) and fludarabine (30 mg/m2 daily x 3 doses) followed by CAR T-cell infusion 2 days later.
The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.
Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.
“But questions remain about determining the durability of response and the causes of therapy failure,” he said.
One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.
“We have now escalated the dose to 3 x 106 CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.
A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.
Dr. Hossain reported having no financial disclosures.
SOURCE: Hossain N et al. ASH 2018, Abstract 490.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Grade 1 cytokine release syndrome occurred in five patients, and grade 2 CRS occurred in one patient; there were no dose-limiting toxicities.
Study details: A phase 1 dose escalation study of nine patients.
Disclosures: Dr. Hossain reported having no financial disclosures.
Source: Hossain N et al. ASH 2018, Abstract 490.
Uninterrupted ibrutinib with CAR T could improve CLL outcomes
SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.
The findings come from a comparison of sequential cohorts from a phase 1/2 study.
At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.
Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.
Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.
In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.
Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.
The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 106 CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.
The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 106 CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.
The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.
The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”
Dr. Gauthier reported having no financial disclosures.
SOURCE: Gauthier J et al. ASH 18, Abstract 299.
SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.
The findings come from a comparison of sequential cohorts from a phase 1/2 study.
At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.
Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.
Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.
In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.
Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.
The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 106 CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.
The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 106 CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.
The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.
The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”
Dr. Gauthier reported having no financial disclosures.
SOURCE: Gauthier J et al. ASH 18, Abstract 299.
SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.
The findings come from a comparison of sequential cohorts from a phase 1/2 study.
At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.
Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.
Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.
In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.
Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.
The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 106 CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.
The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 106 CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.
The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.
The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”
Dr. Gauthier reported having no financial disclosures.
SOURCE: Gauthier J et al. ASH 18, Abstract 299.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Severe cytokine release syndrome occurred in 0% versus 25% of patients in the ibrutinib and no-ibrutinib cohorts, respectively.
Study details: A retrospective comparison of 43 patients in two cohorts from a phase 1/2 study.
Disclosures: Dr. Gauthier reported having no financial disclosures.
Source: Gauthier J et al. ASH 2018, Abstract 299.
Avelumab active in recurrent or refractory ovarian cancer
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
FROM JAMA ONCOLOGY
Key clinical point: Single-agent treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients.
Major finding: Treatment yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months.
Study details: Phase 1b results from the JAVELIN solid tumor trial, which included 125 women with recurrent or refractory ovarian cancer.
Disclosures: The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Study authors reported disclosures related to Pfizer, Merck, Celgene, EMD Serono, Epithany, Janssen, and Seattle Genetics, among others.
Source: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Pembrolizumab bests chemo in PD-L1-positive esophageal cancer
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: .
Major finding: Among patients with a PD-L1 combined positive score of 10 or higher, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy (hazard ratio, 0.69; P = .0074).
Study details: A phase 3 randomized controlled trial among 628 patients having progression after first-line therapy for advanced cancer of the esophagus or GEJ (KEYNOTE-181).
Disclosures: Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
Source: Kojima T et al. GI Cancers Symposium, Abstract 2.
Checkpoint inhibitors linked to rare, but serious immune-related side effects
Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.
“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”
Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.
The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.
Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.
The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).
Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.
These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.
In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.
“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.
This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.
“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”
Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.
The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.
Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.
The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).
Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.
These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.
In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.
“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.
This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.
“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”
Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.
The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.
Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.
The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).
Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.
These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.
In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.
“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.
This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
FROM THE LANCET HAEMATOLOGY
Key clinical point:
Major finding: Checkpoint inhibitor therapy led to hematological toxicity in 0.5% of patients.
Study details: A study of 948 patients in French registries who were observed prospectively or retrospectively, including a case series of 35 patients treated with checkpoint inhibitor therapy who developed hematologic, immune-related adverse events.
Disclosures: This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
Source: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
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Stories include: uUing low-dose tamoxifen, the latest findings from the KATHERINE trial, results of a meta-analysis of neoadjuvant chemotherapy, and capecitabine in early stage triple negative breast cancer.
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Stories include: uUing low-dose tamoxifen, the latest findings from the KATHERINE trial, results of a meta-analysis of neoadjuvant chemotherapy, and capecitabine in early stage triple negative breast cancer.
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Stories include: uUing low-dose tamoxifen, the latest findings from the KATHERINE trial, results of a meta-analysis of neoadjuvant chemotherapy, and capecitabine in early stage triple negative breast cancer.
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Adverse events a potential concern for chemotherapy-nivolumab in advanced gastric cancer
Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.
Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.
Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m2 orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m2 orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m2 intravenously on day 1 every 3 weeks).
For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.
Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.
Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.
Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.
SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.
Although ATTRACTION-4 investigators called the safety profile of nivolumab plus chemotherapy in gastric cancer “manageable,” 95% of patients required chemotherapy dose delays or reductions because of treatment-emergent adverse events, noted Elizabeth Cartwright, MBBS, and Ian Chau, MD, in an editorial accompanying the study.
“Given the small safety population in the study, comparisons between arms cannot be made; nonetheless, the overall high rate of treatment-related adverse events across arms could impact patient care and standard chemotherapy dose intensity,” they wrote.
The small cohort sizes also limit conclusions regarding efficacy, they added. Although the data seem encouraging, the efficacy population of 38 patients “is more reflective of a safety run-in rather than a true randomized, phase 2 design, and the results are too preliminary to draw comparisons or conclusions against first-line standard-of-care chemotherapy.”
Finally, the study lacked quality-of-life data and was conducted exclusively in Japan and Korea. Gastric cancers from Asian and non-Asian patients show differences in the expression of genes related to immune function, which could affect treatment response, the experts wrote. Hence, they await results not only from the larger second part of ATTRACTION-4, but also from CheckMate 649, which “will provide a large, randomized, global parallel.”
Both editorialists are with Royal Marsden Hospital in London. Dr. Cartwright reported having no conflicts of interest. Dr. Chau reported ties to Bristol-Myers Squibb, which markets nivolumab in the United States, and to several other pharmaceutical companies. These comments are from their editorial (Ann Oncol. 2018 Dec 28. doi: 10.1093/annonc/mdy555).
Although ATTRACTION-4 investigators called the safety profile of nivolumab plus chemotherapy in gastric cancer “manageable,” 95% of patients required chemotherapy dose delays or reductions because of treatment-emergent adverse events, noted Elizabeth Cartwright, MBBS, and Ian Chau, MD, in an editorial accompanying the study.
“Given the small safety population in the study, comparisons between arms cannot be made; nonetheless, the overall high rate of treatment-related adverse events across arms could impact patient care and standard chemotherapy dose intensity,” they wrote.
The small cohort sizes also limit conclusions regarding efficacy, they added. Although the data seem encouraging, the efficacy population of 38 patients “is more reflective of a safety run-in rather than a true randomized, phase 2 design, and the results are too preliminary to draw comparisons or conclusions against first-line standard-of-care chemotherapy.”
Finally, the study lacked quality-of-life data and was conducted exclusively in Japan and Korea. Gastric cancers from Asian and non-Asian patients show differences in the expression of genes related to immune function, which could affect treatment response, the experts wrote. Hence, they await results not only from the larger second part of ATTRACTION-4, but also from CheckMate 649, which “will provide a large, randomized, global parallel.”
Both editorialists are with Royal Marsden Hospital in London. Dr. Cartwright reported having no conflicts of interest. Dr. Chau reported ties to Bristol-Myers Squibb, which markets nivolumab in the United States, and to several other pharmaceutical companies. These comments are from their editorial (Ann Oncol. 2018 Dec 28. doi: 10.1093/annonc/mdy555).
Although ATTRACTION-4 investigators called the safety profile of nivolumab plus chemotherapy in gastric cancer “manageable,” 95% of patients required chemotherapy dose delays or reductions because of treatment-emergent adverse events, noted Elizabeth Cartwright, MBBS, and Ian Chau, MD, in an editorial accompanying the study.
“Given the small safety population in the study, comparisons between arms cannot be made; nonetheless, the overall high rate of treatment-related adverse events across arms could impact patient care and standard chemotherapy dose intensity,” they wrote.
The small cohort sizes also limit conclusions regarding efficacy, they added. Although the data seem encouraging, the efficacy population of 38 patients “is more reflective of a safety run-in rather than a true randomized, phase 2 design, and the results are too preliminary to draw comparisons or conclusions against first-line standard-of-care chemotherapy.”
Finally, the study lacked quality-of-life data and was conducted exclusively in Japan and Korea. Gastric cancers from Asian and non-Asian patients show differences in the expression of genes related to immune function, which could affect treatment response, the experts wrote. Hence, they await results not only from the larger second part of ATTRACTION-4, but also from CheckMate 649, which “will provide a large, randomized, global parallel.”
Both editorialists are with Royal Marsden Hospital in London. Dr. Cartwright reported having no conflicts of interest. Dr. Chau reported ties to Bristol-Myers Squibb, which markets nivolumab in the United States, and to several other pharmaceutical companies. These comments are from their editorial (Ann Oncol. 2018 Dec 28. doi: 10.1093/annonc/mdy555).
Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.
Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.
Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m2 orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m2 orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m2 intravenously on day 1 every 3 weeks).
For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.
Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.
Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.
Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.
SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.
Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.
Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.
Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m2 orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m2 orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m2 intravenously on day 1 every 3 weeks).
For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.
Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.
Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.
Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.
SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.
FROM ANNALS OF ONCOLOGY
Key clinical point: Adverse events limited the dose intensity of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer.
Major finding: Almost all (95%) patients required dose delays or reductions because of adverse events. Serious adverse events affected 15% of patients and in most cases led to treatment discontinuation.
Study details: A phase 2 trial of nivolumab, plus either S-1 or capecitabine, plus oxaliplatin in 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer.
Disclosures: Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.
Source: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.
No link between sex and survival on checkpoint inhibitors in latest meta-analysis
Men and women with cancer may derive a similar survival benefit from immune checkpoint inhibitor therapy, results of a recent meta-analysis suggest.
Both men and women had an overall survival benefit from immunotherapy versus standard of care therapy, with no significant difference between the sexes, according to authors of this meta-analysis, which included 23 randomized clinical trials comprising nearly 14,000 patients.
The findings, reported in JAMA Oncology, contrast with those of another recent analysis, which suggested that men had a greater advantage of receiving immunotherapy versus standard of care than women did.
“We found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” said Christopher J.D. Wallis, MD, PhD, of the University of Toronto, and his coauthors said in their report.
The present meta-analysis was based on a “more contemporary and comprehensive” literature search strategy than the earlier one, according to Dr. Wallis and his coinvestigators.
Specifically, they considered immunotherapy agents not included in the previous analysis, added seven new studies published since the previous analysis, and excluded three trials that compared immunotherapy agents, rather than comparing immunotherapy with standard of care, they explained in their report.
Their resulting meta-analysis included a total of 9,322 men and 4,399 women, most of whom were in their 70s. Overall, they found that immune checkpoint inhibitor therapy offered a statistically significant overall survival advantage versus standard systemic therapy, with a hazard ratio of 0.75 (95% confidence interval, 0.70-0.81; P less than .001).
That overall survival advantage was found for both men, with a hazard ratio of 0.75 (95% CI, 0.69-0.81; P less than .001) and women, at 0.77 (95% CI, 0.67-0.88; P = .002), investigators further reported. There was no statistically significant difference in overall survival advantage between men and women, both overall (P = 0.60) and in subgroup analyses that accounted for tumor type, line of treatment, and prevalence of women in the study.
The previous meta-analysis, published in the Lancet, found an overall survival hazard ratio of 0.72 for men receiving checkpoint inhibitors and 0.86 for women receiving checkpoint inhibitors (P = .0019), prompting those investigators to conclude that the magnitude of benefit was sex-dependent and that different immunotherapeutic approaches may be needed for men versus women.
“The present meta-analysis provides a more specific assessment of the research question while including a greater number of immunotherapy agents and an updated search,” Dr. Wallis and his coauthors said in a discussion of their more recent findings.
Dr. Wallis reported no disclosures related to the study. Study coauthors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
SOURCE: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.
Men and women with cancer may derive a similar survival benefit from immune checkpoint inhibitor therapy, results of a recent meta-analysis suggest.
Both men and women had an overall survival benefit from immunotherapy versus standard of care therapy, with no significant difference between the sexes, according to authors of this meta-analysis, which included 23 randomized clinical trials comprising nearly 14,000 patients.
The findings, reported in JAMA Oncology, contrast with those of another recent analysis, which suggested that men had a greater advantage of receiving immunotherapy versus standard of care than women did.
“We found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” said Christopher J.D. Wallis, MD, PhD, of the University of Toronto, and his coauthors said in their report.
The present meta-analysis was based on a “more contemporary and comprehensive” literature search strategy than the earlier one, according to Dr. Wallis and his coinvestigators.
Specifically, they considered immunotherapy agents not included in the previous analysis, added seven new studies published since the previous analysis, and excluded three trials that compared immunotherapy agents, rather than comparing immunotherapy with standard of care, they explained in their report.
Their resulting meta-analysis included a total of 9,322 men and 4,399 women, most of whom were in their 70s. Overall, they found that immune checkpoint inhibitor therapy offered a statistically significant overall survival advantage versus standard systemic therapy, with a hazard ratio of 0.75 (95% confidence interval, 0.70-0.81; P less than .001).
That overall survival advantage was found for both men, with a hazard ratio of 0.75 (95% CI, 0.69-0.81; P less than .001) and women, at 0.77 (95% CI, 0.67-0.88; P = .002), investigators further reported. There was no statistically significant difference in overall survival advantage between men and women, both overall (P = 0.60) and in subgroup analyses that accounted for tumor type, line of treatment, and prevalence of women in the study.
The previous meta-analysis, published in the Lancet, found an overall survival hazard ratio of 0.72 for men receiving checkpoint inhibitors and 0.86 for women receiving checkpoint inhibitors (P = .0019), prompting those investigators to conclude that the magnitude of benefit was sex-dependent and that different immunotherapeutic approaches may be needed for men versus women.
“The present meta-analysis provides a more specific assessment of the research question while including a greater number of immunotherapy agents and an updated search,” Dr. Wallis and his coauthors said in a discussion of their more recent findings.
Dr. Wallis reported no disclosures related to the study. Study coauthors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
SOURCE: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.
Men and women with cancer may derive a similar survival benefit from immune checkpoint inhibitor therapy, results of a recent meta-analysis suggest.
Both men and women had an overall survival benefit from immunotherapy versus standard of care therapy, with no significant difference between the sexes, according to authors of this meta-analysis, which included 23 randomized clinical trials comprising nearly 14,000 patients.
The findings, reported in JAMA Oncology, contrast with those of another recent analysis, which suggested that men had a greater advantage of receiving immunotherapy versus standard of care than women did.
“We found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” said Christopher J.D. Wallis, MD, PhD, of the University of Toronto, and his coauthors said in their report.
The present meta-analysis was based on a “more contemporary and comprehensive” literature search strategy than the earlier one, according to Dr. Wallis and his coinvestigators.
Specifically, they considered immunotherapy agents not included in the previous analysis, added seven new studies published since the previous analysis, and excluded three trials that compared immunotherapy agents, rather than comparing immunotherapy with standard of care, they explained in their report.
Their resulting meta-analysis included a total of 9,322 men and 4,399 women, most of whom were in their 70s. Overall, they found that immune checkpoint inhibitor therapy offered a statistically significant overall survival advantage versus standard systemic therapy, with a hazard ratio of 0.75 (95% confidence interval, 0.70-0.81; P less than .001).
That overall survival advantage was found for both men, with a hazard ratio of 0.75 (95% CI, 0.69-0.81; P less than .001) and women, at 0.77 (95% CI, 0.67-0.88; P = .002), investigators further reported. There was no statistically significant difference in overall survival advantage between men and women, both overall (P = 0.60) and in subgroup analyses that accounted for tumor type, line of treatment, and prevalence of women in the study.
The previous meta-analysis, published in the Lancet, found an overall survival hazard ratio of 0.72 for men receiving checkpoint inhibitors and 0.86 for women receiving checkpoint inhibitors (P = .0019), prompting those investigators to conclude that the magnitude of benefit was sex-dependent and that different immunotherapeutic approaches may be needed for men versus women.
“The present meta-analysis provides a more specific assessment of the research question while including a greater number of immunotherapy agents and an updated search,” Dr. Wallis and his coauthors said in a discussion of their more recent findings.
Dr. Wallis reported no disclosures related to the study. Study coauthors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
SOURCE: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.
FROM JAMA ONCOLOGY
Key clinical point: In contrast to an earlier meta-analysis, a more recent meta-analysis suggests no difference in overall survival benefit between men and women with cancer receiving immune checkpoint inhibitor therapy.
Major finding: An overall survival advantage was found for both men and women receiving checkpoint inhibitors versus standard therapy, with hazard ratios of 0.75 and 0.77, respectively (P = .60).
Study details: A systematic review and meta-analysis including nearly 14,000 patients in 23 randomized, clinical trials.
Disclosures: Study authors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
Source: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.