Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia: The Phase 2 RAINSTORM Randomized Clinical Trial

Abstract

Importance: Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting.

Objective: To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer.

Design, setting, and participants: This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018.

Interventions: Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle).

Main outcomes and measures: The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events.

Results: In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]).

Conclusions and relevance: In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified.

Trial registration: ClinicalTrials.gov identifier: NCT02539225.

Conflict of interest statement

Conflict of Interest Disclosures: Dr T. Yoshikawa reported honoraria from Eli Lilly, Abbott Nutrition, Ajinomoto, Chugai Pharmaceutical, Daiichi Sankyo, Johnson & Johnson, Medtronic, Nippon Kayaku, Olympus, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha; a consulting/advisory role for Chugai Pharmaceutical, MSD Oncology, and Novartis; research funding from Chugai Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha; and personal fees from Taiho, Ono, BMS, MSD, Chugai Pharmaceutical, Daiichi Sankyo, Nippon Kayaku, TERUMO, Covidien Japan, and Olympus as well as grants and personal fees from Lilly outside of the submitted work. Dr Muro reported honoraria from Eli Lilly, Chugai Pharmaceutical, Merck Serono, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha; research funding from Daiichi Sankyo, Gilead Sciences, Kyowa Hakko Kirin, MSD, Ono Pharmaceutical, and Shionogi; grants and personal fees from Eli Lilly during the conduct of the study; grants from Gilead Sciences, Merck Serono, MSD, Daiichi Sankyo, Shionogi, Pfizer, Kyowa Hakko Kirin; personal fees from Chugai Pharmaceutical, Takeda, Taiho, Bayer, and Bristol-Myers Squibb outside of the submitted work; and grants and personal fees from Sanofi and Ono. Dr Shitara reported honoraria from AbbVie, Novartis, and Yakult Honsha; a consulting/advisory role for Eli Lilly, Astellas Pharma, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, and Takeda Pharmaceutical; research funding from Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; grants and personal fees from Astellas Pharma, Lilly, Ono Pharmaceutical, and MSD; personal fees from Bristol-Myers Squibb, Takeda, Pfizer, Novartis, AbbVie, and Yakult Honsha; and grants from Dainippon Sumitomo Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, and Medi Science outside of the submitted work. Dr Oh reported a consulting/advisory role with AstraZeneca, Baxalta, and Merck and research funding from Array BioPharma, AstraZeneca, and Threshold Pharmaceuticals. Dr Kang reported a consulting/advisory role with Eli Lilly/ImClone, Bristol-Myers Squibb, DAE HWA Pharmaceutical, Merck Serono, Ono Pharmaceutical, Roche/Genetech, and Taiho Pharmaceutical; research funding from DAE HWA Pharmaceutical and LSK Biopharma; nonfinancial support from Eli Lilly; personal fees from Taiho, Ono, BMS, Blueprint, Daehwa, LSK Biopharma, and Merck Serono outside of the submitted work; and grants from Novartis. Dr Chung reported a consulting/advisory role with Eli Lilly, Bristol-Myers Squibb, Celltrion Pharma, Merck, MSD, Quintiles, and Taiho Pharmaceutical; participation in speakers’ bureaus for Eli Lilly, Foundation Medicine, and Merck Serono; research funding from Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, MSD, and Taiho Pharmaceutical; and grants from Eli Lilly, MSD, Merck-Serono, BMS-ONO, Taiho, and GlaxoSmithKline outside of the submitted work. Dr Kudo reported honoraria from Eli Lilly, Bayer, Chugai Pharmaceutical, Merck Serono, Taiho Pharmaceutical, and Takeda Pharmaceutical; research funding from Eli Lilly, Bayer Yakuhin, Chugai Pharmaceutical, Ono Pharmaceutical, and Yakult Honsha; and grants from Yakult Honsha, Chugai Pharmaceutical, and Ono Pharmaceutical outside of the submitted work. Dr Chin reported research funding from Eli Lilly, AstraZeneca, MDS, Ono Pharmaceutical, Shionogi, and Taiho Pharmaceutical. Dr Kadowaki reported honoraria from Eli Lilly, Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical, Ono Pharmaceutical, and Yakult Honsha; research funding from Eli Lilly Japan KK, Boehringer Ingelheim, Bristol-Myers Squibb, Ono Pharmaceutical, and Taiho Pharmaceutical; grants and personal fees from Taiho Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb; and personal fees from Bayer, Yakult Honsha, and Chugai Pharmaceutical outside of the submitted work. Dr Hamamoto reported honoraria from Eli Lilly, Bristol-Myers Squibb KK, Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha during the conduct of the study. Dr Hironaka reported honoraria from Eli Lilly, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha and personal fees from Eli Lilly, Taiho Pharmaceutical, and Yakult Honsha during the conduct of the study. Dr Yoshida reported honoraria from Eli Lilly Japan KK, Bayer Yakuhin, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Covidien, Daiichi Sankyo, Denka, EA Pharma, Eisai, Johnson & Johnson, Merck Serono, MSD KK, Nippon Kayaku, Olympus, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, Terumo Pharmaceutical, and Yakult Honsha; research funding from Eli Lilly, Abbott Laboratories, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharmaceutical, Covidien, Daiichi Sankyo, Eisai, Johnson & Johnson, KCI Pharma, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, Toyama Chemical, Tsumura, and Yakult Honsha; travel grants from Eli Lilly Japan KK, Bayer Yakuhin, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Covidien, Daiichi Sankyo, Denka, EA Pharma, Eisai, Johnson & Johnson, Merck Serono, MSD KK, Nippon Kayaku, Olympus, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, Terumo Pharmaceutical, and Yakult Honsha; grants and personal fees from Eli Lilly during the conduct of the study; grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Yakult Honsha, MSD, Daiichi Sankyo, Ono Pharmaceutical, Merck Serono, Johnson & Johnson, Covidien, Eisai, Otsuka Pharmaceutical, Sanofi, Nippon Kayaku, Asahi Kasei, and Tsumura; grants from Kyowa Hakko Kirin, Astellas, Toyama Chemical, KCI, Abbott Japan, and Toray Medical; and personal fees from EA Pharmaceutical, Bayer Yakuhin, Olympus, Terumo, Bristol Myers Japan, Denka, Teijin, SBI Pharmaceutical, Intuitive Surgical, Novartis, and Pfizer outside of the submitted work. Dr Omuro reported research funding from Eli Lilly, MSD, and Ono Pharmaceutical; grants from Eli Lilly during the conduct of the study; and grants from Astellas Pharma, MSD, Daiichisankyo, and Ono Pharmaceutical outside of the submitted work. Dr Bai reported a consulting/advisory role with Eli Lilly and MSD. Mr Maeda reported employment at and stock ownership in Eli Lilly Japan KK. Dr Ozeki reported employment at Eli Lilly Japan KK as well as research funding and travel, accommodations, and expenses from Eli Lilly Japan KK. Dr R. Yoshikawa reported employment at and stock ownership in Eli Lilly Japan KK during the conduct of the study. Dr Kitagawa reported honoraria from Asahi Kasei Pharma, Chugai Pharmaceutical, Ethicon, Nippon Kayaku, Olympus, Ono Pharmaceutical, and Taiho Pharmaceutical; research funding from Eli Lilly, Ajinomoto, Asahi Kasei Pharma, Astellas Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, CSL Behring, Daiichi Sankyo, Dainippon Sumitomo Pharma, EA Pharma, GlaxoSmithKline, Kaken Pharmaceutical, Kowa Pharmaceutical, Kureha, Kyowa Hakko Kirin, Medicon, Medtronic, Merck Serono, Nippon Kayaku, Novartis, Otsuka Pharmaceutical, Pfizer, Sanofi, Shionogi, Taiho Pharmaceutical, Taisho Toyama Pharma, Takeda Pharmaceutical, Teijin Pharma, Tsumura, and Yakult Honsha; and grants and personal fees from Taiho Pharmaceutical, Yakult Honsha, and Eli Lilly during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

At the time of data cutoff, 15 patients were still receiving treatment in part A, 2 patients were in the follow-up period after part A, and 17 patients were still receiving treatment in part B. The 2 patients in the ramucirumab plus S-1 and oxaliplatin (RAM+SOX) arm and the 1 patient in the placebo plus S-1 and oxaliplatin (PBO+SOX) arm who discontinued part A for the reason of death are not included in the numbers of patients after part A. In part B, all patients were to receive second-line paclitaxel plus ramucirumab (PTX+RAM) treatment.

Figure 2.. Progression-Free Survival (PFS), Overall Survival (OS), and Second Disease Progression (PFS2) in Patients Receiving Ramucirumab Plus S-1 and Oxaliplatin (RAM+SOX) or Placebo Plus S-1 and Oxaliplatin (PBO+SOX) in Part A

Stratified log-rank test was used to analyze PFS, OS, and PFS2. Hazard ratios (HRs) were estimated with a stratified Cox proportional hazards regression model, and both were stratified by Eastern Cooperative Oncology Group Performance Status, region, and disease measurability. Median PFS was 6.34 (80% CI, 5.65-6.93) months in the RAM+SOX arm and 6.74 (80% CI, 5.75-7.13) months in the PBO+SOX arm (HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median OS was 14.65 (80% CI, 12.39-15.67) months in the RAM+SOX arm and 14.26 (80% CI, 13.83-17.31) months in the PBO+SOX arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). Median PFS2 was 10.94 (80% CI, 9.63-12.52) months in the RAM+SOX arm and 11.99 (80% CI, 9.82-13.83) months in the PBO+SOX arm (HR, 1.11; 80% CI, 0.89-1.39; P = .55).