Pavlakis Nick, Shitara Kohei, Sjoquist Katrin, Martin Andrew, Jaworski Anthony, Tebbutt Niall, Bang Yung-Jue, Alcindor Thierry, O'Callaghan Chris, Strickland Andrew, Rha Sun Young, Lee Keun-Wook, Kim Jin-Soo, Bai Li-Yuan, Hara Hiroki, Oh Do-Youn, Yip Sonia, Zalcberg John, Price Tim, Simes John, Goldstein David
Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia.
University of Sydney, Sydney, NSW, Australia.
J Clin Oncol. 2025 Feb;43(4):453-463. doi: 10.1200/JCO.24.00055. Epub 2024 Oct 4.
Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS).
A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL).
INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; = .0043). The toxicity profile was consistent with that of previous reports.
Regorafenib improves survival compared with placebo in refractory AGOC.
难治性晚期胃癌和食管胃交界癌（AGOC）的治疗选择有限。瑞戈非尼是一种口服多激酶抑制剂，在INTEGRATE I期II期试验中，与安慰剂相比可延长无进展生存期（PFS）。INTEGRATE IIa旨在研究瑞戈非尼是否能改善总生存期（OS）。
一项双盲安慰剂对照III期试验，将瑞戈非尼联合最佳支持治疗（BSC）与安慰剂联合BSC进行比较，纳入确诊可评估的转移性/晚期AGOC患者，这些患者之前至少接受过≥两种治疗且治疗失败，按2:1随机分组，根据肿瘤位置、地理区域（亚洲/世界其他地区）和既往血管内皮生长因子抑制剂进行分层。主要终点为OS。首先在INTEGRATE I + INTEGRATE IIa联合队列中测试OS的治疗疗效，若有显著差异，则在INTEGRATE IIa队列中进行测试。次要终点为PFS、客观缓解率、安全性和生活质量（QoL）。
INTEGRATE IIa纳入了251名参与者：157名来自亚洲，94名来自世界其他地区，169名接受瑞戈非尼治疗，82名接受安慰剂治疗。在INTEGRATE I和INTEGRATE IIa研究之间未观察到OS的显著异质性。联合OS分析风险比（HR）为0.70（95%CI，0.56至0.87；P = 0.001；361例事件）。单独INTEGRATE IIa的OS HR为0.68（95%CI，0.52至0.90；P = 0.006；238例事件），瑞戈非尼组与安慰剂组的中位OS分别为4.5个月和4.0个月，12个月生存率分别为19%和6%。经过预先计划的多重性调整后，各区域或其他预先指定的亚组之间无统计学显著差异。瑞戈非尼改善了PFS（HR，0.53 [95%CI，0.40至0.70]；P < 0.0001）并延缓了总体QoL的恶化（HR，0.68 [95%CI，0.52至0.89]；P = 0.0043）。毒性特征与既往报告一致。
在难治性AGOC中，与安慰剂相比，瑞戈非尼可改善生存期。
