User login
Better survival with S-1 plus docetaxel in stage III gastric cancer
A new recommendation for the treatment of patients with gastric cancer has been proposed on the basis of final results from the phase 3 trial GC-07, which showed survival benefit. The trial was conducted by the Japan Clinical Cancer Research Organization.
, say the researchers.
The 3-year relapse-free survival (RFS) and 3-year overall survival rates were significantly superior among patients treated with S-1/docetaxel, compared with those treated with S-1 alone, commented lead study author Kazuhiro Yoshida, PhD, MD, director of Gifu University Hospital and professor and chairman of the department of surgical oncology, Gifu (Japan) University.
“The study met its primary endpoint and improved the RFS [recurrence-free survival],” he said. “Postoperative S-1 plus docetaxel was safe and manageable.”
Dr. Yoshida presented the updated findings of the GC-07 trial at the Gastrointestinal Cancers Symposium (GICS) 2021, which was held online this year.
S-1 widely used in Asia
S-1 is a novel oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine. The drug, which is a biochemical modulation of 5-fluorouracil, comprises tegafur and two types of enzyme inhibitor. It is widely used to treat various solid tumors in Asia.
“S1 is a standard postoperative adjuvant chemotherapy for patients with p-stage II/III gastric cancer in Asia,” said Dr. Yoshida, but the “outcome in p-stage III is unsatisfactory,” he added.
The GC-07 trial set out to further investigate the use of this drug in this patient population. Dr. Yoshida and colleagues included 915 patients with stage III gastric cancer who had undergone R0 resection and D2 lymphadenectomy and who tested negative on peritoneal-washing cytology. The patients were randomly assigned to receive either S-1 plus docetaxel or S-1 alone for up to 1 year in the postoperative setting.
The data presented at the meeting are the final results from GC-07. They confirm earlier data.
Previously, a second interim analysis showed that the trial had met its primary endpoint. As a result of that analysis, the study was terminated.
That interim analysis showed that the 3-year RFS of the S-1/docetaxel arm was significantly superior to that of the S-1 arm (65.9% vs. 49.6%; hazard ratio, 0.632; P = .0007).
Now, the final results, at a median follow-up of 48.2 months, show that there were 400 recurrences and 324 deaths. The 3-year RFS was 67.7% in the S-1/docetaxel group, which was significantly superior to the 57.4% reported in the S-1 group (HR, 0.715; P = .0008). Similarly, 3-year overall survival was 77.7% in the S-1/docetaxel group, vs. 71.2% in the S-1 group (HR, 0.742; P = .0076).
At 12 months, 62.7% of patients in the S-1 group had experienced treatment failure, compared with 56.2% in the combination-therapy group.
In addition to reducing overall relapse, treatment with combination therapy also decreased the incidence of relapse at specific sites, compared with S-1 alone. These included reductions in lymphatic recurrence (6.4% vs. 15.0%), hematogenous recurrence (9.7% vs. 15.5%), local recurrence (2.9% vs. 4.4%), and peritoneal recurrence (18.8% vs. 21.4%).
No new safety signals were observed, Dr. Yoshida commented. Grade 3/4 adverse events that occurred more frequently with S-1/docetaxel than with S-1 alone included neutropenia (39.2% vs. 16.4%), leukopenia (22.4% vs. 2.7%), and febrile neutropenia (5.7% vs. 0.4%).
However, the authors noted that, in a subgroup analysis, patients with stage IIIB disease did not derive the same benefit in RFS and overall survival with combination therapy as the patients with stage IIIA or IIIC disease.
The discussant for this paper, Rutika Mehta, MD, MPH, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., highlighted differences in benefit among the subgroups, as well as the finding that patients with stage IIIB appeared to benefit less.
However, she noted that the seventh edition of the American Joint Committee on Cancer TNM classification, which distinguishes patients on the basis of prognostic subgroups, is inaccurate for stage III disease, and this might have affected the study results. Dr. Mehta pointed to a previous analysis in which more than 33% of individuals with stage IIIB disease, determined in accordance with the seventh edition of the AJCC staging system, were reclassified as having stage IIIC disease, as determined using the more recent eighth edition.
“There were also few T2, N0, and N1 patients, making meaningful deductions in these subgroups not possible,” she said.
She said that despite these limitations, these “results are meaningful and impactful, and the combination of docetaxel and S-1 showed better RFS and overall survival than S-1 alone.
“These results do favor a new recommendation for the use of docetaxel plus S-1 for stage III gastric cancer patients after D2 lymphadenectomy,” she concluded.
The study was funded by the Japan Clinical Cancer Research Organization. Dr. Yoshida has received honoraria and research funding from many pharmaceutical companies, as listed in the abstract.
A version of this article first appeared on Medscape.com.
A new recommendation for the treatment of patients with gastric cancer has been proposed on the basis of final results from the phase 3 trial GC-07, which showed survival benefit. The trial was conducted by the Japan Clinical Cancer Research Organization.
, say the researchers.
The 3-year relapse-free survival (RFS) and 3-year overall survival rates were significantly superior among patients treated with S-1/docetaxel, compared with those treated with S-1 alone, commented lead study author Kazuhiro Yoshida, PhD, MD, director of Gifu University Hospital and professor and chairman of the department of surgical oncology, Gifu (Japan) University.
“The study met its primary endpoint and improved the RFS [recurrence-free survival],” he said. “Postoperative S-1 plus docetaxel was safe and manageable.”
Dr. Yoshida presented the updated findings of the GC-07 trial at the Gastrointestinal Cancers Symposium (GICS) 2021, which was held online this year.
S-1 widely used in Asia
S-1 is a novel oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine. The drug, which is a biochemical modulation of 5-fluorouracil, comprises tegafur and two types of enzyme inhibitor. It is widely used to treat various solid tumors in Asia.
“S1 is a standard postoperative adjuvant chemotherapy for patients with p-stage II/III gastric cancer in Asia,” said Dr. Yoshida, but the “outcome in p-stage III is unsatisfactory,” he added.
The GC-07 trial set out to further investigate the use of this drug in this patient population. Dr. Yoshida and colleagues included 915 patients with stage III gastric cancer who had undergone R0 resection and D2 lymphadenectomy and who tested negative on peritoneal-washing cytology. The patients were randomly assigned to receive either S-1 plus docetaxel or S-1 alone for up to 1 year in the postoperative setting.
The data presented at the meeting are the final results from GC-07. They confirm earlier data.
Previously, a second interim analysis showed that the trial had met its primary endpoint. As a result of that analysis, the study was terminated.
That interim analysis showed that the 3-year RFS of the S-1/docetaxel arm was significantly superior to that of the S-1 arm (65.9% vs. 49.6%; hazard ratio, 0.632; P = .0007).
Now, the final results, at a median follow-up of 48.2 months, show that there were 400 recurrences and 324 deaths. The 3-year RFS was 67.7% in the S-1/docetaxel group, which was significantly superior to the 57.4% reported in the S-1 group (HR, 0.715; P = .0008). Similarly, 3-year overall survival was 77.7% in the S-1/docetaxel group, vs. 71.2% in the S-1 group (HR, 0.742; P = .0076).
At 12 months, 62.7% of patients in the S-1 group had experienced treatment failure, compared with 56.2% in the combination-therapy group.
In addition to reducing overall relapse, treatment with combination therapy also decreased the incidence of relapse at specific sites, compared with S-1 alone. These included reductions in lymphatic recurrence (6.4% vs. 15.0%), hematogenous recurrence (9.7% vs. 15.5%), local recurrence (2.9% vs. 4.4%), and peritoneal recurrence (18.8% vs. 21.4%).
No new safety signals were observed, Dr. Yoshida commented. Grade 3/4 adverse events that occurred more frequently with S-1/docetaxel than with S-1 alone included neutropenia (39.2% vs. 16.4%), leukopenia (22.4% vs. 2.7%), and febrile neutropenia (5.7% vs. 0.4%).
However, the authors noted that, in a subgroup analysis, patients with stage IIIB disease did not derive the same benefit in RFS and overall survival with combination therapy as the patients with stage IIIA or IIIC disease.
The discussant for this paper, Rutika Mehta, MD, MPH, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., highlighted differences in benefit among the subgroups, as well as the finding that patients with stage IIIB appeared to benefit less.
However, she noted that the seventh edition of the American Joint Committee on Cancer TNM classification, which distinguishes patients on the basis of prognostic subgroups, is inaccurate for stage III disease, and this might have affected the study results. Dr. Mehta pointed to a previous analysis in which more than 33% of individuals with stage IIIB disease, determined in accordance with the seventh edition of the AJCC staging system, were reclassified as having stage IIIC disease, as determined using the more recent eighth edition.
“There were also few T2, N0, and N1 patients, making meaningful deductions in these subgroups not possible,” she said.
She said that despite these limitations, these “results are meaningful and impactful, and the combination of docetaxel and S-1 showed better RFS and overall survival than S-1 alone.
“These results do favor a new recommendation for the use of docetaxel plus S-1 for stage III gastric cancer patients after D2 lymphadenectomy,” she concluded.
The study was funded by the Japan Clinical Cancer Research Organization. Dr. Yoshida has received honoraria and research funding from many pharmaceutical companies, as listed in the abstract.
A version of this article first appeared on Medscape.com.
A new recommendation for the treatment of patients with gastric cancer has been proposed on the basis of final results from the phase 3 trial GC-07, which showed survival benefit. The trial was conducted by the Japan Clinical Cancer Research Organization.
, say the researchers.
The 3-year relapse-free survival (RFS) and 3-year overall survival rates were significantly superior among patients treated with S-1/docetaxel, compared with those treated with S-1 alone, commented lead study author Kazuhiro Yoshida, PhD, MD, director of Gifu University Hospital and professor and chairman of the department of surgical oncology, Gifu (Japan) University.
“The study met its primary endpoint and improved the RFS [recurrence-free survival],” he said. “Postoperative S-1 plus docetaxel was safe and manageable.”
Dr. Yoshida presented the updated findings of the GC-07 trial at the Gastrointestinal Cancers Symposium (GICS) 2021, which was held online this year.
S-1 widely used in Asia
S-1 is a novel oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine. The drug, which is a biochemical modulation of 5-fluorouracil, comprises tegafur and two types of enzyme inhibitor. It is widely used to treat various solid tumors in Asia.
“S1 is a standard postoperative adjuvant chemotherapy for patients with p-stage II/III gastric cancer in Asia,” said Dr. Yoshida, but the “outcome in p-stage III is unsatisfactory,” he added.
The GC-07 trial set out to further investigate the use of this drug in this patient population. Dr. Yoshida and colleagues included 915 patients with stage III gastric cancer who had undergone R0 resection and D2 lymphadenectomy and who tested negative on peritoneal-washing cytology. The patients were randomly assigned to receive either S-1 plus docetaxel or S-1 alone for up to 1 year in the postoperative setting.
The data presented at the meeting are the final results from GC-07. They confirm earlier data.
Previously, a second interim analysis showed that the trial had met its primary endpoint. As a result of that analysis, the study was terminated.
That interim analysis showed that the 3-year RFS of the S-1/docetaxel arm was significantly superior to that of the S-1 arm (65.9% vs. 49.6%; hazard ratio, 0.632; P = .0007).
Now, the final results, at a median follow-up of 48.2 months, show that there were 400 recurrences and 324 deaths. The 3-year RFS was 67.7% in the S-1/docetaxel group, which was significantly superior to the 57.4% reported in the S-1 group (HR, 0.715; P = .0008). Similarly, 3-year overall survival was 77.7% in the S-1/docetaxel group, vs. 71.2% in the S-1 group (HR, 0.742; P = .0076).
At 12 months, 62.7% of patients in the S-1 group had experienced treatment failure, compared with 56.2% in the combination-therapy group.
In addition to reducing overall relapse, treatment with combination therapy also decreased the incidence of relapse at specific sites, compared with S-1 alone. These included reductions in lymphatic recurrence (6.4% vs. 15.0%), hematogenous recurrence (9.7% vs. 15.5%), local recurrence (2.9% vs. 4.4%), and peritoneal recurrence (18.8% vs. 21.4%).
No new safety signals were observed, Dr. Yoshida commented. Grade 3/4 adverse events that occurred more frequently with S-1/docetaxel than with S-1 alone included neutropenia (39.2% vs. 16.4%), leukopenia (22.4% vs. 2.7%), and febrile neutropenia (5.7% vs. 0.4%).
However, the authors noted that, in a subgroup analysis, patients with stage IIIB disease did not derive the same benefit in RFS and overall survival with combination therapy as the patients with stage IIIA or IIIC disease.
The discussant for this paper, Rutika Mehta, MD, MPH, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., highlighted differences in benefit among the subgroups, as well as the finding that patients with stage IIIB appeared to benefit less.
However, she noted that the seventh edition of the American Joint Committee on Cancer TNM classification, which distinguishes patients on the basis of prognostic subgroups, is inaccurate for stage III disease, and this might have affected the study results. Dr. Mehta pointed to a previous analysis in which more than 33% of individuals with stage IIIB disease, determined in accordance with the seventh edition of the AJCC staging system, were reclassified as having stage IIIC disease, as determined using the more recent eighth edition.
“There were also few T2, N0, and N1 patients, making meaningful deductions in these subgroups not possible,” she said.
She said that despite these limitations, these “results are meaningful and impactful, and the combination of docetaxel and S-1 showed better RFS and overall survival than S-1 alone.
“These results do favor a new recommendation for the use of docetaxel plus S-1 for stage III gastric cancer patients after D2 lymphadenectomy,” she concluded.
The study was funded by the Japan Clinical Cancer Research Organization. Dr. Yoshida has received honoraria and research funding from many pharmaceutical companies, as listed in the abstract.
A version of this article first appeared on Medscape.com.
Gut microbiome may predict nivolumab efficacy in gastric cancer
Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.
“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.
Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.
The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.
Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.
“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”
In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.
The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.
Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.
Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.
The phylogenetic composition of common bacterial taxa was similar for both cohorts.
In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.
The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.
An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.
Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
Still some gaps
In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”
However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.
“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”
Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.
But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.
The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
A version of this article first appeared on Medscape.com.
Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.
“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.
Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.
The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.
Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.
“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”
In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.
The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.
Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.
Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.
The phylogenetic composition of common bacterial taxa was similar for both cohorts.
In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.
The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.
An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.
Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
Still some gaps
In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”
However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.
“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”
Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.
But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.
The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
A version of this article first appeared on Medscape.com.
Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.
“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.
Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.
The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.
Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.
“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”
In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.
The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.
Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.
Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.
The phylogenetic composition of common bacterial taxa was similar for both cohorts.
In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.
The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.
An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.
Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
Still some gaps
In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”
However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.
“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”
Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.
But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.
The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
A version of this article first appeared on Medscape.com.
Bemarituzumab FIGHTs gastric/GEJ cancers, improving survival
Among 155 patients followed for a median of 10.9 months, the combination of bemarituzumab and modified FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin) resulted in a median progression-free survival (PFS) of 9.5 months, compared with 7.4 months with chemotherapy alone.
The median overall survival (OS) was not reached in the combination arm but was 12.9 months for patients treated with modified FOLFOX plus placebo
Zev A. Wainberg, MD, of the University of California, Los Angeles, presented these results at the 2021 Gastrointestinal Cancers Symposium.
Dr. Wainberg explained that bemarituzumab is an IgG1 antibody targeted specifically to the FGFR2b receptor to block growth factor signaling. The findings from FIGHT suggest FGFR2b is a new biomarker and therapeutic target for advanced gastric and GEJ cancers.
“The FIGHT trial results support a prospective, randomized, phase 3 study in gastric and gastroesophageal adenocarcinoma and the evaluation of bemarituzumab in other FGFR2b tumor types,” Dr. Wainberg said.
FGFR2b is a splice isoform of FGFR2 that is thought to be overexpressed in anywhere from 3% to 61% of gastric cancers, depending on the tumor stage and assay used, he explained at the meeting sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Study downgrading and design
The FIGHT trial was originally designed as a phase 3, randomized trial with the primary endpoint of OS, but it was converted to a phase 2 trial with a PFS primary endpoint and OS secondary endpoint.
In the question-and-answer phase following his presentation, Dr. Wainberg explained that the trial was downgraded because “we wanted to get a little more comfortable with the biomarker,” and because the prevalence of FGFR2b, which was unknown during the planning phase, played a large role in the statistical assumptions.
Patients were eligible for FIGHT if they had received no prior therapy for unresectable, locally advanced or metastatic gastric or GEJ cancers. They also had to have FGFR2b overexpression on immunohistochemistry and/or FGFR2 gene amplification by circulating tumor DNA. They had to have good Eastern Cooperative Oncology Group performance status (0 or 1) and could not have tumors positive for HER2.
Patients were allowed to have one cycle of FOLFOX while their FGFR2b status was being determined, prior to randomization.
After stratification for geographic region, FOLFOX use during screenings, and prior adjuvant or neoadjuvant chemotherapy, the patients were randomized to receive FOLFOX with either placebo or 15 mg/kg of bemarituzumab every 2 weeks, plus an additional 7.5-mg/kg dose on day 8 of cycle 1.
A total of 77 patients were randomized to the bemarituzumab arm, and 78 were randomized to the placebo arm.
Patient status at cutoff
As of the September 2020 cutoff, 14 patients continued on bemarituzumab, and 63 were off the assigned drug: 26 because of radiographic progression, 3 for consent withdrawal, 5 because of death, 20 because of adverse events, and 9 for other unspecified causes.
There were 42 patients in the bemarituzumab arm who were still being followed at the cutoff, and 35 were off study. Of this latter group, 28 died, 6 withdrew consent, and 1 was off study for an unspecified cause.
In the placebo arm, 8 patients were still receiving the assigned therapy, and 70 were off that treatment. Of the patients who discontinued study treatment, 4 died, 39 had radiographic progression, 7 withdrew consent, 3 had adverse events, and 17 discontinued for other unspecified reasons.
A total of 27 patients assigned to placebo were still on follow-up at the data cutoff. Of the remaining 51 patients, 40 died, 10 withdrew consent, and 1 had other, unspecified causes for going off study.
Primary endpoint met
The PFS rate at 9 months was 52.5% in the experimental arm and 33.8% in the control arm. The median PFS was 9.5 months with bemarituzumab and 7.4 months with placebo, which translated to a hazard ratio of 0.68 (P = .0727). This met the prespecified level of statistical significance for the phase 2 version of the trial, which required a two-sided alpha of 0.2
OS at 12 months was also superior in the experimental arm, at 65.3% with bemarituzumab and 56.9% with placebo (HR, 0.58; P = .0268).
The benefit of bemarituzumab for both PFS and OS was greatest among patients whose tumors had the highest levels of FGFR2b expression.
Overall response rates were 47% in the experimental arm and 33% in the placebo arm. Among patients with measurable disease at baseline, the respective response rates were 53% and 40%. The median duration of response was 12.2 months in the bemarituzumab arm and 7.1 months in the placebo arm.
Corneal toxicities, stomatitis
The incidence of grade 3 or greater adverse events was 82.9% in the experimental arm and 74% in the placebo arm. Five patients in the bemarituzumab arm and four in the placebo arm died from treatment-related causes.
Grade 3 or greater stomatitis occurred in seven patients in the experimental arm, compared with just one patient in the placebo arm. Grade 3 or greater dry eye occurred in two patients in the experimental arm but none in the placebo arm.
Corneal adverse events occurred in 67.1% of patients treated with bemarituzumab and 10.4% of patients on placebo. Respective rates of grade 3 or greater corneal events were 23.7% and 0%.
Twenty patients assigned to bemarituzumab had to discontinue the drug because of corneal problems, compared with no patients on placebo.
At last follow-up, corneal adverse events had resolved in 60% of patients, while 40% had continuing problems. The median time to resolution of corneal adverse events was 27 weeks.
New biomarker
“FIGHT study is the first study to demonstrate that biomarker selection exists beyond HER2,” commented invited discussant Rutika Mehta, MD, of the Moffitt Cancer Center and University of South Florida, both in Tampa.
“These are promising results, with toxicities that need to be watched out for. It calls for a larger phase 3 study with special attention to the toxicity profile for bema[rituzumab],” she added.
The trial was supported by Five Prime Therapeutics. Dr. Wainberg disclosed relationships with Five Prime and other companies. Dr. Mehta disclosed relationships with several companies, not including Five Prime.
Among 155 patients followed for a median of 10.9 months, the combination of bemarituzumab and modified FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin) resulted in a median progression-free survival (PFS) of 9.5 months, compared with 7.4 months with chemotherapy alone.
The median overall survival (OS) was not reached in the combination arm but was 12.9 months for patients treated with modified FOLFOX plus placebo
Zev A. Wainberg, MD, of the University of California, Los Angeles, presented these results at the 2021 Gastrointestinal Cancers Symposium.
Dr. Wainberg explained that bemarituzumab is an IgG1 antibody targeted specifically to the FGFR2b receptor to block growth factor signaling. The findings from FIGHT suggest FGFR2b is a new biomarker and therapeutic target for advanced gastric and GEJ cancers.
“The FIGHT trial results support a prospective, randomized, phase 3 study in gastric and gastroesophageal adenocarcinoma and the evaluation of bemarituzumab in other FGFR2b tumor types,” Dr. Wainberg said.
FGFR2b is a splice isoform of FGFR2 that is thought to be overexpressed in anywhere from 3% to 61% of gastric cancers, depending on the tumor stage and assay used, he explained at the meeting sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Study downgrading and design
The FIGHT trial was originally designed as a phase 3, randomized trial with the primary endpoint of OS, but it was converted to a phase 2 trial with a PFS primary endpoint and OS secondary endpoint.
In the question-and-answer phase following his presentation, Dr. Wainberg explained that the trial was downgraded because “we wanted to get a little more comfortable with the biomarker,” and because the prevalence of FGFR2b, which was unknown during the planning phase, played a large role in the statistical assumptions.
Patients were eligible for FIGHT if they had received no prior therapy for unresectable, locally advanced or metastatic gastric or GEJ cancers. They also had to have FGFR2b overexpression on immunohistochemistry and/or FGFR2 gene amplification by circulating tumor DNA. They had to have good Eastern Cooperative Oncology Group performance status (0 or 1) and could not have tumors positive for HER2.
Patients were allowed to have one cycle of FOLFOX while their FGFR2b status was being determined, prior to randomization.
After stratification for geographic region, FOLFOX use during screenings, and prior adjuvant or neoadjuvant chemotherapy, the patients were randomized to receive FOLFOX with either placebo or 15 mg/kg of bemarituzumab every 2 weeks, plus an additional 7.5-mg/kg dose on day 8 of cycle 1.
A total of 77 patients were randomized to the bemarituzumab arm, and 78 were randomized to the placebo arm.
Patient status at cutoff
As of the September 2020 cutoff, 14 patients continued on bemarituzumab, and 63 were off the assigned drug: 26 because of radiographic progression, 3 for consent withdrawal, 5 because of death, 20 because of adverse events, and 9 for other unspecified causes.
There were 42 patients in the bemarituzumab arm who were still being followed at the cutoff, and 35 were off study. Of this latter group, 28 died, 6 withdrew consent, and 1 was off study for an unspecified cause.
In the placebo arm, 8 patients were still receiving the assigned therapy, and 70 were off that treatment. Of the patients who discontinued study treatment, 4 died, 39 had radiographic progression, 7 withdrew consent, 3 had adverse events, and 17 discontinued for other unspecified reasons.
A total of 27 patients assigned to placebo were still on follow-up at the data cutoff. Of the remaining 51 patients, 40 died, 10 withdrew consent, and 1 had other, unspecified causes for going off study.
Primary endpoint met
The PFS rate at 9 months was 52.5% in the experimental arm and 33.8% in the control arm. The median PFS was 9.5 months with bemarituzumab and 7.4 months with placebo, which translated to a hazard ratio of 0.68 (P = .0727). This met the prespecified level of statistical significance for the phase 2 version of the trial, which required a two-sided alpha of 0.2
OS at 12 months was also superior in the experimental arm, at 65.3% with bemarituzumab and 56.9% with placebo (HR, 0.58; P = .0268).
The benefit of bemarituzumab for both PFS and OS was greatest among patients whose tumors had the highest levels of FGFR2b expression.
Overall response rates were 47% in the experimental arm and 33% in the placebo arm. Among patients with measurable disease at baseline, the respective response rates were 53% and 40%. The median duration of response was 12.2 months in the bemarituzumab arm and 7.1 months in the placebo arm.
Corneal toxicities, stomatitis
The incidence of grade 3 or greater adverse events was 82.9% in the experimental arm and 74% in the placebo arm. Five patients in the bemarituzumab arm and four in the placebo arm died from treatment-related causes.
Grade 3 or greater stomatitis occurred in seven patients in the experimental arm, compared with just one patient in the placebo arm. Grade 3 or greater dry eye occurred in two patients in the experimental arm but none in the placebo arm.
Corneal adverse events occurred in 67.1% of patients treated with bemarituzumab and 10.4% of patients on placebo. Respective rates of grade 3 or greater corneal events were 23.7% and 0%.
Twenty patients assigned to bemarituzumab had to discontinue the drug because of corneal problems, compared with no patients on placebo.
At last follow-up, corneal adverse events had resolved in 60% of patients, while 40% had continuing problems. The median time to resolution of corneal adverse events was 27 weeks.
New biomarker
“FIGHT study is the first study to demonstrate that biomarker selection exists beyond HER2,” commented invited discussant Rutika Mehta, MD, of the Moffitt Cancer Center and University of South Florida, both in Tampa.
“These are promising results, with toxicities that need to be watched out for. It calls for a larger phase 3 study with special attention to the toxicity profile for bema[rituzumab],” she added.
The trial was supported by Five Prime Therapeutics. Dr. Wainberg disclosed relationships with Five Prime and other companies. Dr. Mehta disclosed relationships with several companies, not including Five Prime.
Among 155 patients followed for a median of 10.9 months, the combination of bemarituzumab and modified FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin) resulted in a median progression-free survival (PFS) of 9.5 months, compared with 7.4 months with chemotherapy alone.
The median overall survival (OS) was not reached in the combination arm but was 12.9 months for patients treated with modified FOLFOX plus placebo
Zev A. Wainberg, MD, of the University of California, Los Angeles, presented these results at the 2021 Gastrointestinal Cancers Symposium.
Dr. Wainberg explained that bemarituzumab is an IgG1 antibody targeted specifically to the FGFR2b receptor to block growth factor signaling. The findings from FIGHT suggest FGFR2b is a new biomarker and therapeutic target for advanced gastric and GEJ cancers.
“The FIGHT trial results support a prospective, randomized, phase 3 study in gastric and gastroesophageal adenocarcinoma and the evaluation of bemarituzumab in other FGFR2b tumor types,” Dr. Wainberg said.
FGFR2b is a splice isoform of FGFR2 that is thought to be overexpressed in anywhere from 3% to 61% of gastric cancers, depending on the tumor stage and assay used, he explained at the meeting sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Study downgrading and design
The FIGHT trial was originally designed as a phase 3, randomized trial with the primary endpoint of OS, but it was converted to a phase 2 trial with a PFS primary endpoint and OS secondary endpoint.
In the question-and-answer phase following his presentation, Dr. Wainberg explained that the trial was downgraded because “we wanted to get a little more comfortable with the biomarker,” and because the prevalence of FGFR2b, which was unknown during the planning phase, played a large role in the statistical assumptions.
Patients were eligible for FIGHT if they had received no prior therapy for unresectable, locally advanced or metastatic gastric or GEJ cancers. They also had to have FGFR2b overexpression on immunohistochemistry and/or FGFR2 gene amplification by circulating tumor DNA. They had to have good Eastern Cooperative Oncology Group performance status (0 or 1) and could not have tumors positive for HER2.
Patients were allowed to have one cycle of FOLFOX while their FGFR2b status was being determined, prior to randomization.
After stratification for geographic region, FOLFOX use during screenings, and prior adjuvant or neoadjuvant chemotherapy, the patients were randomized to receive FOLFOX with either placebo or 15 mg/kg of bemarituzumab every 2 weeks, plus an additional 7.5-mg/kg dose on day 8 of cycle 1.
A total of 77 patients were randomized to the bemarituzumab arm, and 78 were randomized to the placebo arm.
Patient status at cutoff
As of the September 2020 cutoff, 14 patients continued on bemarituzumab, and 63 were off the assigned drug: 26 because of radiographic progression, 3 for consent withdrawal, 5 because of death, 20 because of adverse events, and 9 for other unspecified causes.
There were 42 patients in the bemarituzumab arm who were still being followed at the cutoff, and 35 were off study. Of this latter group, 28 died, 6 withdrew consent, and 1 was off study for an unspecified cause.
In the placebo arm, 8 patients were still receiving the assigned therapy, and 70 were off that treatment. Of the patients who discontinued study treatment, 4 died, 39 had radiographic progression, 7 withdrew consent, 3 had adverse events, and 17 discontinued for other unspecified reasons.
A total of 27 patients assigned to placebo were still on follow-up at the data cutoff. Of the remaining 51 patients, 40 died, 10 withdrew consent, and 1 had other, unspecified causes for going off study.
Primary endpoint met
The PFS rate at 9 months was 52.5% in the experimental arm and 33.8% in the control arm. The median PFS was 9.5 months with bemarituzumab and 7.4 months with placebo, which translated to a hazard ratio of 0.68 (P = .0727). This met the prespecified level of statistical significance for the phase 2 version of the trial, which required a two-sided alpha of 0.2
OS at 12 months was also superior in the experimental arm, at 65.3% with bemarituzumab and 56.9% with placebo (HR, 0.58; P = .0268).
The benefit of bemarituzumab for both PFS and OS was greatest among patients whose tumors had the highest levels of FGFR2b expression.
Overall response rates were 47% in the experimental arm and 33% in the placebo arm. Among patients with measurable disease at baseline, the respective response rates were 53% and 40%. The median duration of response was 12.2 months in the bemarituzumab arm and 7.1 months in the placebo arm.
Corneal toxicities, stomatitis
The incidence of grade 3 or greater adverse events was 82.9% in the experimental arm and 74% in the placebo arm. Five patients in the bemarituzumab arm and four in the placebo arm died from treatment-related causes.
Grade 3 or greater stomatitis occurred in seven patients in the experimental arm, compared with just one patient in the placebo arm. Grade 3 or greater dry eye occurred in two patients in the experimental arm but none in the placebo arm.
Corneal adverse events occurred in 67.1% of patients treated with bemarituzumab and 10.4% of patients on placebo. Respective rates of grade 3 or greater corneal events were 23.7% and 0%.
Twenty patients assigned to bemarituzumab had to discontinue the drug because of corneal problems, compared with no patients on placebo.
At last follow-up, corneal adverse events had resolved in 60% of patients, while 40% had continuing problems. The median time to resolution of corneal adverse events was 27 weeks.
New biomarker
“FIGHT study is the first study to demonstrate that biomarker selection exists beyond HER2,” commented invited discussant Rutika Mehta, MD, of the Moffitt Cancer Center and University of South Florida, both in Tampa.
“These are promising results, with toxicities that need to be watched out for. It calls for a larger phase 3 study with special attention to the toxicity profile for bema[rituzumab],” she added.
The trial was supported by Five Prime Therapeutics. Dr. Wainberg disclosed relationships with Five Prime and other companies. Dr. Mehta disclosed relationships with several companies, not including Five Prime.
FROM GI CANCERS SYMPOSIUM 2021