Randomized Phase III Trial of Ramucirumab Beyond Progression Plus Irinotecan in Patients With Ramucirumab-Refractory Advanced Gastric Cancer - RINDBeRG Trial

Sep 23, 2026

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Continuous use of antiangiogenic agents has shown survival benefits across cancers, prompting a Phase III comparison in advanced or recurrent gastric and gastroesophageal cancer after progression on prior ramucirumab-based chemotherapy. Patients received either ramucirumab plus irinotecan or irinotecan alone, with overall survival as the primary endpoint. Among 402 Japanese patients, progression-free survival and disease control improved with the combination, but overall survival showed no significant advantage and safety was manageable.

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Original Reports | Gastrointestinal Cancer Randomized Phase III Trial of Ramucirumab Beyond Progression Plus Irinotecan in Patients With Ramucirumab-Refractory Advanced Gastric Cancer: RINDBeRG Trial Daisuke Sakai, MD1,2 ; Shigenori Kadowaki, MD, PhD3 ; Ryohei Kawabata, MD, PhD4; Hiroki Hara, MD5 ; Hironaga Satake, MD, PhD6 ; Masazumi Takahashi, MD, PhD7 ; Atsushi Takeno, MD, PhD8; Hiroo Imai, MD, PhD9; Keiko Minashi, MD10 ; Takeshi Kawakami, MD, PhD11 ; Shogen Boku, MD, PhD12 ; Jin Matsuyama, MD, PhD13; Yasuhiro Sakamoto, MD, PhD14; Kentaro Sawada, MD, PhD15 ; Masato Kataoka, MD, PhD16; Hisato Kawakami, MD, PhD9,17 ; Toshio Shimokawa, PhD18; Narikazu Boku, MD, PhD19 ; and Taroh Satoh, MD, PhD2 DOI [https://doi.org/10.1200/JCO.24.01](https://doi.org/10.1200/JCO.24.01)119 | ABSTRACT | | | --- | --- | | PURPOSE | Continuous use of antiangiogenic agents has demonstrated survival beneﬁtsin various cancers. This trial aimed to compare the efﬁcacy and safety of ramucirumab plus irinotecan with irinotecan monotherapy as a third-or later-line treatment for patients with advanced or recurrent gastric or gastroesophageal cancer (AGC) that has progressed on previous ramucirumabbased chemotherapy. | | METHODS | Patients age 20 years and older with AGC, who had experienced disease progression during ramucirumab-based chemotherapy, were randomly assigned to receive either ramucirumab plus irinotecan or irinotecan monotherapy. The primary endpoint was overall survival (OS) expecting a hazard ratio (HR) of 0.77 (a power of 80% and a signiﬁcance level of one-sided 0.05) . Secondary endpoints included progression-free survival (PFS), response rate, disease control rate (DCR), and safety. | | RESULTS | Between February 2017 and August 2022, 402 patients in Japan were randomly assigned to receive ramucirumab plus irinotecan (n 5 202) or irinotecan monotherapy (n 5 200). The median OS was 9.4 months in the combination armand 8.5 months in the monotherapy arm, with an adjusted HR of 0.91 (95% CI, 0.74 to 1.12; P 5 .49) . PFS was improved (median, 3.8 v 2.8 months; HR, 0.72 [95% CI, 0.59 to 0.89]; P 5 .002), while the DCR was signiﬁcantly better (64.4% v 52.1%; P 5 .03) with the combination therapy. The adverse events of the combination therapy were manageable. | | CONCLUSION | Adding ramucirumab to irinotecan does not provide a signiﬁcant advantage in OS over irinotecan alone in patients with AGC who have progressed during ramucirumab-containing chemotherapy. | ACCOMPANYING CONTENT Appendix Data Sharing Statement Protocol Accepted February 19, 2025 Published May 23, 2025 J Clin Oncol 43:2196-2207 © 2025 by American Society of Clinical Oncology View Online Article Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION Gastric cancer is the ﬁfth most common malignancy worldwide and is the third leading cause of cancer-related mortality.1 Systemic chemotherapy is the standard of care for patients with advanced unresectable or recurrent gastric cancer (AGC), to improve survival and quality of life. However, the prognosis remains poor, highlighting the urgent need for innovative therapeutic strategies.2 In Japan, third-or later-line chemotherapy is recommended for AGC patients with good performance status (PS), for whom irinotecan is an important option. In the WJOG4007 study, which compared paclitaxel and irinotecan in a second-line setting in a Japanese population, 89% and 72% of patients in the paclitaxel and irinotecan groups, respectively, received third-line therapy.3 Moreover, to improve patient survival after second-line treatment, a powerful treatment strategy is needed. Ramucirumab is a human monoclonal antibody (IgG1) speciﬁcally targeting the vascular endothelial growth factor receptor 2 (VEGFR-2). It inhibits angiogenesis by blocking the binding of VEGFR ligands, such as VEGF-A, VEGF-C, and 2196 | Volume 43, Issue [19 |](19 | ascopubs.org/journal/jco)[ ascopubs.org/j

FAQs

What was the main goal of the RINDBeRG Phase III trial?

To evaluate whether adding ramucirumab to irinotecan improves efficacy and safety for patients with advanced gastric cancer after progression on prior ramucirumab-based chemotherapy.

How were patients assigned in the study?

Patients aged 20 years and older with AGC progressed during ramucirumab-based chemotherapy were randomly assigned to ramucirumab plus irinotecan or irinotecan monotherapy.

Did the combination therapy improve overall survival compared with irinotecan alone?

No. Adding ramucirumab to irinotecan did not provide a significant advantage in overall survival over irinotecan alone, though progression-free survival and disease control were better.

Sep 23, 2026

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