2018 GI CANCERS SYMPOSIUM: First-Line Ramucirumab in Gastric Cancer Improves Progression-Free but Not Overall Survival


Key Points

  • Ramucirumab plus capecitabine/cisplatin was evaluated as a first-line treatment.
  • The study met its primary endpoint of improved progression-free survival (P = .011). Median overall survival and response rates were not improved.
  • Data do not support ramucirumab in the first-line setting.

The monoclonal antibody ramucirumab (Cyramza) was evaluated as first-line therapy for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma in the international phase III RAINFALL trialCharles Fuchs, MD, of Yale New Haven Health in Connecticut, presented findings from the study at the 2018 Gastrointestinal Cancers Symposium in San Francisco.

The study was designed based on efficacy seen with ramucirumab in the second-line setting for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma.

Second-Line Therapy

Ramucirumab is a monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGFR2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation.  In the second-line treatment of advanced gastric or gastroesophageal adenocarcinoma, as reported in the REGARD trial, ramucirumab improved overall survival; median overall survival with single-agent ramucirumab was 5.2 months vs 3.8 months with best supportive care (hazard ratio [HR] = 0.776; P = .047). 

In the phase III RAINBOW trial in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma, the combination of ramucirumab with paclitaxel significantly increased overall survival compared with placebo plus paclitaxel. The investigators reported that ramucirumab could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.

About the RAINFALL Study

Based on the efficacy seen with ramucirumab in the second-line setting for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma, investigators sought to evaluate the drug in the first-line setting. The RAINFALL study randomized 645 patients (> 60% European) to ramucirumab (8 mg/kg days 1 and 8) or placebo plus capecitabine/cisplatin. The primary endpoint was progression-free survival for the first 508 patients based on investigator assessment. Overall survival for the intent-to-treat population of 645 patients was a powered secondary endpoint.

Median progression-free survival was significantly prolonged in patients receiving ramucirumab. The hazard ratio was 0.75 and the P value was statistically significant (P = .011); however, median progression-free survival was 5.72 months with ramucirumab vs 5.39 months with placebo—a difference of 0.3 months, or only 9 days.

There was no significant improvement in overall survival. Median overall survival was 11.17 months vs 10.74 months, respectively (HR = 0.96; P = .68). Overall response rates were also not different at 41% vs 36%, respectively (P = .017). Drug exposure, relative dose intensity, and duration of therapy (19 weeks) were all similar among the arms.

In an exploratory analysis, the investigators examined the impact of subsequent treatment on overall survival from the time of randomization. For patients initially receiving ramucirumab and being treated with it again after progression (ie, post-discontinuation), median overall survival was 16.2 months, compared to only 13.2 months for ramucirumab-treated patients not receiving the drug again. For first-line placebo recipients who ultimately got the drug, median overall survival was 14.9 months. Overall survival from the time of subsequent treatment was approximately 1 month longer for patients in either arm who subsequently received ramucirumab post-discontinuation, he noted.

There was more gastrointestinal perforation and proteinuria among patients receiving ramucirumab.

The investigators concluded that the data do not support the use of ramucirumab in first-line therapy for patients with gastric or gastroesophageal junction adenocarcinomas. Ramucirumab is approved as both a single agent and in combination with paclitaxel in the second-line treatment of gastric or gastroesophageal junction adenocarcinomas.

DISCLOSURE: Dr. Fuchs reported consulting or advisory roles for Lilly, Sanofi, Bayer, Merck, Etrinsic Health, Five Prime Therapeutics, Agios, Gilead Sciences, Dicerna, Merrimack, Taiho Pharmaceutical, KEW, and Genentech/Roche.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.