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Ramucirumab reduces risk for progression in certain gastric cancers
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The addition of ramucirumab to first-line chemotherapy conferred a 25% reduction in risk for disease progression or death among treatment-naive patients with metastatic gastric or gastroesophageal junction adenocarcinoma, according to results of a randomized phase 3 study scheduled for presentation at the Gastrointestinal Cancers Symposium.
However, ramucirumab (Cyramza, Eli Lilly) did not improve OS.
Ramucirumab is a VEGFR-2 IgG1 human monoclonal antibody and is the only biologic with proven efficacy as both a single agent and in combination with paclitaxel in the second-line treatment of gastric or gastroesophageal junction (G-GEJ) adenocarcinoma.
During RAINFALL — a global, double-blind, placebo-controlled randomized clinical trial — researchers addressed the hypothesis that adding ramucirumab to first-line cisplatin plus capecitabine or 5-FU would produce significant clinical benefit.
Charles S. Fuchs, MD, MPH, director of Yale Cancer Center, and colleagues randomly assigned 645 patients with metastatic G-GEJ adenocarcinoma who were eligible for first-line chemotherapy and had an ECOG performance status of 0 to 1 to ramucirumab (8 mg/kg via IV on days 1 and 8; n = 326) or placebo (n = 319) every 21 days. All patients received capecitabine or 5-FU plus cisplatin for up to six cycles. Patients continued capecitabine plus ramucirumab or placebo until progressive disease, toxicity or other discontinuation criteria.
PFS served as the primary endpoint for the first 508 patients. OS for the intent-to-treat population served as a secondary endpoint.
PFS appeared significantly prolonged among patients treated with ramucirumab plus capecitabine or cisplatin compared with placebo plus capecitabine or cisplatin (median, 5.7 months vs. 5.4 months; HR = 0.75; 95% CI, 0.61-0.94), meeting the study’s primary endpoint.
Researchers observed no survival benefit for patients treated with ramucirumab compared with placebo (median, 11.2 months vs 10.7 months; HR = 0.96; 95% CI, 0.8-1.16).
Overall response rate in the intent-to-treat population was 41.1% (95% CI, 35.8-46.4) in the ramucirumab arm and 36.4% (95% CI, 31.1-41.6) in the placebo arm.
At least 10% of patients in the ramucirumab arm reported grade 3 or greater adverse events that included neutropenia (26.3% ramucirumab vs. 27% placebo), anemia (12.1% vs. 14%), and hypertension (9.9% vs. 1.6%). – by Chuck Gormley
Disclosures: Eli Lilly funded the study. Fuchs reports consultant/advisory roles with Agios, Bayer, Dicerna, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech/Roche, Gilead Sciences, KEW, Merck, Merrimack, Sanofi and Taiho Pharmaceutical. Please see the abstract for all other authors’ relevant financial disclosures.
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Jimmy J. Hwang, MD
Fuchs and colleagues reported results from RAINFALL, a study of ramucirumab as first-line therapy for patients with metastatic gastric or gastroesophageal junction adenocarcinoma. In this phase 3 clinical trial, 645 patients who had not received prior chemotherapy for metastatic disease were randomly assigned to receive cisplatin and fluoropyrimidine (either infused 5-FU or capecitabine) with either ramucirumab or placebo.
An increase in PFS by 25% (HR = 0.75; P = .011) indicated the study met its primary endpoint; however, median PFS measured 5.72 months with ramucirumab and 5.39 months with placebo. Also, there was no significant increase in either response rate or survival.
These results were disappointing, but consistent with the randomized phase 3 AVAGAST study with bevacizumab (Avastin, Genentech) employing the same chemotherapy backbone. Results also showed improved PFS, but not OS. In addition, a randomized phase 2 study of oxaliplatin, 5-FU and leucovorin on a modified FOLFOX6 schedule did not demonstrate an improvement in response, PFS or OS.
The failures of antivascular endothelial growth factor agents as first-line therapy stand in contrast to the clear survival and response benefits of ramucirumab, either alone or in combination with paclitaxel, as second-line or later therapy, after platinum and/or fluoropyrimidines. The reasons for these discrepancies are unclear but could relate to the chemotherapy backbone, or the first-line treatment setting.
For example, perhaps ramucirumab is more effective in combination with taxanes compared with platinums, as reflected by survival improvements in combination with taxanes in lung and bladder cancers. Alternatively, the survival benefits with ramucirumab in these diseases are in the second-line setting, perhaps suggesting that in these malignancies exposure to recent prior chemotherapies renders them more sensitive to or dependent upon vascular endothelial growth factor. Unfortunately, no clear biomarkers have been identified for the efficacy of ramucirumab, which may hamper further development. At this time, it is unclear whether further development of ramucirumab as part of first-line therapy in gastric cancer will occur.
References:
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Yoon HH, et al. Ann Oncol. 2014;doi:10.1093/annonc/mdw423.
Fuchs CS, et al. Lancet. 2014;doi: 10.1016/S0140-6736(13)61719-5.
Wilke H, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70420-6.
Garon EB, et al. Lancet. 2014;doi: 10.1016/S0140-6736(14)60845-X.
Petrylak DP, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32365-6.
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