LBA76 - The primary results of an intergroup phase III randomized controlled trial comparing ramucirumab plus irinotecan with irinotecan in the third or later line treatment beyond progression after ramucirumab for advanced gastric cancer (RINDBeRG trial)

Background

Ramucirumab is a monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and has been shown to improve survival of patients with advanced gastric cancer. It has been reported that sustained VEGF blockade beyond progression had a survival benefit in various cancers.

Methods

This is a multicenter, open-label, randomized phase III study that enrolled patients with unresectable gastric cancer who had received previously ramucirumab containing chemotherapy. Patients were randomly allocated to either irinotecan plus ramucirumab arm or irinotecan alone arm in a 1:1 ratio. Irinotecan was administered at a dose of 150 mg/m², every two weeks, in both arms, and ramucirumab at a dose of 8 mg/kg was added biweekly. The primary endpoint was overall survival (OS), expecting a hazard ratio (HR) of 0.77 (a power of 80% with significance level of one-sided 0.05) for full analysis set (FAS). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), and safety.

Results

From February 2019 to August 2022, 402 patients from 121 institutions participating 9 Japanese clinical trial groups were recruited. As of the data cutoff, 362 events for OS were observed. Median OS in the combination of irinotecan plus ramucirumab and irinotecan alone were 9.4 months and 8.5 months (adjusted HR 0.909, 95% confidence interval [CI] 0.738 – 1.119; p=0.369). Median PFS were 3.8 months and 2.8 months (HR 0.722, 95% CI 0.590 - 0.884; p=0.001) and ORR were 22.1% (33/149) and 15.0% (25/167), respectively. The safety profile was consistent with the known profiles of both irinotecan and ramucirumab, and there were no new safety findings.

Conclusions

This is the first report of the phase III trial to evaluate sustained anti-angiogenic therapy in advanced gastric cancer. In this study, although the addition of ramucirumab to irinotecan after disease progression of ramucirumab improved PFS and ORR with manageable toxicity, the primary endpoint of OS was not met.

Clinical trial identification

This trial was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000023065 from JUL. 13, 2016, and changed to the Japan Registry of Clinical Trials (jRCT) as jRCTs051180187 from Mar. 26, 2019, in accordance with the change of the regulation for clinical research in Japan.

Editorial acknowledgement

Legal entity responsible for the study

Osaka Gastrointestinal cancer chemotherapy Study Group (OGSG).

Funding

Eli Lilly, National Cancer Center Research and Development Fund.

Disclosure

S. Kadowaki: Financial Interests, Personal, Invited Speaker: Taiho, MSD, Ono, Daiichi Sankyo, BMS, Bayer, Merck, Eisai, Otsuka; Financial Interests, Institutional, Funding: Eli Lilly, MSD, Ono, Daiichi Sankyo, Chugai, Nobelpharma, Yansen. D. Sakai: Financial Interests, Personal, Invited Speaker: Daiichi sankyo, Chugai Pharmaceutical; Financial Interests, Institutional, Local PI: Daiichi sankyo, Chugai Pharmaceutical, Taiho Pharmaceutical, Incyte, Ono Pharmaceutical; Financial Interests, Institutional, Funding: Eli Lilly. H. Hara: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol-Myers Squibb; Financial Interests, Institutional, Coordinating PI: Amgen, Astellas, AstraZeneca, Bayel, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX oncology. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin; Financial Interests, Institutional, Local PI: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen. K. Minashi: Financial Interests, Institutional, Research Grant: Amgen, Taiho Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Astellas, Pharmaceutical Co., Ltd,. T. Kawakami: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Other, honoraria: Bristol Myers-Squibb, Ono Pharmaceutical, Yakult Honsha, Daiichi Sankyo. H. Satake: Financial Interests, Personal, Invited Speaker: Bayer Co., Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., MSD Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Co., Ltd., Yakult Honsha Co., Ltd., Novartis Pharma; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co. Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Sanofi; Financial Interests, Institutional, Local PI: Asahi Kasei; Non-Financial Interests, Member: ASCO, JSMO. Y. Sakamoto: Financial Interests, Institutional, Advisory Board: Eli Lilly Japan K.K., Daiichi Sankyo Co. Ltd., Merck Biopharma Japan Co. Ltd., Novartis Pharmaceutical Co. Ltd.; Financial Interests, Institutional, Invited Speaker: MSD K.K., Hisamitsu Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd.. H. Kawakami: Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd., Bayer Yakuhin Ltd, Eli Lilly Japan K.K., MSD K.K., Chugai Pharmaceutical Co. Ltd., Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Teijin Pharma Ltd., Taiho Pharmaceutical Co. Ltd.; Financial Interests, Personal, Advisory Board: Daiichi Sankyo Co. Ltd.; Financial Interests, Personal, Other, Lecture: GSK K.K, Otsuka Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant, Investigator-Initiated Trial: Bristol-Myers Squibb Co. Ltd.; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co. Ltd, Eisai Co., Ltd., Kobayashi Pharmaceutical Co. Ltd., Parexel International Corp., PRA Healthsciences, EPS Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan Clinical Research Operations, Chugai Pharmaceutical Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., GSK K.K., Sanofi K.K., Nippon Boehringer Ingelheim Co.,Ltd., Sysmex Corporation, Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., SRL, Inc., Daiichi Sankyo Co., Ltd., Amgen Inc., Medical Reserch Support, Eli Lilly Japan K.K.. N. Boku: Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Eli Lily, Ono Pharmaceutical, Taiho Pharma, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical, Ono Pharmaceutical. T. Satoh: Financial Interests, Personal, Invited Speaker, invited speaker and advisory: Ono Pharmaceutical, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Invited speaer and adovisory: Bristol-Myers; Financial Interests, Personal, Invited Speaker, Invited speaker and advisory: Elli-Lilly, Yakult-HOnsha; Financial Interests, Personal, Invited Speaker: Chugai Pharmazeutical, Merck-Biopharm, Takeda, Taiho; Financial Interests, Personal, Advisory Board: Takara-Bio; Financial Interests, Institutional, Local PI: Merck-Biopharm; Financial Interests, Institutional, Local PI, Research Grant and Endosed Department: Ono Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Local PI, Research Grant: Bristol-Myers, Elli-Lilly, Daiichi Sankyo, Parexell, Giliad, Taiho, Hutch-Med. All other authors have declared no conflicts of interest.