Ramucirumab/Chemotherapy in Gastric Cancer: ‘Positive’ Trial but Insufficient Benefit


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BASED ON EFFICACY seen in the second-line setting for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma, ramucirumab (Cyramza) was evaluated as first-line therapy in the international phase III RAINFALL trial. Although the study met its primary endpoint, with a 25% improvement in progression-free survival, the addition of ramucirumab to first-line chemotherapy with cisplatin/ capecitabine did not improve overall survival. 

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“We did observe a statistically significant benefit in progression-free survival, but we did not see a survival benefit by any measure, so I would not purport that ramucirumab should be a first-line therapy. The data do not support it supplanting existing front-line therapy,” said Charles S. Fuchs, MD, MPH, Director of the Yale Cancer Center and Physician-in-Chief of Smilow Cancer Hospital, who presented the findings at the 2018 Gastrointestinal Cancers Symposium.1 

Ramucirumab Background 

VASCULAR ENDOTHELIAL growth factor receptor 2 (VEGFR2) and its ligands are important mediators of angiogenesis and contribute to gastric cancer pathogenesis. 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. It 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 adenocarcinomas, for which it is approved. 

In the second-line treatment of advanced gastric or gastroesophageal adenocarcinoma, ramucirumab improved overall survival. In the REGARD trial, 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),2 and in the RAINBOW trial of ramucirumab plus paclitaxel compared with paclitaxel alone, it was 9.6 months vs 7.4 months (HR = 0.807, P = .017).3 

“We did observe a statistically significant benefit in progression-free survival, but we did not see a survival benefit by any measure, so I would not purport that ramucirumab should be a first-line therapy.”
— Charles S. Fuchs, MD, MPH

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The benefit seen in previously treated patients led to the investigation of ramucirumab as upfront treatment. 

RAINFALL Details 

THE RAINFALL TRIAL randomized 645 patients (> 60% European) to ramucirumab (8 mg/kg on 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 9 days. 

“We saw a 25% reduction in the risk of disease progression or death in the investigator-assessed progression-free survival primary endpoint. The progression-free survival benefit was consistent across virtually all subgroups,” Dr. Fuchs reported. “There was no improvement, however, 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 significantly different at 41% vs 36%, respectively (P = .017). Drug exposure, relative dose intensity, and duration of therapy (19 weeks) were all similar between the arms. 

FIRST-LINE RAMUCIRUMAB IN GASTRIC CANCER

  • In the phase III RAINFALL trial, ramucirumab met its primary endpoint as a first-line treatment for metastatic gastric or gastroesophageal junction adenocarcinoma.
  • Median overall survival and response rates were not improved with the addition of ramucirumab.
  • The results are not expected to change the current standard of care.

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 disease progression (ie, post-discontinuation), median overall survival was 16.2 months, compared to 13.2 months for ramucirumab-treated patients who did not receive the drug again. 

For first-line placebo recipients who ultimately received 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 were “modestly” more cases of gastrointestinal perforation and proteinuria among patients receiving ramucirumab, Dr. Fuchs noted. “No new or unexpected safety findings emerged.” ■

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

REFERENCES 

1. Fuchs CS, Shitara K, Di Bartolomeo M, et al: RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin plus capecitabine or 5FU with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. 2018 Gastrointestinal Cancers Symposium. Abstract 5. Presented January 18, 2018. 

2. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31-39, 2014. 

3. Wilke H, Muro K, Van Cutsem E, et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol 15:1224-1235, 2014.


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