Adjuvant Imatinib or Observation in Patients With Gastrointestinal Stromal Tumors With KIT Exon 9 Mutations
Year: 2026
Type: article
Study design: Observational Study
Abstract: Importance: Gastrointestinal stromal tumors (GISTs) harboring KIT exon 9 mutations represent a biologically distinct subgroup with reduced sensitivity to standard-dose imatinib in the advanced setting. The benefit of adjuvant imatinib in this population remains uncertain. Objective: To evaluate the association between adjuvant imatinib and recurrence-free survival (RFS) and overall survival (OS) in patients with resected GISTs with KIT exon 9 mutations. Design, Setting, and Participants: This international, multicenter cohort study included patients with localized, molecularly confirmed GISTs with KIT exon 9 mutations who underwent curative-intent surgery between January 1990 and July 2022 at 35 referral centers in Europe, the US, and Japan, or were registered in the Life Raft Group database. The analysis took place between January 2025 and November 2025. Exposures: Adjuvant imatinib initiated after curative surgery, modeled as a time-dependent covariate to account for immortal time bias. Main Outcomes and Measures: The primary end points were RFS (time from surgery to recurrence or death) and OS (time from surgery to death) in the full cohort and in the high-risk subgroup defined by modified National Institutes of Health (mNIH) criteria. Multivariable Cox regression models included established prognostic covariates and cluster-robust standard errors. Overlap weighting (OW) based on propensity scores was used as a causal inference model. Secondary analyses evaluated 400 mg/d vs 800 mg/d dosing in the mNIH high-risk subgroup. Results: A total of 367 patients were included, 187 (51.0%) male and 180 (49%) female, with a mean (SD) age of 56 (13) years. Among these, 91 (24.8%) were observed and 276 (75.2%) received adjuvant imatinib (median [IQR] duration, 27.3 [13.5-36.0] months; 116 [42.0%] treated ≥3 years). Consistent with a cytostatic activity, adjuvant imatinib in the full cohort was associated with a reduced early hazard of recurrence or death (HR, 0.19; 95% CI, 0.10-0.36), with attenuation over time (time-interaction hazard ratio [HR], 1.85 per log-year). Treatment was also associated with improved OS (HR, 0.37; 95% CI, 0.17-0.83). Similar results were obtained when limiting the analysis to patients with mNIH high-risk disease. OW models and sensitivity analyses confirmed similar associations with RFS and OS. Among 257 patients with mNIH high-risk disease receiving imatinib, no significant difference was observed between 400 mg/d and 800 mg/d dosing. Conclusion and relevance: In this large international cohort study of resected GISTs with KIT exon 9 mutations, adjuvant imatinib was independently associated with delayed recurrence and improved survival. These findings support the use of adjuvant imatinib in mNIH high-risk GISTs with KIT exon 9 mutations and underscore the need for prospective studies to define optimal dosing and treatment duration.
Source: JAMA Oncology
Authors: Andrea Napolitano, Heikki Joensuu, Sara Rothschild, Denisse Evans, Michael C. Heinrich, Thomas L. Sutton, Skye C. Mayo, Kjetil Boye, Johanna Falkenhorst, Axel Le Cesne, Peter Hohenberger, Piotr Rutkowski, Winan J. van Houdt, Neeltje Steeghs, Hans Gelderblom, Ingrid M. E. Desar, Maria A. Pantaleo, Toshiro Nishida, Peter Reichardt, Jean-Yves Blay, Neeta Somaiah, Elise F. Nassif Haddad, Giovanni Grignani, Giacomo G. Baldi, Sonja E. Steigen, Chiara Braconi, Bengt Nilsson, Arun S. Singh, Elena Fumagalli, Ferdinando C. M. Cananzi, Antoine Italiano, Mariella Spalato Ceruso, Antonella Brunello, Magnús K. Magnússon, Jon G. Jonasson, Gloria Marquina, Nadia Hindi, Claudia Cirilli, Massimo Federico, Valentina Fausti, Andrea Bordoni, Jozef Sufliarsky, Alessandro Mazzocca, Javier Martin-Broto, Alessandro Gronchi, Jonathan C. Trent, Paolo G. Casali, Sebastian Bauer, Robin L. Jones, Bruno Vincenzi
Institutions: Institute of Cancer Research, Royal Marsden Hospital, University of Helsinki, Helsinki University Hospital, Life Raft Group, Oregon Health & Science University, Portland VA Medical Center, OHSU Knight Cancer Institute, Oslo University Hospital, Essen University Hospital, Institut Gustave Roussy, Heidelberg University, University Medical Centre Mannheim, The Maria Sklodowska-Curie National Research Institute of Oncology, The Netherlands Cancer Institute, Leiden University Medical Center, Radboud University Medical Center, University of Bologna, National Cancer Center Hospital East, Helios Hospital Berlin-Buch, Centre Léon Bérard, The University of Texas MD Anderson Cancer Center, Candiolo Cancer Institute, Azienda Usl Toscana Centro, Hospital of Prato, University Hospital of North Norway, UiT The Arctic University of Norway, University of Glasgow, Sahlgrenska University Hospital, University of California, Los Angeles, Fondazione IRCCS Istituto Nazionale dei Tumori, Humanitas University, IRCCS Humanitas Research Hospital, Institut Bergonié, Istituto Oncologico Veneto, University of Iceland, National University Hospital of Iceland, Universidad Complutense de Madrid, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, University of Modena and Reggio Emilia, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto Cantonale di Patologia, Comenius University Bratislava, Università Campus Bio-Medico, Campus Bio Medico University Hospital, University of Miami Health System, Sylvester Comprehensive Cancer Center
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7131659643