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Pancreatic cancer expression signature is linked to chemoresistance
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox 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.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox 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.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox 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.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Molecular features of pancreatic cancer may help estimate prognosis and predict response to chemotherapy.
Major finding: Compared with peers whose tumors had a classic RNA expression signature, patients whose tumors had a basal-like RNA expression signature had poorer overall survival when given mFOLFIRINOX (hazard ratio, 0.33; P = .0005).
Study details: Prospective trial with whole-genome sequencing and RNA sequencing of tumors in 150 patients with advanced pancreatic ductal adenocarcinoma before start of first-line therapy (COMPASS trial).
Disclosures: Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
Source: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
Gastrectomy does not alter benefit of new oral chemo in gastric cancer
SAN FRANCISCO – suggests a preplanned subgroup analysis of the global phase 3 randomized controlled TAGS trial. Results were reported at the 2019 GI Cancers Symposium.
“The standard of care for early-stage gastric cancer is surgery, which is the only potentially curative treatment,” noted lead investigator David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York. “Forty percent of patients with metastatic disease have had a history of previous gastrectomy.”
The TAGS trial assessed efficacy of combined trifluridine and tipiracil (Lonsurf) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens. (This combination chemotherapy is currently approved in the United States as later-line therapy for metastatic colorectal cancer.)
Compared with placebo, trifluridine/tipiracil prolonged overall survival by 2.6 months in the subgroup who had previously undergone gastrectomy, a benefit slightly greater than the 2.1 months previously reported for the entire trial population (Lancet Oncol. 2018;19:1437-48). And although the gastrectomy subgroup experienced more grade 3 or 4 adverse events, they were not more likely to stop treatment because of toxicity.
“The data from this analysis reinforce the benefit for trifluridine/tipiracil as prolonging survival versus placebo, and this is regardless of prior gastrectomy,” Dr. Ilson summarized. “Hematologic adverse events, such as neutropenia and leukopenia, may have been somewhat more frequent among the trifluridine/tipiracil–treated patients with gastrectomy than in the overall population, but this did not result in more treatment discontinuations. Exposure to the drug was similar between patients with gastrectomy and those in the overall population.”
“Trifluridine/tipiracil is an effective treatment option with a manageable toxicity profile for patients with metastatic gastric cancer, regardless of prior gastrectomy status,” he concluded.
Still fit for treatment
The disconnect between toxicity and treatment discontinuation seen in the TAGS trial is not new, according to invited discussant Martine Extermann, MD, PhD, leader of the Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa. Previous data among geriatric cancer patients have similarly shown that, despite substantial chemotherapy toxicity, by and large, there are only modest effects on health-related quality of life, performance status, and instrumental activities of daily living, she noted.
“The CTCAE [Common Terminology Criteria for Adverse Events] toxicity differences do not always translate into functional impact and treatment cessation. So this is only part of the picture. It’s a convenient part. It’s easily measurable. It’s well acknowledged as a measurement of side effects. But it does not tell the whole story. Quality of life and functional status add to the picture,” Dr. Extermann elaborated. “What the TAGS study is telling us is, despite a gastrectomy, these patients can be treated as a third-line treatment population for gastric cancer, which is not necessarily obvious to every oncologist.”
At the same time, she added that it would be helpful to have nutritional data on the study patients – and on all patients in similar trials, for that matter – because nutritional status is one of the components of the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score used to predict chemotherapy toxicity in older adults.
“I would support that [trifluridine/tipiracil] is an effective third-line chemotherapy in gastric cancer patients with or without prior gastrectomy, and this can be given safely,” Dr. Extermann concluded.
Study details
Patients in TAGS were randomized 2:1 to trifluridine/tipiracil (formerly TAS-102) or placebo, each added to best supportive care. (Trifluridine is a novel oral thymidine analogue, and tipiracil prevents trifluridine degradation.) Overall, 44% had undergone gastrectomy before entering the trial.
In the entire trial population, overall survival was 5.7 months with trifluridine/tipiracil and 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.85; P = .0006), as previously reported.
Among the subgroup who had undergone prior gastrectomy, overall survival was 6.0 months with trifluridine/tipiracil and 3.4 months with placebo (HR, 0.57; 95% CI, 0.41-0.79), Dr. Ilson reported at the symposium, which 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. The combination also netted better progression-free survival (2.2 vs. 1.8 months; HR, 0.48; 95% CI, 0.35-0.65). “These data mirror the data seen in the overall treatment population,” he commented.
In a multivariate analysis including all prespecified factors, prior gastrectomy was neither prognostic nor predictive. Moreover, the treatment effect size remained the same after adjustment for potential prognostic factors.
Exposure to trifluridine/tipiracil was similar for the gastrectomy subgroup and the entire trial population in terms of relative dose intensity, median number of cycles, and treatment duration.
The rate of grade 3 or 4 treatment-related adverse events with trifluridine/tipiracil in the gastrectomy subgroup, 64%, was higher than that in the entire trial population, 53%, but the rate of discontinuation because of any-grade adverse events was similar, at 10% and 13%, respectively.
The difference in grade 3 or 4 adverse events between the gastrectomy subgroup and the entire trial population was mainly driven by higher rates of neutropenia (44% vs. 34%) and leukopenia (14% vs. 9%) in the former.
Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
SOURCE: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
SAN FRANCISCO – suggests a preplanned subgroup analysis of the global phase 3 randomized controlled TAGS trial. Results were reported at the 2019 GI Cancers Symposium.
“The standard of care for early-stage gastric cancer is surgery, which is the only potentially curative treatment,” noted lead investigator David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York. “Forty percent of patients with metastatic disease have had a history of previous gastrectomy.”
The TAGS trial assessed efficacy of combined trifluridine and tipiracil (Lonsurf) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens. (This combination chemotherapy is currently approved in the United States as later-line therapy for metastatic colorectal cancer.)
Compared with placebo, trifluridine/tipiracil prolonged overall survival by 2.6 months in the subgroup who had previously undergone gastrectomy, a benefit slightly greater than the 2.1 months previously reported for the entire trial population (Lancet Oncol. 2018;19:1437-48). And although the gastrectomy subgroup experienced more grade 3 or 4 adverse events, they were not more likely to stop treatment because of toxicity.
“The data from this analysis reinforce the benefit for trifluridine/tipiracil as prolonging survival versus placebo, and this is regardless of prior gastrectomy,” Dr. Ilson summarized. “Hematologic adverse events, such as neutropenia and leukopenia, may have been somewhat more frequent among the trifluridine/tipiracil–treated patients with gastrectomy than in the overall population, but this did not result in more treatment discontinuations. Exposure to the drug was similar between patients with gastrectomy and those in the overall population.”
“Trifluridine/tipiracil is an effective treatment option with a manageable toxicity profile for patients with metastatic gastric cancer, regardless of prior gastrectomy status,” he concluded.
Still fit for treatment
The disconnect between toxicity and treatment discontinuation seen in the TAGS trial is not new, according to invited discussant Martine Extermann, MD, PhD, leader of the Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa. Previous data among geriatric cancer patients have similarly shown that, despite substantial chemotherapy toxicity, by and large, there are only modest effects on health-related quality of life, performance status, and instrumental activities of daily living, she noted.
“The CTCAE [Common Terminology Criteria for Adverse Events] toxicity differences do not always translate into functional impact and treatment cessation. So this is only part of the picture. It’s a convenient part. It’s easily measurable. It’s well acknowledged as a measurement of side effects. But it does not tell the whole story. Quality of life and functional status add to the picture,” Dr. Extermann elaborated. “What the TAGS study is telling us is, despite a gastrectomy, these patients can be treated as a third-line treatment population for gastric cancer, which is not necessarily obvious to every oncologist.”
At the same time, she added that it would be helpful to have nutritional data on the study patients – and on all patients in similar trials, for that matter – because nutritional status is one of the components of the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score used to predict chemotherapy toxicity in older adults.
“I would support that [trifluridine/tipiracil] is an effective third-line chemotherapy in gastric cancer patients with or without prior gastrectomy, and this can be given safely,” Dr. Extermann concluded.
Study details
Patients in TAGS were randomized 2:1 to trifluridine/tipiracil (formerly TAS-102) or placebo, each added to best supportive care. (Trifluridine is a novel oral thymidine analogue, and tipiracil prevents trifluridine degradation.) Overall, 44% had undergone gastrectomy before entering the trial.
In the entire trial population, overall survival was 5.7 months with trifluridine/tipiracil and 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.85; P = .0006), as previously reported.
Among the subgroup who had undergone prior gastrectomy, overall survival was 6.0 months with trifluridine/tipiracil and 3.4 months with placebo (HR, 0.57; 95% CI, 0.41-0.79), Dr. Ilson reported at the symposium, which 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. The combination also netted better progression-free survival (2.2 vs. 1.8 months; HR, 0.48; 95% CI, 0.35-0.65). “These data mirror the data seen in the overall treatment population,” he commented.
In a multivariate analysis including all prespecified factors, prior gastrectomy was neither prognostic nor predictive. Moreover, the treatment effect size remained the same after adjustment for potential prognostic factors.
Exposure to trifluridine/tipiracil was similar for the gastrectomy subgroup and the entire trial population in terms of relative dose intensity, median number of cycles, and treatment duration.
The rate of grade 3 or 4 treatment-related adverse events with trifluridine/tipiracil in the gastrectomy subgroup, 64%, was higher than that in the entire trial population, 53%, but the rate of discontinuation because of any-grade adverse events was similar, at 10% and 13%, respectively.
The difference in grade 3 or 4 adverse events between the gastrectomy subgroup and the entire trial population was mainly driven by higher rates of neutropenia (44% vs. 34%) and leukopenia (14% vs. 9%) in the former.
Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
SOURCE: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
SAN FRANCISCO – suggests a preplanned subgroup analysis of the global phase 3 randomized controlled TAGS trial. Results were reported at the 2019 GI Cancers Symposium.
“The standard of care for early-stage gastric cancer is surgery, which is the only potentially curative treatment,” noted lead investigator David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York. “Forty percent of patients with metastatic disease have had a history of previous gastrectomy.”
The TAGS trial assessed efficacy of combined trifluridine and tipiracil (Lonsurf) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens. (This combination chemotherapy is currently approved in the United States as later-line therapy for metastatic colorectal cancer.)
Compared with placebo, trifluridine/tipiracil prolonged overall survival by 2.6 months in the subgroup who had previously undergone gastrectomy, a benefit slightly greater than the 2.1 months previously reported for the entire trial population (Lancet Oncol. 2018;19:1437-48). And although the gastrectomy subgroup experienced more grade 3 or 4 adverse events, they were not more likely to stop treatment because of toxicity.
“The data from this analysis reinforce the benefit for trifluridine/tipiracil as prolonging survival versus placebo, and this is regardless of prior gastrectomy,” Dr. Ilson summarized. “Hematologic adverse events, such as neutropenia and leukopenia, may have been somewhat more frequent among the trifluridine/tipiracil–treated patients with gastrectomy than in the overall population, but this did not result in more treatment discontinuations. Exposure to the drug was similar between patients with gastrectomy and those in the overall population.”
“Trifluridine/tipiracil is an effective treatment option with a manageable toxicity profile for patients with metastatic gastric cancer, regardless of prior gastrectomy status,” he concluded.
Still fit for treatment
The disconnect between toxicity and treatment discontinuation seen in the TAGS trial is not new, according to invited discussant Martine Extermann, MD, PhD, leader of the Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa. Previous data among geriatric cancer patients have similarly shown that, despite substantial chemotherapy toxicity, by and large, there are only modest effects on health-related quality of life, performance status, and instrumental activities of daily living, she noted.
“The CTCAE [Common Terminology Criteria for Adverse Events] toxicity differences do not always translate into functional impact and treatment cessation. So this is only part of the picture. It’s a convenient part. It’s easily measurable. It’s well acknowledged as a measurement of side effects. But it does not tell the whole story. Quality of life and functional status add to the picture,” Dr. Extermann elaborated. “What the TAGS study is telling us is, despite a gastrectomy, these patients can be treated as a third-line treatment population for gastric cancer, which is not necessarily obvious to every oncologist.”
At the same time, she added that it would be helpful to have nutritional data on the study patients – and on all patients in similar trials, for that matter – because nutritional status is one of the components of the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score used to predict chemotherapy toxicity in older adults.
“I would support that [trifluridine/tipiracil] is an effective third-line chemotherapy in gastric cancer patients with or without prior gastrectomy, and this can be given safely,” Dr. Extermann concluded.
Study details
Patients in TAGS were randomized 2:1 to trifluridine/tipiracil (formerly TAS-102) or placebo, each added to best supportive care. (Trifluridine is a novel oral thymidine analogue, and tipiracil prevents trifluridine degradation.) Overall, 44% had undergone gastrectomy before entering the trial.
In the entire trial population, overall survival was 5.7 months with trifluridine/tipiracil and 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.85; P = .0006), as previously reported.
Among the subgroup who had undergone prior gastrectomy, overall survival was 6.0 months with trifluridine/tipiracil and 3.4 months with placebo (HR, 0.57; 95% CI, 0.41-0.79), Dr. Ilson reported at the symposium, which 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. The combination also netted better progression-free survival (2.2 vs. 1.8 months; HR, 0.48; 95% CI, 0.35-0.65). “These data mirror the data seen in the overall treatment population,” he commented.
In a multivariate analysis including all prespecified factors, prior gastrectomy was neither prognostic nor predictive. Moreover, the treatment effect size remained the same after adjustment for potential prognostic factors.
Exposure to trifluridine/tipiracil was similar for the gastrectomy subgroup and the entire trial population in terms of relative dose intensity, median number of cycles, and treatment duration.
The rate of grade 3 or 4 treatment-related adverse events with trifluridine/tipiracil in the gastrectomy subgroup, 64%, was higher than that in the entire trial population, 53%, but the rate of discontinuation because of any-grade adverse events was similar, at 10% and 13%, respectively.
The difference in grade 3 or 4 adverse events between the gastrectomy subgroup and the entire trial population was mainly driven by higher rates of neutropenia (44% vs. 34%) and leukopenia (14% vs. 9%) in the former.
Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
SOURCE: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Patients with metastatic gastric cancer experience largely similar efficacy and safety outcomes with oral trifluridine/tipiracil regardless of prior gastrectomy.
Major finding: Compared with placebo, trifluridine/tipiracil improved overall survival in the gastrectomy subgroup (hazard ratio, 0.57) with a higher rate of grade 3/4 adverse events in that subgroup (64% vs. 53%) but similar rate of discontinuation because of adverse events (10% vs. 13%).
Study details: Preplanned subgroup analysis of a phase 3 randomized controlled trial (TAGS trial) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens.
Disclosures: Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
Source: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
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.
Dual BRAF, MEK inhibition proves highly active in biliary tract cancer
SAN FRANCISCO – Simultaneously targeting two components of the same signaling pathway in BRAF V600E–mutated biliary tract cancer is a winning strategy, suggests an analysis of the multicenter phase 2 ROAR basket trial.
“Recently, a number of genetic targets have been identified with distinct rates of frequency in intrahepatic, extrahepatic, and gallbladder cancer that are the subject of a number of ongoing clinical trials. In retrospective studies, mutations in BRAF have been identified in about 5%-7% of patients, predominantly in the intrahepatic cohort,” lead investigator Zev A. Wainberg, MD, noted at the 2019 GI Cancers Symposium. Previous research has shown combined inhibition of BRAF and MEK – two sequential proteins on the MAP kinase signaling pathway – to be efficacious in BRAF V600E–mutated melanoma, non–small cell lung cancer, and anaplastic thyroid cancer.
In the ROAR trial, 178 patients with advanced or metastatic BRAF V600E–mutated rare cancers who had exhausted standard treatment options were treated with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Dr. Wainberg reported results for the 35 patients having biliary tract cancer, most of whom were heavily pretreated.
With a median duration of follow-up of 8 months, the overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers. More than half of patients had a grade 3 or 4 adverse event, but just one had to permanently stop treatment because of toxicity.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E–mutated biliary tract cancers treated with the combination of BRAF and MEK inhibition. Efficacy in this patient population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” pointed out Dr. Wainberg, codirector of the GI oncology program and an assistant professor of medicine at the University of California, Los Angeles.
“Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancers and should be considered a meaningful therapeutic option for these patients,” he contended. “BRAF V600E is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with biliary tract cancers. In addition, among all the other data [that are] emerging in molecular analysis of this malignancy, perhaps among all the GI malignancies, this has the potential to undergo multiple studies of other targeted therapies.”
Why stop there?
“I don’t think there is anything needed to convince you that this treatment is very effective. It’s incredibly impressive,” commented invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the gastrointestinal cancers program, University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
But experience with other BRAF-mutant malignancies, such as BRAF-mutant colorectal cancer, suggests that further benefit can accrue from hitting additional molecular targets, he said. For example, rationally selected triplet combinations can suppress emergence of resistant clones up front.
“How can we do even better? I think we need to be smart in how we inhibit downstream signaling of BRAF-mutant disease,” Dr. Lenz maintained, as downstream targeting is potentially more effective. Therefore, a logical candidate for improving on the combination of BRAF and MEK inhibitors in biliary tract cancer is an ERK inhibitor. Alternatively, the combination may be synergistic when used with immune checkpoint inhibitors that target programmed death-1 or programmed death–ligand 1.
Oncologists should perform next-generation sequencing for all patients with biliary tract cancer, in Dr. Lenz’s opinion. “Biliary cancer is one of these cancers where we have many potentially actionable mutations. I know there is no drug approved, but many trials are ongoing,” he elaborated. “So I just encourage you to do that in order to identify potential trials or treatment options.”
Study details
In the ROAR trial, patients received open-label dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) until unacceptable toxicity, disease progression, or death.
All 35 patients with biliary cancer had received gemcitabine, and 80% had received at least two lines of prior systemic therapy.
The median treatment duration was 6 months, Dr. Wainberg 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. Fully 86% of patients were on treatment for longer than 3 months.
In addition to the impressive response rates, the patients had a median progression-free survival of 9.2 months, and a median overall survival of 11.7 months.
Adverse events were as expected based on previous experience with these targeted therapies, according to Dr. Wainberg. The rate of grade 3 or 4 adverse events was 57%. “These were predominantly pyrexia, a known side effect of BRAF inhibitors, which is managed with antipyretic therapy and dexamethasone,” he noted. Rash and gastrointestinal toxicity were also common.
Although adverse events often led to dose reductions and dose interruptions, only a single patient (3% of the cohort) had to stop treatment early because of an event (cholangitis).
SOURCE: Wainberg ZA et al. 2019 GI Cancers Symposium, Abstract 187.
SAN FRANCISCO – Simultaneously targeting two components of the same signaling pathway in BRAF V600E–mutated biliary tract cancer is a winning strategy, suggests an analysis of the multicenter phase 2 ROAR basket trial.
“Recently, a number of genetic targets have been identified with distinct rates of frequency in intrahepatic, extrahepatic, and gallbladder cancer that are the subject of a number of ongoing clinical trials. In retrospective studies, mutations in BRAF have been identified in about 5%-7% of patients, predominantly in the intrahepatic cohort,” lead investigator Zev A. Wainberg, MD, noted at the 2019 GI Cancers Symposium. Previous research has shown combined inhibition of BRAF and MEK – two sequential proteins on the MAP kinase signaling pathway – to be efficacious in BRAF V600E–mutated melanoma, non–small cell lung cancer, and anaplastic thyroid cancer.
In the ROAR trial, 178 patients with advanced or metastatic BRAF V600E–mutated rare cancers who had exhausted standard treatment options were treated with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Dr. Wainberg reported results for the 35 patients having biliary tract cancer, most of whom were heavily pretreated.
With a median duration of follow-up of 8 months, the overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers. More than half of patients had a grade 3 or 4 adverse event, but just one had to permanently stop treatment because of toxicity.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E–mutated biliary tract cancers treated with the combination of BRAF and MEK inhibition. Efficacy in this patient population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” pointed out Dr. Wainberg, codirector of the GI oncology program and an assistant professor of medicine at the University of California, Los Angeles.
“Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancers and should be considered a meaningful therapeutic option for these patients,” he contended. “BRAF V600E is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with biliary tract cancers. In addition, among all the other data [that are] emerging in molecular analysis of this malignancy, perhaps among all the GI malignancies, this has the potential to undergo multiple studies of other targeted therapies.”
Why stop there?
“I don’t think there is anything needed to convince you that this treatment is very effective. It’s incredibly impressive,” commented invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the gastrointestinal cancers program, University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
But experience with other BRAF-mutant malignancies, such as BRAF-mutant colorectal cancer, suggests that further benefit can accrue from hitting additional molecular targets, he said. For example, rationally selected triplet combinations can suppress emergence of resistant clones up front.
“How can we do even better? I think we need to be smart in how we inhibit downstream signaling of BRAF-mutant disease,” Dr. Lenz maintained, as downstream targeting is potentially more effective. Therefore, a logical candidate for improving on the combination of BRAF and MEK inhibitors in biliary tract cancer is an ERK inhibitor. Alternatively, the combination may be synergistic when used with immune checkpoint inhibitors that target programmed death-1 or programmed death–ligand 1.
Oncologists should perform next-generation sequencing for all patients with biliary tract cancer, in Dr. Lenz’s opinion. “Biliary cancer is one of these cancers where we have many potentially actionable mutations. I know there is no drug approved, but many trials are ongoing,” he elaborated. “So I just encourage you to do that in order to identify potential trials or treatment options.”
Study details
In the ROAR trial, patients received open-label dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) until unacceptable toxicity, disease progression, or death.
All 35 patients with biliary cancer had received gemcitabine, and 80% had received at least two lines of prior systemic therapy.
The median treatment duration was 6 months, Dr. Wainberg 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. Fully 86% of patients were on treatment for longer than 3 months.
In addition to the impressive response rates, the patients had a median progression-free survival of 9.2 months, and a median overall survival of 11.7 months.
Adverse events were as expected based on previous experience with these targeted therapies, according to Dr. Wainberg. The rate of grade 3 or 4 adverse events was 57%. “These were predominantly pyrexia, a known side effect of BRAF inhibitors, which is managed with antipyretic therapy and dexamethasone,” he noted. Rash and gastrointestinal toxicity were also common.
Although adverse events often led to dose reductions and dose interruptions, only a single patient (3% of the cohort) had to stop treatment early because of an event (cholangitis).
SOURCE: Wainberg ZA et al. 2019 GI Cancers Symposium, Abstract 187.
SAN FRANCISCO – Simultaneously targeting two components of the same signaling pathway in BRAF V600E–mutated biliary tract cancer is a winning strategy, suggests an analysis of the multicenter phase 2 ROAR basket trial.
“Recently, a number of genetic targets have been identified with distinct rates of frequency in intrahepatic, extrahepatic, and gallbladder cancer that are the subject of a number of ongoing clinical trials. In retrospective studies, mutations in BRAF have been identified in about 5%-7% of patients, predominantly in the intrahepatic cohort,” lead investigator Zev A. Wainberg, MD, noted at the 2019 GI Cancers Symposium. Previous research has shown combined inhibition of BRAF and MEK – two sequential proteins on the MAP kinase signaling pathway – to be efficacious in BRAF V600E–mutated melanoma, non–small cell lung cancer, and anaplastic thyroid cancer.
In the ROAR trial, 178 patients with advanced or metastatic BRAF V600E–mutated rare cancers who had exhausted standard treatment options were treated with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Dr. Wainberg reported results for the 35 patients having biliary tract cancer, most of whom were heavily pretreated.
With a median duration of follow-up of 8 months, the overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers. More than half of patients had a grade 3 or 4 adverse event, but just one had to permanently stop treatment because of toxicity.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E–mutated biliary tract cancers treated with the combination of BRAF and MEK inhibition. Efficacy in this patient population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” pointed out Dr. Wainberg, codirector of the GI oncology program and an assistant professor of medicine at the University of California, Los Angeles.
“Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancers and should be considered a meaningful therapeutic option for these patients,” he contended. “BRAF V600E is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with biliary tract cancers. In addition, among all the other data [that are] emerging in molecular analysis of this malignancy, perhaps among all the GI malignancies, this has the potential to undergo multiple studies of other targeted therapies.”
Why stop there?
“I don’t think there is anything needed to convince you that this treatment is very effective. It’s incredibly impressive,” commented invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the gastrointestinal cancers program, University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
But experience with other BRAF-mutant malignancies, such as BRAF-mutant colorectal cancer, suggests that further benefit can accrue from hitting additional molecular targets, he said. For example, rationally selected triplet combinations can suppress emergence of resistant clones up front.
“How can we do even better? I think we need to be smart in how we inhibit downstream signaling of BRAF-mutant disease,” Dr. Lenz maintained, as downstream targeting is potentially more effective. Therefore, a logical candidate for improving on the combination of BRAF and MEK inhibitors in biliary tract cancer is an ERK inhibitor. Alternatively, the combination may be synergistic when used with immune checkpoint inhibitors that target programmed death-1 or programmed death–ligand 1.
Oncologists should perform next-generation sequencing for all patients with biliary tract cancer, in Dr. Lenz’s opinion. “Biliary cancer is one of these cancers where we have many potentially actionable mutations. I know there is no drug approved, but many trials are ongoing,” he elaborated. “So I just encourage you to do that in order to identify potential trials or treatment options.”
Study details
In the ROAR trial, patients received open-label dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) until unacceptable toxicity, disease progression, or death.
All 35 patients with biliary cancer had received gemcitabine, and 80% had received at least two lines of prior systemic therapy.
The median treatment duration was 6 months, Dr. Wainberg 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. Fully 86% of patients were on treatment for longer than 3 months.
In addition to the impressive response rates, the patients had a median progression-free survival of 9.2 months, and a median overall survival of 11.7 months.
Adverse events were as expected based on previous experience with these targeted therapies, according to Dr. Wainberg. The rate of grade 3 or 4 adverse events was 57%. “These were predominantly pyrexia, a known side effect of BRAF inhibitors, which is managed with antipyretic therapy and dexamethasone,” he noted. Rash and gastrointestinal toxicity were also common.
Although adverse events often led to dose reductions and dose interruptions, only a single patient (3% of the cohort) had to stop treatment early because of an event (cholangitis).
SOURCE: Wainberg ZA et al. 2019 GI Cancers Symposium, Abstract 187.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: The overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers.
Study details: A multicenter, single-arm, open-label phase 2 basket trial with reporting of data for 35 patients having BRAF V600E–mutated biliary tract cancer (ROAR trial).
Disclosures: Dr. Wainberg disclosed that he has a consulting or advisory role with and receives research funding from numerous pharmaceutical companies including Novartis. The trial was sponsored by GlaxoSmithKline and Novartis.
Source: Wainberg ZA et al. GI Cancers Symposium, Abstract 187.
mRECIST response to kinase inhibitors predicts survival in HCC
SAN FRANCISCO – Patients with hepatocellular carcinoma (HCC) who have a response to first-line kinase inhibitors based on modified RECIST (mRECIST) criteria live almost a year longer than counterparts who have stable or progressive disease, finds a retrospective post hoc analysis of the REFLECT trial.
“The inability to accurately evaluate response to targeted or locoregional therapies resulted in the adaptation of RECIST to mRECIST, guidelines specifically designed to evaluate response to treatment in HCC,” noted lead investigator Masatoshi Kudo, MD, PhD, of the department of gastroenterology and hepatology, Kindai University Faculty of Medicine, Osaka, Japan. “Based on recommendations from the EASL [European Association for the Study of the Liver] consensus conference in 2000, mRECIST was developed to assess response based on the reduction of viable tumor burden … rather than overall tumor shrinkage. However, EASL clinical practice guidelines also suggested additional studies are needed to validate this approach.”
The investigators analyzed data from REFLECT, a global phase 3 noninferiority, randomized, controlled trial that showed overall survival with the novel kinase inhibitor lenvatinib (Lenvima) was not inferior to that with the older kinase inhibitor sorafenib (Nexavar) in 954 patients with untreated, unresectable HCC (Lancet. 2018;391:1163-73).
The new analysis, reported at the 2019 GI Cancers Symposium, showed that, among all randomized patients, those having an objective response according to mRECIST criteria were 39% less likely to die after other factors were taken into account. The finding was consistent in a landmark analysis, which addresses the issue of lead-time bias.
“Objective response by mRECIST was an independent predictor of overall survival in patients with HCC regardless of treatment,” Dr. Kudo concluded, adding that the findings are consistent with those of several previous studies. “Thus, patients who achieve an objective response can potentially expect a longer overall survival. However, additional studies are needed to further validate the correlation between objective response and overall survival.”
Findings in context
Although the mRECIST criteria overcome some issues with the size-based RECIST criteria in assessing HCC, the former are not without their limitations, noted invited discussant Andrew X. Zhu, MD, PhD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
These limitations include, for example, the need for more stringent selection of target lesions and the potential for antiangiogenic agents to cause vasoconstriction, complicating measurement. “There is tremendous intraobserver and interobserver variability, and a tremendous learning curve,” he added, noting that in REFLECT the mRECIST overall response rate assessed by independent reviewers was considerably higher than that assessed by investigators.
To date, three other trials of targeted therapies have similarly found an association between mRECIST response and overall survival. But a fourth did not.
“In the era of immunotherapy being actively applied to HCC, it’s important to recognize that this association actually may be agent dependent,” Dr. Zhu said. “Even though the TKIs with antiangiogenic [activity] have shown an improved overall response [going] from RECIST to mRECIST, this has not been recapitulated, at least based on the current experience that we have, with checkpoint inhibitors.”
The REFLECT investigators’ conclusion “is certainly backed by the large dataset from a positive phase 3 trial. It has very sound statistical methodology, and it may actually provide the initial evidence that this biomarker may serve as a potentially relevant surrogate to predict overall survival,” he said.
At the same time, there is reason to be cautious given the post hoc, retrospective nature of the study; the lack of a comparison with conventional RECIST response; absence of analysis of the potential correlation of stable disease with overall survival; and the lumping together of two agents, among other issues.
“For these reasons, I do think additional studies are warranted for prospective validation of the findings,” Dr. Zhu concluded.
Study details
REFLECT patients had an investigator-assessed mRECIST objective response rate of 16.7% overall (24.1% with lenvatinib and 9.2% with sorafenib) and a median overall survival of 13.0 months (13.6 months with lenvatinib and 12.3 months with sorafenib).
Median overall survival was 22.4 months for mRECIST responders and 11.4 months for nonresponders (P less than .001), Dr. Kudo 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.
In a multivariate analysis, this difference translated to a 39% reduction in risk of death for responders (hazard ratio, 0.61; P less than .0001).
Moreover, the survival advantage of response was evident in landmark analyses, whether response was assessed at 2 months (HR, 0.75; P = .033), at 4 months (HR, 0.72; P = .009), or at 6 months (HR, 0.73; P = .010).
Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 186.
SAN FRANCISCO – Patients with hepatocellular carcinoma (HCC) who have a response to first-line kinase inhibitors based on modified RECIST (mRECIST) criteria live almost a year longer than counterparts who have stable or progressive disease, finds a retrospective post hoc analysis of the REFLECT trial.
“The inability to accurately evaluate response to targeted or locoregional therapies resulted in the adaptation of RECIST to mRECIST, guidelines specifically designed to evaluate response to treatment in HCC,” noted lead investigator Masatoshi Kudo, MD, PhD, of the department of gastroenterology and hepatology, Kindai University Faculty of Medicine, Osaka, Japan. “Based on recommendations from the EASL [European Association for the Study of the Liver] consensus conference in 2000, mRECIST was developed to assess response based on the reduction of viable tumor burden … rather than overall tumor shrinkage. However, EASL clinical practice guidelines also suggested additional studies are needed to validate this approach.”
The investigators analyzed data from REFLECT, a global phase 3 noninferiority, randomized, controlled trial that showed overall survival with the novel kinase inhibitor lenvatinib (Lenvima) was not inferior to that with the older kinase inhibitor sorafenib (Nexavar) in 954 patients with untreated, unresectable HCC (Lancet. 2018;391:1163-73).
The new analysis, reported at the 2019 GI Cancers Symposium, showed that, among all randomized patients, those having an objective response according to mRECIST criteria were 39% less likely to die after other factors were taken into account. The finding was consistent in a landmark analysis, which addresses the issue of lead-time bias.
“Objective response by mRECIST was an independent predictor of overall survival in patients with HCC regardless of treatment,” Dr. Kudo concluded, adding that the findings are consistent with those of several previous studies. “Thus, patients who achieve an objective response can potentially expect a longer overall survival. However, additional studies are needed to further validate the correlation between objective response and overall survival.”
Findings in context
Although the mRECIST criteria overcome some issues with the size-based RECIST criteria in assessing HCC, the former are not without their limitations, noted invited discussant Andrew X. Zhu, MD, PhD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
These limitations include, for example, the need for more stringent selection of target lesions and the potential for antiangiogenic agents to cause vasoconstriction, complicating measurement. “There is tremendous intraobserver and interobserver variability, and a tremendous learning curve,” he added, noting that in REFLECT the mRECIST overall response rate assessed by independent reviewers was considerably higher than that assessed by investigators.
To date, three other trials of targeted therapies have similarly found an association between mRECIST response and overall survival. But a fourth did not.
“In the era of immunotherapy being actively applied to HCC, it’s important to recognize that this association actually may be agent dependent,” Dr. Zhu said. “Even though the TKIs with antiangiogenic [activity] have shown an improved overall response [going] from RECIST to mRECIST, this has not been recapitulated, at least based on the current experience that we have, with checkpoint inhibitors.”
The REFLECT investigators’ conclusion “is certainly backed by the large dataset from a positive phase 3 trial. It has very sound statistical methodology, and it may actually provide the initial evidence that this biomarker may serve as a potentially relevant surrogate to predict overall survival,” he said.
At the same time, there is reason to be cautious given the post hoc, retrospective nature of the study; the lack of a comparison with conventional RECIST response; absence of analysis of the potential correlation of stable disease with overall survival; and the lumping together of two agents, among other issues.
“For these reasons, I do think additional studies are warranted for prospective validation of the findings,” Dr. Zhu concluded.
Study details
REFLECT patients had an investigator-assessed mRECIST objective response rate of 16.7% overall (24.1% with lenvatinib and 9.2% with sorafenib) and a median overall survival of 13.0 months (13.6 months with lenvatinib and 12.3 months with sorafenib).
Median overall survival was 22.4 months for mRECIST responders and 11.4 months for nonresponders (P less than .001), Dr. Kudo 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.
In a multivariate analysis, this difference translated to a 39% reduction in risk of death for responders (hazard ratio, 0.61; P less than .0001).
Moreover, the survival advantage of response was evident in landmark analyses, whether response was assessed at 2 months (HR, 0.75; P = .033), at 4 months (HR, 0.72; P = .009), or at 6 months (HR, 0.73; P = .010).
Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 186.
SAN FRANCISCO – Patients with hepatocellular carcinoma (HCC) who have a response to first-line kinase inhibitors based on modified RECIST (mRECIST) criteria live almost a year longer than counterparts who have stable or progressive disease, finds a retrospective post hoc analysis of the REFLECT trial.
“The inability to accurately evaluate response to targeted or locoregional therapies resulted in the adaptation of RECIST to mRECIST, guidelines specifically designed to evaluate response to treatment in HCC,” noted lead investigator Masatoshi Kudo, MD, PhD, of the department of gastroenterology and hepatology, Kindai University Faculty of Medicine, Osaka, Japan. “Based on recommendations from the EASL [European Association for the Study of the Liver] consensus conference in 2000, mRECIST was developed to assess response based on the reduction of viable tumor burden … rather than overall tumor shrinkage. However, EASL clinical practice guidelines also suggested additional studies are needed to validate this approach.”
The investigators analyzed data from REFLECT, a global phase 3 noninferiority, randomized, controlled trial that showed overall survival with the novel kinase inhibitor lenvatinib (Lenvima) was not inferior to that with the older kinase inhibitor sorafenib (Nexavar) in 954 patients with untreated, unresectable HCC (Lancet. 2018;391:1163-73).
The new analysis, reported at the 2019 GI Cancers Symposium, showed that, among all randomized patients, those having an objective response according to mRECIST criteria were 39% less likely to die after other factors were taken into account. The finding was consistent in a landmark analysis, which addresses the issue of lead-time bias.
“Objective response by mRECIST was an independent predictor of overall survival in patients with HCC regardless of treatment,” Dr. Kudo concluded, adding that the findings are consistent with those of several previous studies. “Thus, patients who achieve an objective response can potentially expect a longer overall survival. However, additional studies are needed to further validate the correlation between objective response and overall survival.”
Findings in context
Although the mRECIST criteria overcome some issues with the size-based RECIST criteria in assessing HCC, the former are not without their limitations, noted invited discussant Andrew X. Zhu, MD, PhD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
These limitations include, for example, the need for more stringent selection of target lesions and the potential for antiangiogenic agents to cause vasoconstriction, complicating measurement. “There is tremendous intraobserver and interobserver variability, and a tremendous learning curve,” he added, noting that in REFLECT the mRECIST overall response rate assessed by independent reviewers was considerably higher than that assessed by investigators.
To date, three other trials of targeted therapies have similarly found an association between mRECIST response and overall survival. But a fourth did not.
“In the era of immunotherapy being actively applied to HCC, it’s important to recognize that this association actually may be agent dependent,” Dr. Zhu said. “Even though the TKIs with antiangiogenic [activity] have shown an improved overall response [going] from RECIST to mRECIST, this has not been recapitulated, at least based on the current experience that we have, with checkpoint inhibitors.”
The REFLECT investigators’ conclusion “is certainly backed by the large dataset from a positive phase 3 trial. It has very sound statistical methodology, and it may actually provide the initial evidence that this biomarker may serve as a potentially relevant surrogate to predict overall survival,” he said.
At the same time, there is reason to be cautious given the post hoc, retrospective nature of the study; the lack of a comparison with conventional RECIST response; absence of analysis of the potential correlation of stable disease with overall survival; and the lumping together of two agents, among other issues.
“For these reasons, I do think additional studies are warranted for prospective validation of the findings,” Dr. Zhu concluded.
Study details
REFLECT patients had an investigator-assessed mRECIST objective response rate of 16.7% overall (24.1% with lenvatinib and 9.2% with sorafenib) and a median overall survival of 13.0 months (13.6 months with lenvatinib and 12.3 months with sorafenib).
Median overall survival was 22.4 months for mRECIST responders and 11.4 months for nonresponders (P less than .001), Dr. Kudo 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.
In a multivariate analysis, this difference translated to a 39% reduction in risk of death for responders (hazard ratio, 0.61; P less than .0001).
Moreover, the survival advantage of response was evident in landmark analyses, whether response was assessed at 2 months (HR, 0.75; P = .033), at 4 months (HR, 0.72; P = .009), or at 6 months (HR, 0.73; P = .010).
Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 186.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: .
Major finding: Median overall survival was a respective 22.4 months and 11.4 months in patients who did and did not have a response according to mRECIST criteria (HR, 0.61; P less than .0001).
Study details: A retrospective post hoc analysis of a phase 3 randomized controlled trial of lenvatinib versus sorafenib among 954 patients with untreated, unresectable HCC (REFLECT trial).
Disclosures: Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
Source: Kudo M et al. 2019 GI Cancers Symposium, Abstract 186.
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.
Age may dictate benefit of andecaliximab in gastric cancer
SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”
Study details
Patients in GAMMA-1 were randomized evenly to receive the mFOLFOX-6 regimen plus either placebo or andecaliximab given intravenously every 2 weeks.
Median overall survival, the primary outcome, was 12.5 months with the antibody and 11.8 months with placebo, a nonsignificant difference (hazard ratio, 0.93; P = .56), Dr. Shah reported at the symposium, which 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.
However, exploratory analyses showed benefit increased with quartile of age, and the difference in overall survival was significant for those 65 years and older at 13.9 months versus 10.5 months (HR, 0.64; P = .029).
The pattern was similar for progression-free survival, with only a trend among all patients (7.5 vs. 7.1 months; HR, 0.84; P = .10) but a significant reduction in risk for the older subgroup (8.7 vs 5.6 months; HR, 0.5; P less than .001).
Overall response rate was better with andecaliximab than with placebo in the entire trial population (51% vs. 41%; odds ratio, 1.47; P = .049). The rate of complete response was 8.3% and 4.7%, respectively.
“There were no meaningful differences in the safety profile of andecaliximab versus placebo in the groups treated,” Dr. Shah said. Rates and types of treatment-emergent adverse events of any grade and of grade 3 or higher were similar, with gastrointestinal and hematologic events predominating.
“We were intrigued with this phenomenon by age,” he said, and the investigators therefore assessed factors differing by age. “We looked at chemotherapy treatment and toxicity, things like that, and it didn’t appear that we could find any factor that was really associated. We did find that older patients actually received more treatment, but that’s likely because they had somewhat of a benefit with andecaliximab.”
Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
SOURCE: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
This article was updated 1/24/19.
SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”
Study details
Patients in GAMMA-1 were randomized evenly to receive the mFOLFOX-6 regimen plus either placebo or andecaliximab given intravenously every 2 weeks.
Median overall survival, the primary outcome, was 12.5 months with the antibody and 11.8 months with placebo, a nonsignificant difference (hazard ratio, 0.93; P = .56), Dr. Shah reported at the symposium, which 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.
However, exploratory analyses showed benefit increased with quartile of age, and the difference in overall survival was significant for those 65 years and older at 13.9 months versus 10.5 months (HR, 0.64; P = .029).
The pattern was similar for progression-free survival, with only a trend among all patients (7.5 vs. 7.1 months; HR, 0.84; P = .10) but a significant reduction in risk for the older subgroup (8.7 vs 5.6 months; HR, 0.5; P less than .001).
Overall response rate was better with andecaliximab than with placebo in the entire trial population (51% vs. 41%; odds ratio, 1.47; P = .049). The rate of complete response was 8.3% and 4.7%, respectively.
“There were no meaningful differences in the safety profile of andecaliximab versus placebo in the groups treated,” Dr. Shah said. Rates and types of treatment-emergent adverse events of any grade and of grade 3 or higher were similar, with gastrointestinal and hematologic events predominating.
“We were intrigued with this phenomenon by age,” he said, and the investigators therefore assessed factors differing by age. “We looked at chemotherapy treatment and toxicity, things like that, and it didn’t appear that we could find any factor that was really associated. We did find that older patients actually received more treatment, but that’s likely because they had somewhat of a benefit with andecaliximab.”
Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
SOURCE: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
This article was updated 1/24/19.
SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”
Study details
Patients in GAMMA-1 were randomized evenly to receive the mFOLFOX-6 regimen plus either placebo or andecaliximab given intravenously every 2 weeks.
Median overall survival, the primary outcome, was 12.5 months with the antibody and 11.8 months with placebo, a nonsignificant difference (hazard ratio, 0.93; P = .56), Dr. Shah reported at the symposium, which 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.
However, exploratory analyses showed benefit increased with quartile of age, and the difference in overall survival was significant for those 65 years and older at 13.9 months versus 10.5 months (HR, 0.64; P = .029).
The pattern was similar for progression-free survival, with only a trend among all patients (7.5 vs. 7.1 months; HR, 0.84; P = .10) but a significant reduction in risk for the older subgroup (8.7 vs 5.6 months; HR, 0.5; P less than .001).
Overall response rate was better with andecaliximab than with placebo in the entire trial population (51% vs. 41%; odds ratio, 1.47; P = .049). The rate of complete response was 8.3% and 4.7%, respectively.
“There were no meaningful differences in the safety profile of andecaliximab versus placebo in the groups treated,” Dr. Shah said. Rates and types of treatment-emergent adverse events of any grade and of grade 3 or higher were similar, with gastrointestinal and hematologic events predominating.
“We were intrigued with this phenomenon by age,” he said, and the investigators therefore assessed factors differing by age. “We looked at chemotherapy treatment and toxicity, things like that, and it didn’t appear that we could find any factor that was really associated. We did find that older patients actually received more treatment, but that’s likely because they had somewhat of a benefit with andecaliximab.”
Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
SOURCE: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
This article was updated 1/24/19.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Benefit of first-line andecaliximab in advanced gastric/gastroesophageal junction cancer may be age dependent.
Major finding: Compared with placebo plus mFOLFOX-6, andecaliximab plus mFOLFOX-6 did not improve overall survival among all patients, but it did among those aged 65 years and older in exploratory analyses (hazard ratio, 0.64; P = .029).
Study details: A phase 3, randomized, controlled trial among 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (GAMMA-1 trial).
Disclosures: Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck (institutional), and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
Source: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
COLOPEC: Adjuvant HIPEC for high-risk colon cancer disappoints
SAN FRANCISCO – according to primary results of the Dutch COLOPEC trial presented at the 2019 GI Cancers Symposium.
“Despite adjuvant systemic chemotherapy, locally advanced stage II and stage III colon cancer can give rise to metachronous peritoneal metastases in up to 25% of patients,” commented principal investigator Pieter J. Tanis, MD, PhD, a colorectal surgeon at the Academic Medical Center in Amsterdam. “These metastases are very difficult to detect, and when you detect them, they are difficult to treat.”
The 202 patients in COLOPEC, a multicenter, phase 3, randomized, controlled trial, underwent curative resection of primary colon tumors that were large (pT4 or cT4) or perforated, putting them at high risk for peritoneal metastases. All received routine adjuvant systemic chemotherapy.
At 18 months, the proportion of patients alive and free of peritoneal recurrence, assessed by laparoscopy, was 81% with addition of early postoperative oxaliplatin HIPEC and 76% without it, a nonsignificant difference.
“We couldn’t find any superiority of adjuvant HIPEC with oxaliplatin regarding peritoneal metastases–free survival in patients with T4 or perforated colon cancer,” Dr. Tanis summarized.
“We had a problem with the intention-to-treat analysis because 9% of patients already had recurrences before we performed the adjuvant HIPEC,” he added. “But I think we cannot perform an as-treated analysis in this trial because we don’t know the early recurrences in the control group.”
A symposium attendee wondered if the longer time to receiving systemic adjuvant systemic chemotherapy in the HIPEC group, a delay of about 4 weeks relative to the no-HIPEC group, was problematic and warranted consideration of neoadjuvant chemotherapy instead.
“The problem of the delay in chemotherapy, if you look in the literature, is there is no randomized trial looking at, for example, an 8- versus 12-week interval,” Dr. Tanis replied, noting that, in studies, adjuvant chemotherapy has most commonly been delayed because of patient comorbidities or surgical complications. “But you have to look very carefully at the expectation of the direct association between delay of chemotherapy and an effect. We have already looked at the disease-free survival and overall survival [in COLOPEC] and have not seen any difference … now at 23 months of follow-up,” he said.
End of the line for HIPEC?
Invited discussant Elin. R. Sigurdson, MD, PhD, a professor in the department of surgical oncology at the Fox Chase Cancer Center, Philadelphia, framed her discussion by drawing on the words of emeritus surgeon Blake Cady, MD. “ ‘In the world of surgical oncology, biology is the King, selection of cases is Queen, and the technical aspects of the surgical procedures are the Princes and Princesses who frequently try to overthrow the King and the Queen.’ ”
Staging systems, such as the Peritoneal Carcinomatosis Index, have improved patient selection. “It’s obviously very critical to assess these patients appropriately at the time of surgery, and that has influenced this study,” she maintained. “The very early recurrences I think fall into the lap of the surgeons.”
Trials in established disease have helped sort out the roles of tumor debulking and HIPEC. “In our attempt to overcome the biology of this disease, we can see that, in most of these studies, the debulking-only arm did much better than we would have thought. But controversies remain regarding both the duration of the HIPEC and the chemotherapy that we use,” Dr. Sigurdson commented. “Perhaps, as we move forward, more questions will be addressed in the near future as there are ongoing clinical trials both on our side and the European side.”
Symposium attendee Alan P. Venook, MD, of the University of California, San Francisco, noted that there have been three negative clinical trials of HIPEC in the last 3 years. “Is that enough to say enough, or do we still need to study the role of HIPEC in these patients?” he asked.
“The issue becomes, are there new possibilities in the way of new drugs in order to carry on?” Dr. Sigurdson replied. Also, “it clearly has been a learning curve in doing HIPEC, and we have failed to recognize how impactful the surgical part of HIPEC has been.”
“The trials shown today from Europe are the best-designed trials that we have, and I agree, yes, the negative trials are discouraging,” she elaborated. “But if there were drugs where the therapeutic index of giving them intraperitoneally would be beneficial, then it would be useful because it has worked in ovarian cancer, it has worked in other cancers. So hope remains. But I would argue that, in the absence of new drugs, we are getting to the point that repeating the clinical trials with those [same] drugs is not going to be positive.”
Study details
In COLOPEC, adjuvant HIPEC consisted of 30 minutes of intraperitoneal oxaliplatin plus intravenous 5-fluoruracil and leucovorin, Dr. Tanis reported at the symposium, which 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.
HIPEC was usually performed 5-8 weeks after resection (91%) and laparoscopically (71%). Almost a fifth of patients were found to have extensive adhesions, making the procedure more difficult.
The rate of postoperative complications was 88% in the small number of patients having HIPEC at the time of resection, but only 6% in those having it 5-8 weeks after resection. A single patient developed encapsulating peritoneal sclerosis 8 months after HIPEC, requiring parenteral nutrition and surgery.
Patients in the HIPEC and control groups were similarly likely to receive adjuvant systemic chemotherapy (84% vs. 89%, P = .385), but the former had a longer time before starting this therapy (10.2 vs. 6.4 weeks, P less than .001).
Relative to counterparts in the control group, patients in the HIPEC group had a 14% reduction in risk of peritoneal recurrence or death at 18 months, but the difference was not significant (hazard ratio, 0.86; 95% confidence interval, 0.51-1.54). Findings were similar across a variety of subgroups.
In both trial groups, about two-thirds of patients in whom peritoneal metastases were detected underwent cytoreductive surgery and/or (additional) HIPEC to treat them.
“Overall, 21% of patients had peritoneal metastases detected after 23 months of follow-up, demonstrating the magnitude of this clinical problem,” noted Dr. Tanis, who reported that he had no relevant disclosures. The trial was sponsored by the Academic Medical Center, University of Amsterdam.
SOURCE: Tanis PJ et al. GI Cancers Symposium 2019, Abstract 482.
SAN FRANCISCO – according to primary results of the Dutch COLOPEC trial presented at the 2019 GI Cancers Symposium.
“Despite adjuvant systemic chemotherapy, locally advanced stage II and stage III colon cancer can give rise to metachronous peritoneal metastases in up to 25% of patients,” commented principal investigator Pieter J. Tanis, MD, PhD, a colorectal surgeon at the Academic Medical Center in Amsterdam. “These metastases are very difficult to detect, and when you detect them, they are difficult to treat.”
The 202 patients in COLOPEC, a multicenter, phase 3, randomized, controlled trial, underwent curative resection of primary colon tumors that were large (pT4 or cT4) or perforated, putting them at high risk for peritoneal metastases. All received routine adjuvant systemic chemotherapy.
At 18 months, the proportion of patients alive and free of peritoneal recurrence, assessed by laparoscopy, was 81% with addition of early postoperative oxaliplatin HIPEC and 76% without it, a nonsignificant difference.
“We couldn’t find any superiority of adjuvant HIPEC with oxaliplatin regarding peritoneal metastases–free survival in patients with T4 or perforated colon cancer,” Dr. Tanis summarized.
“We had a problem with the intention-to-treat analysis because 9% of patients already had recurrences before we performed the adjuvant HIPEC,” he added. “But I think we cannot perform an as-treated analysis in this trial because we don’t know the early recurrences in the control group.”
A symposium attendee wondered if the longer time to receiving systemic adjuvant systemic chemotherapy in the HIPEC group, a delay of about 4 weeks relative to the no-HIPEC group, was problematic and warranted consideration of neoadjuvant chemotherapy instead.
“The problem of the delay in chemotherapy, if you look in the literature, is there is no randomized trial looking at, for example, an 8- versus 12-week interval,” Dr. Tanis replied, noting that, in studies, adjuvant chemotherapy has most commonly been delayed because of patient comorbidities or surgical complications. “But you have to look very carefully at the expectation of the direct association between delay of chemotherapy and an effect. We have already looked at the disease-free survival and overall survival [in COLOPEC] and have not seen any difference … now at 23 months of follow-up,” he said.
End of the line for HIPEC?
Invited discussant Elin. R. Sigurdson, MD, PhD, a professor in the department of surgical oncology at the Fox Chase Cancer Center, Philadelphia, framed her discussion by drawing on the words of emeritus surgeon Blake Cady, MD. “ ‘In the world of surgical oncology, biology is the King, selection of cases is Queen, and the technical aspects of the surgical procedures are the Princes and Princesses who frequently try to overthrow the King and the Queen.’ ”
Staging systems, such as the Peritoneal Carcinomatosis Index, have improved patient selection. “It’s obviously very critical to assess these patients appropriately at the time of surgery, and that has influenced this study,” she maintained. “The very early recurrences I think fall into the lap of the surgeons.”
Trials in established disease have helped sort out the roles of tumor debulking and HIPEC. “In our attempt to overcome the biology of this disease, we can see that, in most of these studies, the debulking-only arm did much better than we would have thought. But controversies remain regarding both the duration of the HIPEC and the chemotherapy that we use,” Dr. Sigurdson commented. “Perhaps, as we move forward, more questions will be addressed in the near future as there are ongoing clinical trials both on our side and the European side.”
Symposium attendee Alan P. Venook, MD, of the University of California, San Francisco, noted that there have been three negative clinical trials of HIPEC in the last 3 years. “Is that enough to say enough, or do we still need to study the role of HIPEC in these patients?” he asked.
“The issue becomes, are there new possibilities in the way of new drugs in order to carry on?” Dr. Sigurdson replied. Also, “it clearly has been a learning curve in doing HIPEC, and we have failed to recognize how impactful the surgical part of HIPEC has been.”
“The trials shown today from Europe are the best-designed trials that we have, and I agree, yes, the negative trials are discouraging,” she elaborated. “But if there were drugs where the therapeutic index of giving them intraperitoneally would be beneficial, then it would be useful because it has worked in ovarian cancer, it has worked in other cancers. So hope remains. But I would argue that, in the absence of new drugs, we are getting to the point that repeating the clinical trials with those [same] drugs is not going to be positive.”
Study details
In COLOPEC, adjuvant HIPEC consisted of 30 minutes of intraperitoneal oxaliplatin plus intravenous 5-fluoruracil and leucovorin, Dr. Tanis reported at the symposium, which 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.
HIPEC was usually performed 5-8 weeks after resection (91%) and laparoscopically (71%). Almost a fifth of patients were found to have extensive adhesions, making the procedure more difficult.
The rate of postoperative complications was 88% in the small number of patients having HIPEC at the time of resection, but only 6% in those having it 5-8 weeks after resection. A single patient developed encapsulating peritoneal sclerosis 8 months after HIPEC, requiring parenteral nutrition and surgery.
Patients in the HIPEC and control groups were similarly likely to receive adjuvant systemic chemotherapy (84% vs. 89%, P = .385), but the former had a longer time before starting this therapy (10.2 vs. 6.4 weeks, P less than .001).
Relative to counterparts in the control group, patients in the HIPEC group had a 14% reduction in risk of peritoneal recurrence or death at 18 months, but the difference was not significant (hazard ratio, 0.86; 95% confidence interval, 0.51-1.54). Findings were similar across a variety of subgroups.
In both trial groups, about two-thirds of patients in whom peritoneal metastases were detected underwent cytoreductive surgery and/or (additional) HIPEC to treat them.
“Overall, 21% of patients had peritoneal metastases detected after 23 months of follow-up, demonstrating the magnitude of this clinical problem,” noted Dr. Tanis, who reported that he had no relevant disclosures. The trial was sponsored by the Academic Medical Center, University of Amsterdam.
SOURCE: Tanis PJ et al. GI Cancers Symposium 2019, Abstract 482.
SAN FRANCISCO – according to primary results of the Dutch COLOPEC trial presented at the 2019 GI Cancers Symposium.
“Despite adjuvant systemic chemotherapy, locally advanced stage II and stage III colon cancer can give rise to metachronous peritoneal metastases in up to 25% of patients,” commented principal investigator Pieter J. Tanis, MD, PhD, a colorectal surgeon at the Academic Medical Center in Amsterdam. “These metastases are very difficult to detect, and when you detect them, they are difficult to treat.”
The 202 patients in COLOPEC, a multicenter, phase 3, randomized, controlled trial, underwent curative resection of primary colon tumors that were large (pT4 or cT4) or perforated, putting them at high risk for peritoneal metastases. All received routine adjuvant systemic chemotherapy.
At 18 months, the proportion of patients alive and free of peritoneal recurrence, assessed by laparoscopy, was 81% with addition of early postoperative oxaliplatin HIPEC and 76% without it, a nonsignificant difference.
“We couldn’t find any superiority of adjuvant HIPEC with oxaliplatin regarding peritoneal metastases–free survival in patients with T4 or perforated colon cancer,” Dr. Tanis summarized.
“We had a problem with the intention-to-treat analysis because 9% of patients already had recurrences before we performed the adjuvant HIPEC,” he added. “But I think we cannot perform an as-treated analysis in this trial because we don’t know the early recurrences in the control group.”
A symposium attendee wondered if the longer time to receiving systemic adjuvant systemic chemotherapy in the HIPEC group, a delay of about 4 weeks relative to the no-HIPEC group, was problematic and warranted consideration of neoadjuvant chemotherapy instead.
“The problem of the delay in chemotherapy, if you look in the literature, is there is no randomized trial looking at, for example, an 8- versus 12-week interval,” Dr. Tanis replied, noting that, in studies, adjuvant chemotherapy has most commonly been delayed because of patient comorbidities or surgical complications. “But you have to look very carefully at the expectation of the direct association between delay of chemotherapy and an effect. We have already looked at the disease-free survival and overall survival [in COLOPEC] and have not seen any difference … now at 23 months of follow-up,” he said.
End of the line for HIPEC?
Invited discussant Elin. R. Sigurdson, MD, PhD, a professor in the department of surgical oncology at the Fox Chase Cancer Center, Philadelphia, framed her discussion by drawing on the words of emeritus surgeon Blake Cady, MD. “ ‘In the world of surgical oncology, biology is the King, selection of cases is Queen, and the technical aspects of the surgical procedures are the Princes and Princesses who frequently try to overthrow the King and the Queen.’ ”
Staging systems, such as the Peritoneal Carcinomatosis Index, have improved patient selection. “It’s obviously very critical to assess these patients appropriately at the time of surgery, and that has influenced this study,” she maintained. “The very early recurrences I think fall into the lap of the surgeons.”
Trials in established disease have helped sort out the roles of tumor debulking and HIPEC. “In our attempt to overcome the biology of this disease, we can see that, in most of these studies, the debulking-only arm did much better than we would have thought. But controversies remain regarding both the duration of the HIPEC and the chemotherapy that we use,” Dr. Sigurdson commented. “Perhaps, as we move forward, more questions will be addressed in the near future as there are ongoing clinical trials both on our side and the European side.”
Symposium attendee Alan P. Venook, MD, of the University of California, San Francisco, noted that there have been three negative clinical trials of HIPEC in the last 3 years. “Is that enough to say enough, or do we still need to study the role of HIPEC in these patients?” he asked.
“The issue becomes, are there new possibilities in the way of new drugs in order to carry on?” Dr. Sigurdson replied. Also, “it clearly has been a learning curve in doing HIPEC, and we have failed to recognize how impactful the surgical part of HIPEC has been.”
“The trials shown today from Europe are the best-designed trials that we have, and I agree, yes, the negative trials are discouraging,” she elaborated. “But if there were drugs where the therapeutic index of giving them intraperitoneally would be beneficial, then it would be useful because it has worked in ovarian cancer, it has worked in other cancers. So hope remains. But I would argue that, in the absence of new drugs, we are getting to the point that repeating the clinical trials with those [same] drugs is not going to be positive.”
Study details
In COLOPEC, adjuvant HIPEC consisted of 30 minutes of intraperitoneal oxaliplatin plus intravenous 5-fluoruracil and leucovorin, Dr. Tanis reported at the symposium, which 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.
HIPEC was usually performed 5-8 weeks after resection (91%) and laparoscopically (71%). Almost a fifth of patients were found to have extensive adhesions, making the procedure more difficult.
The rate of postoperative complications was 88% in the small number of patients having HIPEC at the time of resection, but only 6% in those having it 5-8 weeks after resection. A single patient developed encapsulating peritoneal sclerosis 8 months after HIPEC, requiring parenteral nutrition and surgery.
Patients in the HIPEC and control groups were similarly likely to receive adjuvant systemic chemotherapy (84% vs. 89%, P = .385), but the former had a longer time before starting this therapy (10.2 vs. 6.4 weeks, P less than .001).
Relative to counterparts in the control group, patients in the HIPEC group had a 14% reduction in risk of peritoneal recurrence or death at 18 months, but the difference was not significant (hazard ratio, 0.86; 95% confidence interval, 0.51-1.54). Findings were similar across a variety of subgroups.
In both trial groups, about two-thirds of patients in whom peritoneal metastases were detected underwent cytoreductive surgery and/or (additional) HIPEC to treat them.
“Overall, 21% of patients had peritoneal metastases detected after 23 months of follow-up, demonstrating the magnitude of this clinical problem,” noted Dr. Tanis, who reported that he had no relevant disclosures. The trial was sponsored by the Academic Medical Center, University of Amsterdam.
SOURCE: Tanis PJ et al. GI Cancers Symposium 2019, Abstract 482.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) is not efficacious in patients undergoing curative resection of high-risk colon cancer.
Major finding: The rate of peritoneal metastasis–free survival at 18 months was 81% with HIPEC and 76% without HIPEC (hazard ratio, 0.86; 95% confidence interval, 0.51-1.54).
Study details: A phase 3, randomized, controlled trial among 202 patients who underwent curative resection of colon cancer having stage T4 or perforated tumors, all given adjuvant systemic chemotherapy (COLOPEC).
Disclosures: Dr. Tanis reported no relevant relationships. The trial was sponsored by the Academic Medical Center, University of Amsterdam.
Source: Tanis PJ et al. GI Cancers Symposium 2019, Abstract 482.