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Cabozantinib shows promise for carcinoid tumors, pNET
SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
Key clinical point:
Major finding: The objective response rate was 15% in both groups; median progression-free survival was 31.4 and 21.8 months in the carcinoid and pNET groups, respectively.
Data source: A phase II trial involving 61 patients.
Disclosures: Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
Nivolumab shows promise for pretreated advanced HCC
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Investigator-assessed objective response rates were 16.2% in phase I and 18.6% in phase II.
Data source: The CheckMate 040 phase I and phase II clinical studies involving 262 patients.
Disclosures: CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
Adjuvant GEMOX disappoints for localized biliary tract cancer
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Relapse-free survival at 4 years was 39.3% and 33.2% with GEMOX and surveillance, respectively.
Data source: The randomized, phase III PRODIGE 12-ACCORD 18 trial.
Disclosures: Dr. Edeline reported having no disclosures.
Bursectomy provides no benefit over omentectomy for gastric cancers
SAN FRANCISCO – Bursectomy was not found to be superior to omentectomy for improving survival in patients with subserosal/serosal gastric cancer in a Japanese randomized phase III study.
The procedure – the dissection of the peritoneal lining covering the pancreas and anterior plane of the transverse mesocolon to prevent peritoneal metastasis – was common worldwide and considered standard in Japan from the 1950s until the mid-1990s, but was replaced by omentectomy following publication of reports questioning its value, according to Masanori Terashima, MD, of Shizuoka Cancer Center, Nagaizumi, Japan.
However, interest in bursectomy was rekindled when a 2012 noninferiority phase II study suggested that bursectomy may improve survival; the authors concluded that it should not be abandoned as a futile procedure until more definitive data could be obtained (Gastric Cancer. 2012;15[1]:42-8).
“So based on this result, [Japanese Clinical Oncology Group] conducted a large-scale randomized phase III trial [JCOG1001] to evaluate the efficacy of bursectomy. The objective of this study was to confirm the superiority of bursectomy for clinical T3 or clinical T4a gastric cancer patients in terms of overall survival,” Dr. Terashima said at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
At a planned interim analysis when 522 patients had been enrolled, the Data and Safety Monitoring Committee approved continued enrollment. However, at a second interim analysis when 54% of expected events had been observed, the committee recommended early release of the survival results because “there was little possibility of demonstration of the superiority of bursectomy,” he said.
Overall 3-year survival was 83.3% among 601 patients in the bursectomy arm, compared with 86% in 600 patients in the nonbursectomy arm (hazard ratio, 1.07). The predictive probability of superiority of bursectomy was 12.7%.
Study subjects were adults aged 20-80 years (median of 65-66 years) with histologically proven adenocarcinoma of the stomach and clinical T3 or T4 disease. They enrolled from 57 institutions and were intraoperatively randomized to the bursectomy or nonbursectomy arm after confirmation of tumor stage. All received adjuvant chemotherapy with S-1 for 1 year for pathologic stage II/III disease.
Patients with bulky nodal metastases, Borrmann type 4 and 8 cm or larger Borrmann type 3 tumors were excluded, as their poor prognosis made them candidates for other clinical trials, Dr. Terashima said.
Patients’ background and operative procedures were well balanced between the arms, he noted.
For those in the bursectomy group, operation time was longer (median, 254 vs. 222 minutes), and blood loss was larger (330 vs. 230 mL), although the incidence of blood transfusion was not significantly different between the groups (4.5% vs. 4.8%).
The incidence of grade 3 or higher complications was slightly higher in the bursectomy arm (13.3% vs. 11.6%). This was due largely to the incidence of pancreatic fistulas, which was nearly double in the bursectomy arm (4.8% vs. 2.5% ).
Mortality was “quite low” in both groups (0.2 vs. 0.8%).
“There was no significant difference in overall survival between the arms. Bursectomy seemed to be a bit inferior to the nonbursectomy arm. Relapse-free survival also demonstrated no significant difference between the arms. Again, bursectomy seemed to be a bit worse than nonbursectomy,” he said.
The most common site of recurrence for all patient was the peritoneum, with 63 and 56 patients in the bursectomy and nonbursectomy arms, respectively, experiencing peritoneal recurrence.
“We could not detect any subgroup who may have a benefit from bursectomy,” Dr. Terashima said.
“Bursectomy is not recommended as a standard treatment for clinical T3 or clinical T4 gastric cancer, while complete omentectomy remains a part of standard procedure,” he concluded.
Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
SAN FRANCISCO – Bursectomy was not found to be superior to omentectomy for improving survival in patients with subserosal/serosal gastric cancer in a Japanese randomized phase III study.
The procedure – the dissection of the peritoneal lining covering the pancreas and anterior plane of the transverse mesocolon to prevent peritoneal metastasis – was common worldwide and considered standard in Japan from the 1950s until the mid-1990s, but was replaced by omentectomy following publication of reports questioning its value, according to Masanori Terashima, MD, of Shizuoka Cancer Center, Nagaizumi, Japan.
However, interest in bursectomy was rekindled when a 2012 noninferiority phase II study suggested that bursectomy may improve survival; the authors concluded that it should not be abandoned as a futile procedure until more definitive data could be obtained (Gastric Cancer. 2012;15[1]:42-8).
“So based on this result, [Japanese Clinical Oncology Group] conducted a large-scale randomized phase III trial [JCOG1001] to evaluate the efficacy of bursectomy. The objective of this study was to confirm the superiority of bursectomy for clinical T3 or clinical T4a gastric cancer patients in terms of overall survival,” Dr. Terashima said at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
At a planned interim analysis when 522 patients had been enrolled, the Data and Safety Monitoring Committee approved continued enrollment. However, at a second interim analysis when 54% of expected events had been observed, the committee recommended early release of the survival results because “there was little possibility of demonstration of the superiority of bursectomy,” he said.
Overall 3-year survival was 83.3% among 601 patients in the bursectomy arm, compared with 86% in 600 patients in the nonbursectomy arm (hazard ratio, 1.07). The predictive probability of superiority of bursectomy was 12.7%.
Study subjects were adults aged 20-80 years (median of 65-66 years) with histologically proven adenocarcinoma of the stomach and clinical T3 or T4 disease. They enrolled from 57 institutions and were intraoperatively randomized to the bursectomy or nonbursectomy arm after confirmation of tumor stage. All received adjuvant chemotherapy with S-1 for 1 year for pathologic stage II/III disease.
Patients with bulky nodal metastases, Borrmann type 4 and 8 cm or larger Borrmann type 3 tumors were excluded, as their poor prognosis made them candidates for other clinical trials, Dr. Terashima said.
Patients’ background and operative procedures were well balanced between the arms, he noted.
For those in the bursectomy group, operation time was longer (median, 254 vs. 222 minutes), and blood loss was larger (330 vs. 230 mL), although the incidence of blood transfusion was not significantly different between the groups (4.5% vs. 4.8%).
The incidence of grade 3 or higher complications was slightly higher in the bursectomy arm (13.3% vs. 11.6%). This was due largely to the incidence of pancreatic fistulas, which was nearly double in the bursectomy arm (4.8% vs. 2.5% ).
Mortality was “quite low” in both groups (0.2 vs. 0.8%).
“There was no significant difference in overall survival between the arms. Bursectomy seemed to be a bit inferior to the nonbursectomy arm. Relapse-free survival also demonstrated no significant difference between the arms. Again, bursectomy seemed to be a bit worse than nonbursectomy,” he said.
The most common site of recurrence for all patient was the peritoneum, with 63 and 56 patients in the bursectomy and nonbursectomy arms, respectively, experiencing peritoneal recurrence.
“We could not detect any subgroup who may have a benefit from bursectomy,” Dr. Terashima said.
“Bursectomy is not recommended as a standard treatment for clinical T3 or clinical T4 gastric cancer, while complete omentectomy remains a part of standard procedure,” he concluded.
Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
SAN FRANCISCO – Bursectomy was not found to be superior to omentectomy for improving survival in patients with subserosal/serosal gastric cancer in a Japanese randomized phase III study.
The procedure – the dissection of the peritoneal lining covering the pancreas and anterior plane of the transverse mesocolon to prevent peritoneal metastasis – was common worldwide and considered standard in Japan from the 1950s until the mid-1990s, but was replaced by omentectomy following publication of reports questioning its value, according to Masanori Terashima, MD, of Shizuoka Cancer Center, Nagaizumi, Japan.
However, interest in bursectomy was rekindled when a 2012 noninferiority phase II study suggested that bursectomy may improve survival; the authors concluded that it should not be abandoned as a futile procedure until more definitive data could be obtained (Gastric Cancer. 2012;15[1]:42-8).
“So based on this result, [Japanese Clinical Oncology Group] conducted a large-scale randomized phase III trial [JCOG1001] to evaluate the efficacy of bursectomy. The objective of this study was to confirm the superiority of bursectomy for clinical T3 or clinical T4a gastric cancer patients in terms of overall survival,” Dr. Terashima said at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
At a planned interim analysis when 522 patients had been enrolled, the Data and Safety Monitoring Committee approved continued enrollment. However, at a second interim analysis when 54% of expected events had been observed, the committee recommended early release of the survival results because “there was little possibility of demonstration of the superiority of bursectomy,” he said.
Overall 3-year survival was 83.3% among 601 patients in the bursectomy arm, compared with 86% in 600 patients in the nonbursectomy arm (hazard ratio, 1.07). The predictive probability of superiority of bursectomy was 12.7%.
Study subjects were adults aged 20-80 years (median of 65-66 years) with histologically proven adenocarcinoma of the stomach and clinical T3 or T4 disease. They enrolled from 57 institutions and were intraoperatively randomized to the bursectomy or nonbursectomy arm after confirmation of tumor stage. All received adjuvant chemotherapy with S-1 for 1 year for pathologic stage II/III disease.
Patients with bulky nodal metastases, Borrmann type 4 and 8 cm or larger Borrmann type 3 tumors were excluded, as their poor prognosis made them candidates for other clinical trials, Dr. Terashima said.
Patients’ background and operative procedures were well balanced between the arms, he noted.
For those in the bursectomy group, operation time was longer (median, 254 vs. 222 minutes), and blood loss was larger (330 vs. 230 mL), although the incidence of blood transfusion was not significantly different between the groups (4.5% vs. 4.8%).
The incidence of grade 3 or higher complications was slightly higher in the bursectomy arm (13.3% vs. 11.6%). This was due largely to the incidence of pancreatic fistulas, which was nearly double in the bursectomy arm (4.8% vs. 2.5% ).
Mortality was “quite low” in both groups (0.2 vs. 0.8%).
“There was no significant difference in overall survival between the arms. Bursectomy seemed to be a bit inferior to the nonbursectomy arm. Relapse-free survival also demonstrated no significant difference between the arms. Again, bursectomy seemed to be a bit worse than nonbursectomy,” he said.
The most common site of recurrence for all patient was the peritoneum, with 63 and 56 patients in the bursectomy and nonbursectomy arms, respectively, experiencing peritoneal recurrence.
“We could not detect any subgroup who may have a benefit from bursectomy,” Dr. Terashima said.
“Bursectomy is not recommended as a standard treatment for clinical T3 or clinical T4 gastric cancer, while complete omentectomy remains a part of standard procedure,” he concluded.
Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Overall 3-year survival was 83.3% and 86% in the bursectomy and nonbursectomy arms, respectively (hazard ratio, 1.07).
Data source: The randomized phase III JCOG1001 trial with more than 1,200 subjects.
Disclosures: Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
Ramucirumab benefits gastric cancer patients across age groups
SAN FRANCISCO – Patients with metastatic gastric or gastroesophageal junction adenocarcinoma benefit from treatment with ramucirumab regardless of their age, according to findings from an exploratory subgroup analysis of the phase III RAINBOW and REGARD studies.
The findings, which show at least a trend toward improvements in most age categories, are important given that nearly two-thirds of patients with these cancers are diagnosed at over age 65 years, and more than half of those are over age 75 years, Kei Muro, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
“At the other end of the age spectrum, there is evidence that young age can also be an unfavorable prognostic characteristic for gastric cancer,” said Dr. Muro of Aichi Cancer Center Hospital in Nagoya, Japan.
Both RAINBOW and REGARD demonstrated statistically significant and clinically meaningful overall and progression-free survival benefits and acceptable and manageable toxicity with ramucirumab among patients with advanced gastric cancer who were randomized, in the second-line treatment setting, to receive active treatment with the fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor–2 or placebo.
RAINBOW subjects were randomized 1:1 to receive 8 mg/kg of ramucirumab plus paclitaxel, or placebo plus paclitaxel. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 months for treatment vs. 4.2 months for placebo (hazard ratio, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
The corresponding median overall survival rates for those aged 45-70 (225 and 230 patients in the groups, respectively), 70 or older (68 patients in each group), and 75 or older (20 and 16 patients in the groups, respectively) were 9.6 vs. 7.6 months (HR, 0.860), 10.8 vs. 8.6 months (HR, 0.881), and 11.0 vs. 11.0 months (HR, 0.971). The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 4.6 vs. 2.8 months (HR, 0.649), 4.7 vs. 2.9 months (HR, 0.676), and 4.2 vs. 2.8 months (HR, 0.330).
REGARD subjects were randomized 2:1 to receive 8 mg/kg of ramucirumab plus best supportive care, or placebo plus best supportive care. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 vs. 4.2 months for treatment vs. placebo (HR, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
Among REGARD subjects aged 45 years or less (28 and 12 patients in the groups, respectively), the median overall survival was 5.8 vs. 2.9 months for treatment vs. placebo (HR, 0.586), and the median progression-free survival was 1.9 vs. 1.4 months (HR, 0.270).
The corresponding median overall survival rates for those aged 45-70 (166 and 70 patients in the groups, respectively), 70 or older (44 and 35 patients in the groups, respectively), and 75 or older (21 and 13 patients in the groups, respectively) were 4.9 vs. 4.1 months (HR, 0.780), 5.9 vs. 3.8 months (HR, 0.730), and 9.3 vs. 5.1 months (HR, 0.588).
The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 2.2 vs. 1.3 months (HR, 0.451), 2.1 vs. 1.4 months (HR, 0.559), 2.8 vs. 1.4 (HR, 0.420).
Baseline characteristics were generally well balanced between arms in each of the age subgroups, Dr. Muro said, noting that no obvious patterns for differential risks in terms of efficacy and adverse events of any grade or of grade 3 or greater were seen according to age. Discontinuation rates for adverse events were similar across different age groups, and quality of life, as determined by global health status, was satisfactory in all age groups.
“Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of ramucirumab for the treatment of our patients with gastric cancer irrespective of age,” he concluded.
RAINBOW was funded by Eli Lilly. REGARD was funded by ImClone Systems. Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
SAN FRANCISCO – Patients with metastatic gastric or gastroesophageal junction adenocarcinoma benefit from treatment with ramucirumab regardless of their age, according to findings from an exploratory subgroup analysis of the phase III RAINBOW and REGARD studies.
The findings, which show at least a trend toward improvements in most age categories, are important given that nearly two-thirds of patients with these cancers are diagnosed at over age 65 years, and more than half of those are over age 75 years, Kei Muro, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
“At the other end of the age spectrum, there is evidence that young age can also be an unfavorable prognostic characteristic for gastric cancer,” said Dr. Muro of Aichi Cancer Center Hospital in Nagoya, Japan.
Both RAINBOW and REGARD demonstrated statistically significant and clinically meaningful overall and progression-free survival benefits and acceptable and manageable toxicity with ramucirumab among patients with advanced gastric cancer who were randomized, in the second-line treatment setting, to receive active treatment with the fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor–2 or placebo.
RAINBOW subjects were randomized 1:1 to receive 8 mg/kg of ramucirumab plus paclitaxel, or placebo plus paclitaxel. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 months for treatment vs. 4.2 months for placebo (hazard ratio, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
The corresponding median overall survival rates for those aged 45-70 (225 and 230 patients in the groups, respectively), 70 or older (68 patients in each group), and 75 or older (20 and 16 patients in the groups, respectively) were 9.6 vs. 7.6 months (HR, 0.860), 10.8 vs. 8.6 months (HR, 0.881), and 11.0 vs. 11.0 months (HR, 0.971). The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 4.6 vs. 2.8 months (HR, 0.649), 4.7 vs. 2.9 months (HR, 0.676), and 4.2 vs. 2.8 months (HR, 0.330).
REGARD subjects were randomized 2:1 to receive 8 mg/kg of ramucirumab plus best supportive care, or placebo plus best supportive care. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 vs. 4.2 months for treatment vs. placebo (HR, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
Among REGARD subjects aged 45 years or less (28 and 12 patients in the groups, respectively), the median overall survival was 5.8 vs. 2.9 months for treatment vs. placebo (HR, 0.586), and the median progression-free survival was 1.9 vs. 1.4 months (HR, 0.270).
The corresponding median overall survival rates for those aged 45-70 (166 and 70 patients in the groups, respectively), 70 or older (44 and 35 patients in the groups, respectively), and 75 or older (21 and 13 patients in the groups, respectively) were 4.9 vs. 4.1 months (HR, 0.780), 5.9 vs. 3.8 months (HR, 0.730), and 9.3 vs. 5.1 months (HR, 0.588).
The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 2.2 vs. 1.3 months (HR, 0.451), 2.1 vs. 1.4 months (HR, 0.559), 2.8 vs. 1.4 (HR, 0.420).
Baseline characteristics were generally well balanced between arms in each of the age subgroups, Dr. Muro said, noting that no obvious patterns for differential risks in terms of efficacy and adverse events of any grade or of grade 3 or greater were seen according to age. Discontinuation rates for adverse events were similar across different age groups, and quality of life, as determined by global health status, was satisfactory in all age groups.
“Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of ramucirumab for the treatment of our patients with gastric cancer irrespective of age,” he concluded.
RAINBOW was funded by Eli Lilly. REGARD was funded by ImClone Systems. Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
SAN FRANCISCO – Patients with metastatic gastric or gastroesophageal junction adenocarcinoma benefit from treatment with ramucirumab regardless of their age, according to findings from an exploratory subgroup analysis of the phase III RAINBOW and REGARD studies.
The findings, which show at least a trend toward improvements in most age categories, are important given that nearly two-thirds of patients with these cancers are diagnosed at over age 65 years, and more than half of those are over age 75 years, Kei Muro, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
“At the other end of the age spectrum, there is evidence that young age can also be an unfavorable prognostic characteristic for gastric cancer,” said Dr. Muro of Aichi Cancer Center Hospital in Nagoya, Japan.
Both RAINBOW and REGARD demonstrated statistically significant and clinically meaningful overall and progression-free survival benefits and acceptable and manageable toxicity with ramucirumab among patients with advanced gastric cancer who were randomized, in the second-line treatment setting, to receive active treatment with the fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor–2 or placebo.
RAINBOW subjects were randomized 1:1 to receive 8 mg/kg of ramucirumab plus paclitaxel, or placebo plus paclitaxel. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 months for treatment vs. 4.2 months for placebo (hazard ratio, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
The corresponding median overall survival rates for those aged 45-70 (225 and 230 patients in the groups, respectively), 70 or older (68 patients in each group), and 75 or older (20 and 16 patients in the groups, respectively) were 9.6 vs. 7.6 months (HR, 0.860), 10.8 vs. 8.6 months (HR, 0.881), and 11.0 vs. 11.0 months (HR, 0.971). The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 4.6 vs. 2.8 months (HR, 0.649), 4.7 vs. 2.9 months (HR, 0.676), and 4.2 vs. 2.8 months (HR, 0.330).
REGARD subjects were randomized 2:1 to receive 8 mg/kg of ramucirumab plus best supportive care, or placebo plus best supportive care. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 vs. 4.2 months for treatment vs. placebo (HR, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
Among REGARD subjects aged 45 years or less (28 and 12 patients in the groups, respectively), the median overall survival was 5.8 vs. 2.9 months for treatment vs. placebo (HR, 0.586), and the median progression-free survival was 1.9 vs. 1.4 months (HR, 0.270).
The corresponding median overall survival rates for those aged 45-70 (166 and 70 patients in the groups, respectively), 70 or older (44 and 35 patients in the groups, respectively), and 75 or older (21 and 13 patients in the groups, respectively) were 4.9 vs. 4.1 months (HR, 0.780), 5.9 vs. 3.8 months (HR, 0.730), and 9.3 vs. 5.1 months (HR, 0.588).
The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 2.2 vs. 1.3 months (HR, 0.451), 2.1 vs. 1.4 months (HR, 0.559), 2.8 vs. 1.4 (HR, 0.420).
Baseline characteristics were generally well balanced between arms in each of the age subgroups, Dr. Muro said, noting that no obvious patterns for differential risks in terms of efficacy and adverse events of any grade or of grade 3 or greater were seen according to age. Discontinuation rates for adverse events were similar across different age groups, and quality of life, as determined by global health status, was satisfactory in all age groups.
“Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of ramucirumab for the treatment of our patients with gastric cancer irrespective of age,” he concluded.
RAINBOW was funded by Eli Lilly. REGARD was funded by ImClone Systems. Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Among patients 45-70 years and 70 and older, the hazard ratios for overall survival were 0.860 and 0.881 with ramucirumab vs. placebo in RAINBOW, and 0.780 and 0.730 in REGARD
Data source: The phase III RAINBOW and REGARD trials, including a total of more than 1,000 patients.
Disclosures: Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
Nivolumab safe, effective for salvage in advanced gastric cancer
SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.
Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.
The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.
The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.
“Median duration of response was 9.53 months,” he said.
Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.
Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.
The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.
ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.
Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.
The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.
The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.
“Median duration of response was 9.53 months,” he said.
Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.
Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.
The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.
ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.
Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.
The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.
The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.
“Median duration of response was 9.53 months,” he said.
Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.
Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.
The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.
ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: The overall survival rate at 12 months was 26.6% vs. 10.9% with nivolumab vs. placebo, respectively.
Data source: The randomized phase III ONO-4538 trial.
Disclosures: ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
PET-directed induction therapy improves esophageal cancer outcomes
SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.
Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..
“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.
Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.
Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.
The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.
The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.
“The efficacy criteria for changing therapy was met for both induction arms,” she said.
“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.
PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.
“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”
Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.
“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”
PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”
During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.
“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.
CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.
SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.
Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..
“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.
Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.
Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.
The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.
The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.
“The efficacy criteria for changing therapy was met for both induction arms,” she said.
“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.
PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.
“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”
Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.
“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”
PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”
During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.
“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.
CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.
SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.
Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..
“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.
Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.
Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.
The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.
The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.
“The efficacy criteria for changing therapy was met for both induction arms,” she said.
“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.
PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.
“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”
Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.
“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”
PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”
During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.
“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.
CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: The pathologic completer response rate among PET nonresponders who switched therapies was 18% vs. an expected rate of 5%.
Data source: The phase II randomized CALGB 80803 of 257 esophageal and GEJ cancer patients.
Disclosures: CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.