INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer
Abstract
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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (21)
Nick Pavlakis
Kohei Shitara
Katrin Sjoquist
Andrew Martin
Anthony Jaworski
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
Niall Tebbutt
Olivia Newton-John Cancer Wellness & Research Centre, Melbourne, VIC, Australia
Yung-Jue Bang
Seoul National University College of Medicine; Seoul National University Graduate School, Seoul, South Korea
Thierry Alcindor
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Chris O'Callaghan
Canadian Cancer Trials Group, Queens University, Kingston, ON, Canada
Andrew Strickland
Department of Medical Oncology, Monash Health, Monash University, Melbourne, VIC, Australia
Sun Young Rha
Keun-Wook Lee
Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
Jin-Soo Kim
Li-Yuan Bai
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
Hiroki Hara
Saitama Cancer Center, Ina, Japan
Do-Youn Oh
Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, and the Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
Sonia Yip
NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
John Zalcberg
Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
Tim Price
John Simes
NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia (J.S.).
David Goldstein