INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer

Author(s): Nick Pavlakis, PhD, MBBS, FRACP1,2; Kohei Shitara, PhD3; Katrin Sjoquist, PhD4,5; Andrew Martin, PhD4; Anthony Jaworski, MPH4; Niall Tebbutt, PhD6; Yung-Jue Bang, PhD7; Thierry Alcindor, PhD8; Chris O’Callaghan, PhD9; Andrew Strickland, PhD10; Sun Young Rha, PhD11; Keun-Wook Lee, PhD7,12; Jin-Soo Kim, PhD13; Li-Yuan Bai, PhD14,15; Hiroki Hara, PhD16; Do-Youn Oh, PhD17,18; Sonia Yip, PhD4; John Zalcberg, PhD19,20; Tim Price, PhD21; John Simes, PhD4; David Goldstein, PhD22
Source: https://doi.org/10.1200/JCO.24.00055
Original Article
Professional photo of Maem Hussein, MD

Dr. Maen Hussein's Thoughts

This is another option for gastric cancer that is showing efficacy in non-HER-2 neutrophils, as Enhertu showed superiority in a recent study in the second line over taxol and cyramza (destiny gastric 4).

PURPOSE

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).

METHODS

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 v 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).

RESULTS

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; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .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]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports.

CONCLUSION

Regorafenib improves survival compared with placebo in refractory AGOC.

Author Affiliations

1Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia; 2University of Sydney, Sydney, NSW, Australia; 3Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan; 4NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; 5Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia; 6Olivia Newton-John Cancer Wellness & Research Centre, Melbourne, VIC, Australia; 7Seoul National University College of Medicine, Seoul, South Korea; 8McGill University Health Centre, Montreal, QC, Canada; 9Canadian Cancer Trials Group, Queens University, Kingston, ON, Canada; 10Department of Medical Oncology, Monash Health, Monash University, Melbourne, VIC, Australia; 11Yonsei Cancer Centre, Yonsei University Health System, Seoul, South Korea; 12Seoul National University Bundang Hospital, Seongnam, South Korea; 13Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea; 14Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan; 15China Medical University, Taichung, Taiwan; 16Saitama Cancer Center, Saitama, Japan; 17Seoul National University Hospital, Cancer Research Institute, Jongno-gu, Seoul National University College of Medicine, South Korea; 18Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea; 19Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia; 20School of Public Health, Faculty of Medicine Monash University, Melbourne, VIC, Australia; 21The Queen Elizabeth Hospital, Adelaide, SA, Australia; 22Nelune Cancer Centre, Prince of Wales Hospital, Sydney, NSW, Australia

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