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No survival boost with atezolizumab vs. regorafenib in mCRC
BARCELONA – There was no overall survival advantage for patients with metastatic colorectal cancer treated with the immune checkpoint inhibitor atezolizumab (Tencentriq) either in combination with cobimetinib (Cotellic) or as monotherapy compared with regorafenib (Stivarga), results of the randomized phase 3 IMblaze370 trial showed.
Median overall survival (OS, the primary endpoint) for 183 patients treated with atezolizumab and cobimetinib was 8.9 months, compared with 7.1 months for 90 patients treated with atezolizumab monotherapy, and 8.5 months for 90 patients treated with regorafenib. None of the differences were statistically significant, reported Johanna C. Bendell, MD, of the Sarah Cannon Research Institute in Nashville, Tenn.
“The lack of clinical activity may be due to the immune-excluded phenotype of metastatic colorectal cancer. The dual inhibition of the PD-L1 immune checkpoint and MAP kinase–mediated immune suppression may not be sufficient to generate that immune response that we need for antitumor activity,” she said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.
In an interview, Dr. Bendell said that “we were all hoping that we were going to see some benefit, and we had some preliminary data suggesting that we would. What we still need to see is whether there are potentially populations of patients who might have benefited more, which hopefully will come out of the biomarker analysis.”
The results demonstrate the need for controlled comparison trials to detect true clinical benefits from a specific agent or combination, she added.
Microsatellite-stable disease, which accounts for approximately 95% of cases of metastatic colorectal cancer (MSS mCRC) is considered to be an immune-excluded or “cold” tumor type due to a lack of tumor-infiltrating lymphocytes. Single agent inhibitors of the programmed death 1 protein and its ligand (PD1/PD-L1) have only minimal activity in MSS mCRC, she noted.
In preclinical studies, there was evidence to suggest that the combination of atezolizumab and cobimetinib could augment antitumor T-cell responses. The combination also was shown to be safe and to demonstrate “promising” clinical activity in a phase 1b trial conducted by Dr. Bendell and her colleagues.
To see whether the initial promise of atezolizumab in this population held up under closer scrutiny, the investigators enrolled patients with MSS mCRC refractory to chemotherapy and randomly assigned them on a 2:1:1 basis to receive either atezolizumab plus cobimetinib, atezolizumab monotherapy, or regorafenib.
Atezolizumab was administered intravenously at 840 mg every 2 weeks in the combination arm, and at 1,200 mg every 3 weeks in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule. Regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule.
As noted, the trial did not meet its primary endpoint of an OS benefit in the intention-to-treat population. In addition, there were no significant differences in either median progression-free survival, overall response rates, or duration of response.
Response rates for both the atezolizumab/cobimetinib combination and atezolizumab monotherapy arms were consistent with published data for other PD-1/PD-L1 inhibitors, and the safety of the combination was consistent with the known safety profiles of the individual agents, Dr. Bendell said.
The investigators are conducting extensive biomarker evaluations and gene expression profiles, and hope to present the results of these studies at a future conference, she added.
SOURCE: Bendell J et al. ESMO GI 2018. Abstract LBA-004.
BARCELONA – There was no overall survival advantage for patients with metastatic colorectal cancer treated with the immune checkpoint inhibitor atezolizumab (Tencentriq) either in combination with cobimetinib (Cotellic) or as monotherapy compared with regorafenib (Stivarga), results of the randomized phase 3 IMblaze370 trial showed.
Median overall survival (OS, the primary endpoint) for 183 patients treated with atezolizumab and cobimetinib was 8.9 months, compared with 7.1 months for 90 patients treated with atezolizumab monotherapy, and 8.5 months for 90 patients treated with regorafenib. None of the differences were statistically significant, reported Johanna C. Bendell, MD, of the Sarah Cannon Research Institute in Nashville, Tenn.
“The lack of clinical activity may be due to the immune-excluded phenotype of metastatic colorectal cancer. The dual inhibition of the PD-L1 immune checkpoint and MAP kinase–mediated immune suppression may not be sufficient to generate that immune response that we need for antitumor activity,” she said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.
In an interview, Dr. Bendell said that “we were all hoping that we were going to see some benefit, and we had some preliminary data suggesting that we would. What we still need to see is whether there are potentially populations of patients who might have benefited more, which hopefully will come out of the biomarker analysis.”
The results demonstrate the need for controlled comparison trials to detect true clinical benefits from a specific agent or combination, she added.
Microsatellite-stable disease, which accounts for approximately 95% of cases of metastatic colorectal cancer (MSS mCRC) is considered to be an immune-excluded or “cold” tumor type due to a lack of tumor-infiltrating lymphocytes. Single agent inhibitors of the programmed death 1 protein and its ligand (PD1/PD-L1) have only minimal activity in MSS mCRC, she noted.
In preclinical studies, there was evidence to suggest that the combination of atezolizumab and cobimetinib could augment antitumor T-cell responses. The combination also was shown to be safe and to demonstrate “promising” clinical activity in a phase 1b trial conducted by Dr. Bendell and her colleagues.
To see whether the initial promise of atezolizumab in this population held up under closer scrutiny, the investigators enrolled patients with MSS mCRC refractory to chemotherapy and randomly assigned them on a 2:1:1 basis to receive either atezolizumab plus cobimetinib, atezolizumab monotherapy, or regorafenib.
Atezolizumab was administered intravenously at 840 mg every 2 weeks in the combination arm, and at 1,200 mg every 3 weeks in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule. Regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule.
As noted, the trial did not meet its primary endpoint of an OS benefit in the intention-to-treat population. In addition, there were no significant differences in either median progression-free survival, overall response rates, or duration of response.
Response rates for both the atezolizumab/cobimetinib combination and atezolizumab monotherapy arms were consistent with published data for other PD-1/PD-L1 inhibitors, and the safety of the combination was consistent with the known safety profiles of the individual agents, Dr. Bendell said.
The investigators are conducting extensive biomarker evaluations and gene expression profiles, and hope to present the results of these studies at a future conference, she added.
SOURCE: Bendell J et al. ESMO GI 2018. Abstract LBA-004.
BARCELONA – There was no overall survival advantage for patients with metastatic colorectal cancer treated with the immune checkpoint inhibitor atezolizumab (Tencentriq) either in combination with cobimetinib (Cotellic) or as monotherapy compared with regorafenib (Stivarga), results of the randomized phase 3 IMblaze370 trial showed.
Median overall survival (OS, the primary endpoint) for 183 patients treated with atezolizumab and cobimetinib was 8.9 months, compared with 7.1 months for 90 patients treated with atezolizumab monotherapy, and 8.5 months for 90 patients treated with regorafenib. None of the differences were statistically significant, reported Johanna C. Bendell, MD, of the Sarah Cannon Research Institute in Nashville, Tenn.
“The lack of clinical activity may be due to the immune-excluded phenotype of metastatic colorectal cancer. The dual inhibition of the PD-L1 immune checkpoint and MAP kinase–mediated immune suppression may not be sufficient to generate that immune response that we need for antitumor activity,” she said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.
In an interview, Dr. Bendell said that “we were all hoping that we were going to see some benefit, and we had some preliminary data suggesting that we would. What we still need to see is whether there are potentially populations of patients who might have benefited more, which hopefully will come out of the biomarker analysis.”
The results demonstrate the need for controlled comparison trials to detect true clinical benefits from a specific agent or combination, she added.
Microsatellite-stable disease, which accounts for approximately 95% of cases of metastatic colorectal cancer (MSS mCRC) is considered to be an immune-excluded or “cold” tumor type due to a lack of tumor-infiltrating lymphocytes. Single agent inhibitors of the programmed death 1 protein and its ligand (PD1/PD-L1) have only minimal activity in MSS mCRC, she noted.
In preclinical studies, there was evidence to suggest that the combination of atezolizumab and cobimetinib could augment antitumor T-cell responses. The combination also was shown to be safe and to demonstrate “promising” clinical activity in a phase 1b trial conducted by Dr. Bendell and her colleagues.
To see whether the initial promise of atezolizumab in this population held up under closer scrutiny, the investigators enrolled patients with MSS mCRC refractory to chemotherapy and randomly assigned them on a 2:1:1 basis to receive either atezolizumab plus cobimetinib, atezolizumab monotherapy, or regorafenib.
Atezolizumab was administered intravenously at 840 mg every 2 weeks in the combination arm, and at 1,200 mg every 3 weeks in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule. Regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule.
As noted, the trial did not meet its primary endpoint of an OS benefit in the intention-to-treat population. In addition, there were no significant differences in either median progression-free survival, overall response rates, or duration of response.
Response rates for both the atezolizumab/cobimetinib combination and atezolizumab monotherapy arms were consistent with published data for other PD-1/PD-L1 inhibitors, and the safety of the combination was consistent with the known safety profiles of the individual agents, Dr. Bendell said.
The investigators are conducting extensive biomarker evaluations and gene expression profiles, and hope to present the results of these studies at a future conference, she added.
SOURCE: Bendell J et al. ESMO GI 2018. Abstract LBA-004.
REPORTING FROM ESMO GI 2018
Key clinical point: Microsatellite stable metastatic colorectal cancer (mCRC) has a poor survival prognosis; better agents or combinations are needed.
Major finding: There were no significant differences in overall or progression-free survival, overall response rates, or duration of responses between atezolizumab with or without cobimetinib vs. regorafenib.
Study details: Randomized phase 3 trial of 363 patients with mCRC.
Disclosures: Hoffman-La Roche sponsored the study. Dr. Bendell reported no relevant disclosures. She is a member of the Oncology Practice editorial advisory board.
Source: Bendell J et al. ESMO GI 2018, Abstract LBA-004.
Hints of nivolumab efficacy seen in biliary tract cancers
BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reported Richard Kim, MD of Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.
BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reported Richard Kim, MD of Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.
BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reported Richard Kim, MD of Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.
REPORTING FROM ESMO GI 2018
Key clinical point: Nivolumab monotherapy appears to have activity in treatment-refractory biliary tract cancers.
Major finding: Five of 27 evaluable patients had partial responses to nivolumab.
Study details: Two-stage phase 2 trial of 34 patients with intrahepatic or extrahepatic cholangiocarcinomas or gallbladder tumors.
Disclosures: Bristol-Myers Squibb sponsored the study. Dr. Kim disclosed honoraria and institutional research funding from that company and others.
Source: Kim R et al. European Society of Medical Oncology World Congress on Gastrointestinal Cancer. Abstract O-009.
Trifluridine/tipiracil improves survival of metastatic gastric cancer
BARCELONA – In patients with heavily pretreated metastatic gastric cancer, trifluridine/tipiracil was associated with a brief but statistically significant survival benefit, compared with placebo.
In the randomized, controlled TAGS (TAS-102 Gastric Study), median overall survival, the primary endpoint, was 5.7 months for patients assigned to receive trifluridine/tipiracil, compared with 3.6 months for patients randomized to placebo, reported Josep Tabernero, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona.
Trifluridine/tipiracil (Lonsurf) is a combination of an oral thymidine analog (trifluridine, or FTD) and a thymidine phosphorylase inhibitor (tipiracil, or TPI).
It was approved by the Food and Drug Administration in 2015 for the treatment of patients with metastatic colorectal cancer who have been previously treated with chemotherapy and biological therapy.
In a phase 2 study conducted in Japan with 29 patients with metastatic gastric cancer that had progressed after chemotherapy with fluoropyrimidine, platinum, taxanes, or irinotecan, FTD/TPI was associated with a median overall survival of 8.7 months and an investigator-assessed disease control rate of 65.5%, Dr. Tabernero noted.
In the TAGS trial, patients with metastatic gastric cancer, including cancers of the gastroesophageal junction who had disease progression after two or more prior lines of therapy were randomized on a 2:1 basis to receive either oral FTD/TPI 35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle or to receive placebo. In both arms, patients also received best supportive care.
As noted, the trial met its primary endpoint, with a 2.1 month improvement in median survival over placebo, which translated into a hazard ratio for death with FTD/TPI of 0.69 (P = .0003).
The 12-month overall survival rate for the FTD/TPI group was 21%, compared with 13% for the placebo group.
Median progression-free survival, a secondary endpoint, was also slightly but significantly better with FTD/TPI at 2.0 vs. 1.8 months (HR, 0.57; P less than .0001). Six-month progression-free survival rates were 15% and 6%, respectively.
Grade 3 or greater adverse events occurred in 80% of patients on FTD/TPI versus 58% of those on placebo. The drug combination was associated with more treatment-related adverse events (81% vs. 57%) but fewer adverse events leading to discontinuation (13% vs. 17%) and fewer treatment-related deaths (0.3 % vs. 0.6%).
FTD/TPI was also associated with more cases of grade 3 or 4 neutropenia, leukopenia, lymphocytopenia, anemia, and thrombocytopenia. Six patients (2%) treated with FTD/TPI had grade 3 or 4 febrile neutropenia, compared with none in the placebo group.
“The safety profile of trifluridine/tipiracil was predictable, manageable, and comparable to the population previously evaluated with metastatic colorectal cancer, with no new safety signals,” Dr. Tabernero said.
SOURCE: Tabernero J et al. ESMO GI 2018, Abstract LBA 002.
BARCELONA – In patients with heavily pretreated metastatic gastric cancer, trifluridine/tipiracil was associated with a brief but statistically significant survival benefit, compared with placebo.
In the randomized, controlled TAGS (TAS-102 Gastric Study), median overall survival, the primary endpoint, was 5.7 months for patients assigned to receive trifluridine/tipiracil, compared with 3.6 months for patients randomized to placebo, reported Josep Tabernero, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona.
Trifluridine/tipiracil (Lonsurf) is a combination of an oral thymidine analog (trifluridine, or FTD) and a thymidine phosphorylase inhibitor (tipiracil, or TPI).
It was approved by the Food and Drug Administration in 2015 for the treatment of patients with metastatic colorectal cancer who have been previously treated with chemotherapy and biological therapy.
In a phase 2 study conducted in Japan with 29 patients with metastatic gastric cancer that had progressed after chemotherapy with fluoropyrimidine, platinum, taxanes, or irinotecan, FTD/TPI was associated with a median overall survival of 8.7 months and an investigator-assessed disease control rate of 65.5%, Dr. Tabernero noted.
In the TAGS trial, patients with metastatic gastric cancer, including cancers of the gastroesophageal junction who had disease progression after two or more prior lines of therapy were randomized on a 2:1 basis to receive either oral FTD/TPI 35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle or to receive placebo. In both arms, patients also received best supportive care.
As noted, the trial met its primary endpoint, with a 2.1 month improvement in median survival over placebo, which translated into a hazard ratio for death with FTD/TPI of 0.69 (P = .0003).
The 12-month overall survival rate for the FTD/TPI group was 21%, compared with 13% for the placebo group.
Median progression-free survival, a secondary endpoint, was also slightly but significantly better with FTD/TPI at 2.0 vs. 1.8 months (HR, 0.57; P less than .0001). Six-month progression-free survival rates were 15% and 6%, respectively.
Grade 3 or greater adverse events occurred in 80% of patients on FTD/TPI versus 58% of those on placebo. The drug combination was associated with more treatment-related adverse events (81% vs. 57%) but fewer adverse events leading to discontinuation (13% vs. 17%) and fewer treatment-related deaths (0.3 % vs. 0.6%).
FTD/TPI was also associated with more cases of grade 3 or 4 neutropenia, leukopenia, lymphocytopenia, anemia, and thrombocytopenia. Six patients (2%) treated with FTD/TPI had grade 3 or 4 febrile neutropenia, compared with none in the placebo group.
“The safety profile of trifluridine/tipiracil was predictable, manageable, and comparable to the population previously evaluated with metastatic colorectal cancer, with no new safety signals,” Dr. Tabernero said.
SOURCE: Tabernero J et al. ESMO GI 2018, Abstract LBA 002.
BARCELONA – In patients with heavily pretreated metastatic gastric cancer, trifluridine/tipiracil was associated with a brief but statistically significant survival benefit, compared with placebo.
In the randomized, controlled TAGS (TAS-102 Gastric Study), median overall survival, the primary endpoint, was 5.7 months for patients assigned to receive trifluridine/tipiracil, compared with 3.6 months for patients randomized to placebo, reported Josep Tabernero, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona.
Trifluridine/tipiracil (Lonsurf) is a combination of an oral thymidine analog (trifluridine, or FTD) and a thymidine phosphorylase inhibitor (tipiracil, or TPI).
It was approved by the Food and Drug Administration in 2015 for the treatment of patients with metastatic colorectal cancer who have been previously treated with chemotherapy and biological therapy.
In a phase 2 study conducted in Japan with 29 patients with metastatic gastric cancer that had progressed after chemotherapy with fluoropyrimidine, platinum, taxanes, or irinotecan, FTD/TPI was associated with a median overall survival of 8.7 months and an investigator-assessed disease control rate of 65.5%, Dr. Tabernero noted.
In the TAGS trial, patients with metastatic gastric cancer, including cancers of the gastroesophageal junction who had disease progression after two or more prior lines of therapy were randomized on a 2:1 basis to receive either oral FTD/TPI 35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle or to receive placebo. In both arms, patients also received best supportive care.
As noted, the trial met its primary endpoint, with a 2.1 month improvement in median survival over placebo, which translated into a hazard ratio for death with FTD/TPI of 0.69 (P = .0003).
The 12-month overall survival rate for the FTD/TPI group was 21%, compared with 13% for the placebo group.
Median progression-free survival, a secondary endpoint, was also slightly but significantly better with FTD/TPI at 2.0 vs. 1.8 months (HR, 0.57; P less than .0001). Six-month progression-free survival rates were 15% and 6%, respectively.
Grade 3 or greater adverse events occurred in 80% of patients on FTD/TPI versus 58% of those on placebo. The drug combination was associated with more treatment-related adverse events (81% vs. 57%) but fewer adverse events leading to discontinuation (13% vs. 17%) and fewer treatment-related deaths (0.3 % vs. 0.6%).
FTD/TPI was also associated with more cases of grade 3 or 4 neutropenia, leukopenia, lymphocytopenia, anemia, and thrombocytopenia. Six patients (2%) treated with FTD/TPI had grade 3 or 4 febrile neutropenia, compared with none in the placebo group.
“The safety profile of trifluridine/tipiracil was predictable, manageable, and comparable to the population previously evaluated with metastatic colorectal cancer, with no new safety signals,” Dr. Tabernero said.
SOURCE: Tabernero J et al. ESMO GI 2018, Abstract LBA 002.
REPORTING FROM ESMO GI 2018
Key clinical point: Trifluridine/tipiracil (FTD/TIP) produced a small but significant survival benefit in patients with advanced gastric cancer.
Major finding: Median overall survival was 5.7 months with trifluridine/tipiracil versus 3.6 months with placebo.
Study details: Randomized, placebo-controlled trial in 506 patients with metastatic gastric cancer that progressed on at least two prior lines of therapy.
Disclosures: The study was sponsored by Taiho Oncology. Dr. Tabernero disclosed a consulting or advisory role for the company and others.
Source: Tabernero J et al. ESMO GI 2018, Abstract LBA 002.
Pembrolizumab does not surpass paclitaxel for gastric cancer
BARCELONA – The immune checkpoint inhibitor pembrolizumab (Keytruda) did not significantly improve overall survival of advanced/metastatic gastric or gastroesophageal junction cancer compared with paclitaxel, the results of the KEYNOTE-061 study show.
Among 395 patients with gastric or gastroesophageal junction (GEJ) cancer who had expression of the programmed death ligand 1 (PD-L1) on 1% or more of their tumor cells, lymphocytes, and macrophages, median overall survival (OS) for patients treated with pembrolizumab was 9.1 months, compared with 8.3 months. This translated into a hazard ratio (HR) for death in the pembrolizumab arm of 0.82, but with the 95% confidence interval crossing 1.00, and a P value (.04205) that did not meet the prespecified threshold for significance (P equal to or less than .0135).
Despite the failure of the trial to reach its primary endpoint, “these results may support further research to identify patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy for gastric cancer,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
Pembrolizumab is approved by the Food and Drug Administration for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with tumors confirmed to carry PD-L1 for whom two or more prior lines of therapy had failed.
The approval was based on results of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score (CPS) of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
The drug is also approved for unresectable of metastatic gastric tumors with high levels of microsatellite instability that progressed on prior therapy.
The KEYNOTE-061 study was designed to test the proposition that pembrolizumab could improve on paclitaxel for treatment of patients with adenocarcinoma of the stomach or GEJ that was metastatic or locally advanced and unresectable, and for which first-line therapy with a platinum agent and fluoropyrimidine had failed.
A total of 592 patients from Europe, Israel, North America, Asia, and Australia were enrolled and randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 35 cycles, or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 4-week cycle. Each treatment was continued until the maximum number of cycles (for pembrolizumab) or until confirmed disease progression, intolerable toxicity, patient withdrawal, or investigator’s decision.
As noted, OS for patients with a CPS score of 1 or greater, the primary endpoint, did not differ between treatment arms, but there was a numerical tilt that appeared to be in favor of pembrolizumab.
For example, the 12-month OS rates were 39.8% in the pembrolizumab groups vs. 27.1% in the paclitaxel group, and respective 18-month OS rates were 25.7% and 14.8%.
In an analysis of protocol-specified subgroups, there were general trends slightly favoring the checkpoint inhibitor over the taxane, but the only significant difference was among patients with GEJ cancers as the primary tumor location (HR, 0.61, 95% confidence interval, 0.41-0.90).
Pembrolizumab offered a small but significant survival advantage among patients with Eastern Cooperative Oncology Group performance status of 0, with a median OS of 12.3 months vs. 9.3 months (HR, 0.69, 95% CI, 0.49-0.97).
Analyses of PFS and OS by CPS score groups (less than 1, 1-10, or 10 and higher) showed no significant differences, however.
Treatment-related adverse events were more frequent with paclitaxel (84.1% vs. 52.7% of patients on pembrolizumab), but pembrolizumab was associated with more treatment-related deaths (three vs. one). Two of the deaths in the pembrolizumab arm were immune mediated. Grade 3 or greater adverse events occurred in 14.3% vs. 34.8%, respectively.
In the question-and-response following Dr. Shitara’s presentation, session comoderator David Cunningham, MD, of Royal Marsden NHS Foundation Trust in Sutton, England, asked why the KEYNOTE-061 investigators did not pit pembrolizumab against the combination of paclitaxel and ramucirumab (Cyramza) “since that’s what many people would use in this situation.”
Dr. Shitara replied that ramucirumab was not available or accepted as an option in many countries when the trial was first planned in 2014. He added that paclitaxel and ramucirumab should be the control arm for clinical trials going forward.
SOURCE: Shitara K. et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
BARCELONA – The immune checkpoint inhibitor pembrolizumab (Keytruda) did not significantly improve overall survival of advanced/metastatic gastric or gastroesophageal junction cancer compared with paclitaxel, the results of the KEYNOTE-061 study show.
Among 395 patients with gastric or gastroesophageal junction (GEJ) cancer who had expression of the programmed death ligand 1 (PD-L1) on 1% or more of their tumor cells, lymphocytes, and macrophages, median overall survival (OS) for patients treated with pembrolizumab was 9.1 months, compared with 8.3 months. This translated into a hazard ratio (HR) for death in the pembrolizumab arm of 0.82, but with the 95% confidence interval crossing 1.00, and a P value (.04205) that did not meet the prespecified threshold for significance (P equal to or less than .0135).
Despite the failure of the trial to reach its primary endpoint, “these results may support further research to identify patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy for gastric cancer,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
Pembrolizumab is approved by the Food and Drug Administration for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with tumors confirmed to carry PD-L1 for whom two or more prior lines of therapy had failed.
The approval was based on results of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score (CPS) of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
The drug is also approved for unresectable of metastatic gastric tumors with high levels of microsatellite instability that progressed on prior therapy.
The KEYNOTE-061 study was designed to test the proposition that pembrolizumab could improve on paclitaxel for treatment of patients with adenocarcinoma of the stomach or GEJ that was metastatic or locally advanced and unresectable, and for which first-line therapy with a platinum agent and fluoropyrimidine had failed.
A total of 592 patients from Europe, Israel, North America, Asia, and Australia were enrolled and randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 35 cycles, or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 4-week cycle. Each treatment was continued until the maximum number of cycles (for pembrolizumab) or until confirmed disease progression, intolerable toxicity, patient withdrawal, or investigator’s decision.
As noted, OS for patients with a CPS score of 1 or greater, the primary endpoint, did not differ between treatment arms, but there was a numerical tilt that appeared to be in favor of pembrolizumab.
For example, the 12-month OS rates were 39.8% in the pembrolizumab groups vs. 27.1% in the paclitaxel group, and respective 18-month OS rates were 25.7% and 14.8%.
In an analysis of protocol-specified subgroups, there were general trends slightly favoring the checkpoint inhibitor over the taxane, but the only significant difference was among patients with GEJ cancers as the primary tumor location (HR, 0.61, 95% confidence interval, 0.41-0.90).
Pembrolizumab offered a small but significant survival advantage among patients with Eastern Cooperative Oncology Group performance status of 0, with a median OS of 12.3 months vs. 9.3 months (HR, 0.69, 95% CI, 0.49-0.97).
Analyses of PFS and OS by CPS score groups (less than 1, 1-10, or 10 and higher) showed no significant differences, however.
Treatment-related adverse events were more frequent with paclitaxel (84.1% vs. 52.7% of patients on pembrolizumab), but pembrolizumab was associated with more treatment-related deaths (three vs. one). Two of the deaths in the pembrolizumab arm were immune mediated. Grade 3 or greater adverse events occurred in 14.3% vs. 34.8%, respectively.
In the question-and-response following Dr. Shitara’s presentation, session comoderator David Cunningham, MD, of Royal Marsden NHS Foundation Trust in Sutton, England, asked why the KEYNOTE-061 investigators did not pit pembrolizumab against the combination of paclitaxel and ramucirumab (Cyramza) “since that’s what many people would use in this situation.”
Dr. Shitara replied that ramucirumab was not available or accepted as an option in many countries when the trial was first planned in 2014. He added that paclitaxel and ramucirumab should be the control arm for clinical trials going forward.
SOURCE: Shitara K. et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
BARCELONA – The immune checkpoint inhibitor pembrolizumab (Keytruda) did not significantly improve overall survival of advanced/metastatic gastric or gastroesophageal junction cancer compared with paclitaxel, the results of the KEYNOTE-061 study show.
Among 395 patients with gastric or gastroesophageal junction (GEJ) cancer who had expression of the programmed death ligand 1 (PD-L1) on 1% or more of their tumor cells, lymphocytes, and macrophages, median overall survival (OS) for patients treated with pembrolizumab was 9.1 months, compared with 8.3 months. This translated into a hazard ratio (HR) for death in the pembrolizumab arm of 0.82, but with the 95% confidence interval crossing 1.00, and a P value (.04205) that did not meet the prespecified threshold for significance (P equal to or less than .0135).
Despite the failure of the trial to reach its primary endpoint, “these results may support further research to identify patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy for gastric cancer,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
Pembrolizumab is approved by the Food and Drug Administration for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with tumors confirmed to carry PD-L1 for whom two or more prior lines of therapy had failed.
The approval was based on results of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score (CPS) of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
The drug is also approved for unresectable of metastatic gastric tumors with high levels of microsatellite instability that progressed on prior therapy.
The KEYNOTE-061 study was designed to test the proposition that pembrolizumab could improve on paclitaxel for treatment of patients with adenocarcinoma of the stomach or GEJ that was metastatic or locally advanced and unresectable, and for which first-line therapy with a platinum agent and fluoropyrimidine had failed.
A total of 592 patients from Europe, Israel, North America, Asia, and Australia were enrolled and randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 35 cycles, or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 4-week cycle. Each treatment was continued until the maximum number of cycles (for pembrolizumab) or until confirmed disease progression, intolerable toxicity, patient withdrawal, or investigator’s decision.
As noted, OS for patients with a CPS score of 1 or greater, the primary endpoint, did not differ between treatment arms, but there was a numerical tilt that appeared to be in favor of pembrolizumab.
For example, the 12-month OS rates were 39.8% in the pembrolizumab groups vs. 27.1% in the paclitaxel group, and respective 18-month OS rates were 25.7% and 14.8%.
In an analysis of protocol-specified subgroups, there were general trends slightly favoring the checkpoint inhibitor over the taxane, but the only significant difference was among patients with GEJ cancers as the primary tumor location (HR, 0.61, 95% confidence interval, 0.41-0.90).
Pembrolizumab offered a small but significant survival advantage among patients with Eastern Cooperative Oncology Group performance status of 0, with a median OS of 12.3 months vs. 9.3 months (HR, 0.69, 95% CI, 0.49-0.97).
Analyses of PFS and OS by CPS score groups (less than 1, 1-10, or 10 and higher) showed no significant differences, however.
Treatment-related adverse events were more frequent with paclitaxel (84.1% vs. 52.7% of patients on pembrolizumab), but pembrolizumab was associated with more treatment-related deaths (three vs. one). Two of the deaths in the pembrolizumab arm were immune mediated. Grade 3 or greater adverse events occurred in 14.3% vs. 34.8%, respectively.
In the question-and-response following Dr. Shitara’s presentation, session comoderator David Cunningham, MD, of Royal Marsden NHS Foundation Trust in Sutton, England, asked why the KEYNOTE-061 investigators did not pit pembrolizumab against the combination of paclitaxel and ramucirumab (Cyramza) “since that’s what many people would use in this situation.”
Dr. Shitara replied that ramucirumab was not available or accepted as an option in many countries when the trial was first planned in 2014. He added that paclitaxel and ramucirumab should be the control arm for clinical trials going forward.
SOURCE: Shitara K. et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
REPORTING FROM ESMO GI 2018
Key clinical point: KEYNOTE-061 did not meet its primary endpoint of a significant survival advantage with pembrolizumab over paclitaxel.
Major finding: There was no significant difference in overall survival between patients with gastric or gastroesophageal junction cancers treated with pembrolizumab or paclitaxel.
Study details: Phase 3 randomized open-label trial in 592 patients with advanced or metastatic and unresectable tumors of the stomach of GEJ.
Disclosures: The trial was supported by Merck. Dr. Shitara has disclosed honoraria from Abbvie, Novartis and Yakult, consulting or advising with Astellas, BMS. Lilly, Ono Pharmaceutical, Pfizer, and Takeda, and institutional research funding from other companies. Dr. Cunningham has disclosed institutional research finding from Merck Serono and others.
Source: Shitara K et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
Ramucirumab improves HCC survival after sorafenib failure
BARCELONA – For patients with hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) levels who have disease progression following first-line sorafenib (Nexavar), the antiangiogenic agent ramucirumab was associated with a modest but significant improvement in overall survival, compared with placebo, a pooled analysis of clinical trial data showed.
Among 316 patients assigned to receive ramucirumab in the phase 3 REACH and REACH-2 trials, median overall survival was 8.1 months, compared with 5.0 months for placebo, an absolute difference of 3.1 months that translated into a hazard ratio favoring ramucirumab of 0.694 (P = .0002), reported Andrew X. Zhu, MD, PhD of the Massachusetts General Hospital Cancer Center in Boston.
Ramucirumab (Cyramza) is a human IgG1 monoclonal antibody directed against ligand activation of the vascular endothelial growth factor receptor 2.
The REACH trial did not meet its primary endpoint of an improvement in overall survival with ramucirumab in an intention-to-treat population. (Lancet Oncol. 2015 Jul;16(7):859-70). REACH-2, however, results of which were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO 2018, Abstract 4003), met its primary endpoint of overall survival with ramucirumab, with a median overall survival of 8.5 months versus 7.3 months for placebo (HR, 0.71; P = .0199) in patients with AFP levels of 400 ng/mL or greater who had experienced disease progression after first-line sorafenib.
The pooled analysis Dr. Zhu presented was designed to provide a better assessment of the efficacy and safety of ramucirumab as a second-line agent in this high-risk population.
In REACH, 250 patients with advanced HCC and AFP 400 ng/mL or greater were enrolled and randomized on a 1:1 basis to ramucirumab or placebo. In REACH 2, patients were randomized on a 2:1 basis to either ramucirumab 8 mg/kg intravenously every 2 weeks (the same dose as in REACH) or placebo. The pooled analysis included 316 patients on ramucirumab and 226 placebo-treated controls.
In each trial, treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, overall response rate, safety, and patient-reported outcomes.
Overall survival in the pooled analysis was as noted before. The benefits of ramucirumab were significantly better for men, for patients younger than 65 years, for patients of white and Asian race, for those with non–hepatitis B or C etiology of liver disease, and in patients with extrahepatic metastases. In addition, those without microvascular invasion, patients with Barcelona Clinic Liver Cancer score C versus B, those with excellent baseline performance status, those who received prior locoregional therapy, and patients who discontinued sorafenib because of disease progression also saw benefit from ramucirumab.
“Ramucirumab’s overall survival treatment benefit was consistent and robust across all subgroups. Sensitivity analyses, include random effect models, were consistent,” Dr. Zhu said.
The median progression-free survival with ramucirumab was 2.8 months, compared with 1.5 months for placebo (P less than .0001). The overall response rate, including all complete and partial responses, was 5.4% for ramucirumab versus 0.9% for placebo (P = .0064). The respective disease control rates, including patients with stable disease, were 56.3% versus 37.2% (P less than .0001).
Adverse events of special interest included grade 3 or greater liver injury or failure in 19.9% of patients on ramucirumab versus 26.5% on placebo, bleeding and/or hemorrhagic events in 4.7% versus 6.7%, and hypertension in 12.7% versus 3.6%.
The REACH trials were supported by Eli Lilly. Dr. Zhu disclosed consulting/advising for Eli Lilly and others, and institutional research from Eli Lilly and others.
SOURCE: Zhu AX et al. ESMO GI 2018, Abstract LBA-001.
BARCELONA – For patients with hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) levels who have disease progression following first-line sorafenib (Nexavar), the antiangiogenic agent ramucirumab was associated with a modest but significant improvement in overall survival, compared with placebo, a pooled analysis of clinical trial data showed.
Among 316 patients assigned to receive ramucirumab in the phase 3 REACH and REACH-2 trials, median overall survival was 8.1 months, compared with 5.0 months for placebo, an absolute difference of 3.1 months that translated into a hazard ratio favoring ramucirumab of 0.694 (P = .0002), reported Andrew X. Zhu, MD, PhD of the Massachusetts General Hospital Cancer Center in Boston.
Ramucirumab (Cyramza) is a human IgG1 monoclonal antibody directed against ligand activation of the vascular endothelial growth factor receptor 2.
The REACH trial did not meet its primary endpoint of an improvement in overall survival with ramucirumab in an intention-to-treat population. (Lancet Oncol. 2015 Jul;16(7):859-70). REACH-2, however, results of which were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO 2018, Abstract 4003), met its primary endpoint of overall survival with ramucirumab, with a median overall survival of 8.5 months versus 7.3 months for placebo (HR, 0.71; P = .0199) in patients with AFP levels of 400 ng/mL or greater who had experienced disease progression after first-line sorafenib.
The pooled analysis Dr. Zhu presented was designed to provide a better assessment of the efficacy and safety of ramucirumab as a second-line agent in this high-risk population.
In REACH, 250 patients with advanced HCC and AFP 400 ng/mL or greater were enrolled and randomized on a 1:1 basis to ramucirumab or placebo. In REACH 2, patients were randomized on a 2:1 basis to either ramucirumab 8 mg/kg intravenously every 2 weeks (the same dose as in REACH) or placebo. The pooled analysis included 316 patients on ramucirumab and 226 placebo-treated controls.
In each trial, treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, overall response rate, safety, and patient-reported outcomes.
Overall survival in the pooled analysis was as noted before. The benefits of ramucirumab were significantly better for men, for patients younger than 65 years, for patients of white and Asian race, for those with non–hepatitis B or C etiology of liver disease, and in patients with extrahepatic metastases. In addition, those without microvascular invasion, patients with Barcelona Clinic Liver Cancer score C versus B, those with excellent baseline performance status, those who received prior locoregional therapy, and patients who discontinued sorafenib because of disease progression also saw benefit from ramucirumab.
“Ramucirumab’s overall survival treatment benefit was consistent and robust across all subgroups. Sensitivity analyses, include random effect models, were consistent,” Dr. Zhu said.
The median progression-free survival with ramucirumab was 2.8 months, compared with 1.5 months for placebo (P less than .0001). The overall response rate, including all complete and partial responses, was 5.4% for ramucirumab versus 0.9% for placebo (P = .0064). The respective disease control rates, including patients with stable disease, were 56.3% versus 37.2% (P less than .0001).
Adverse events of special interest included grade 3 or greater liver injury or failure in 19.9% of patients on ramucirumab versus 26.5% on placebo, bleeding and/or hemorrhagic events in 4.7% versus 6.7%, and hypertension in 12.7% versus 3.6%.
The REACH trials were supported by Eli Lilly. Dr. Zhu disclosed consulting/advising for Eli Lilly and others, and institutional research from Eli Lilly and others.
SOURCE: Zhu AX et al. ESMO GI 2018, Abstract LBA-001.
BARCELONA – For patients with hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) levels who have disease progression following first-line sorafenib (Nexavar), the antiangiogenic agent ramucirumab was associated with a modest but significant improvement in overall survival, compared with placebo, a pooled analysis of clinical trial data showed.
Among 316 patients assigned to receive ramucirumab in the phase 3 REACH and REACH-2 trials, median overall survival was 8.1 months, compared with 5.0 months for placebo, an absolute difference of 3.1 months that translated into a hazard ratio favoring ramucirumab of 0.694 (P = .0002), reported Andrew X. Zhu, MD, PhD of the Massachusetts General Hospital Cancer Center in Boston.
Ramucirumab (Cyramza) is a human IgG1 monoclonal antibody directed against ligand activation of the vascular endothelial growth factor receptor 2.
The REACH trial did not meet its primary endpoint of an improvement in overall survival with ramucirumab in an intention-to-treat population. (Lancet Oncol. 2015 Jul;16(7):859-70). REACH-2, however, results of which were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO 2018, Abstract 4003), met its primary endpoint of overall survival with ramucirumab, with a median overall survival of 8.5 months versus 7.3 months for placebo (HR, 0.71; P = .0199) in patients with AFP levels of 400 ng/mL or greater who had experienced disease progression after first-line sorafenib.
The pooled analysis Dr. Zhu presented was designed to provide a better assessment of the efficacy and safety of ramucirumab as a second-line agent in this high-risk population.
In REACH, 250 patients with advanced HCC and AFP 400 ng/mL or greater were enrolled and randomized on a 1:1 basis to ramucirumab or placebo. In REACH 2, patients were randomized on a 2:1 basis to either ramucirumab 8 mg/kg intravenously every 2 weeks (the same dose as in REACH) or placebo. The pooled analysis included 316 patients on ramucirumab and 226 placebo-treated controls.
In each trial, treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, overall response rate, safety, and patient-reported outcomes.
Overall survival in the pooled analysis was as noted before. The benefits of ramucirumab were significantly better for men, for patients younger than 65 years, for patients of white and Asian race, for those with non–hepatitis B or C etiology of liver disease, and in patients with extrahepatic metastases. In addition, those without microvascular invasion, patients with Barcelona Clinic Liver Cancer score C versus B, those with excellent baseline performance status, those who received prior locoregional therapy, and patients who discontinued sorafenib because of disease progression also saw benefit from ramucirumab.
“Ramucirumab’s overall survival treatment benefit was consistent and robust across all subgroups. Sensitivity analyses, include random effect models, were consistent,” Dr. Zhu said.
The median progression-free survival with ramucirumab was 2.8 months, compared with 1.5 months for placebo (P less than .0001). The overall response rate, including all complete and partial responses, was 5.4% for ramucirumab versus 0.9% for placebo (P = .0064). The respective disease control rates, including patients with stable disease, were 56.3% versus 37.2% (P less than .0001).
Adverse events of special interest included grade 3 or greater liver injury or failure in 19.9% of patients on ramucirumab versus 26.5% on placebo, bleeding and/or hemorrhagic events in 4.7% versus 6.7%, and hypertension in 12.7% versus 3.6%.
The REACH trials were supported by Eli Lilly. Dr. Zhu disclosed consulting/advising for Eli Lilly and others, and institutional research from Eli Lilly and others.
SOURCE: Zhu AX et al. ESMO GI 2018, Abstract LBA-001.
REPORTING FROM ESMO GI 2018
Key clinical point: Second-line therapy with a vascular endothelial growth factor receptor 2 inhibitor modestly improved survival of patients with advanced hepatocellular carcinoma that progressed after first-line sorafenib.
Major finding: Median overall survival was 8.1 months with ramucirumab versus 5 months for placebo.
Study details: An analysis of pooled data from two phase 3 clinical trials with a total of 316 patients treated with ramucirumab and 226 treated with placebo.
Disclosures: The REACH trials were supported by Eli Lilly. Dr. Zhu disclosed consulting/advising for Eli Lilly and others, and institutional research from Eli Lilly and others.
Source: Zhu AX et al. ESMO GI 2018, Abstract LBA-001.