Oncology

Gastrointestinal Stromal Tumors

Advances in the Treatment of Gastrointestinal Stromal Tumors

clinical topic updates by Jonathan C. Trent, MD, PhD

Overview

The outcomes for patients with unresectable and metastatic gastrointestinal stromal tumors (GIST) have greatly improved since the introduction of the first KIT-targeting TKI 20 years ago. Although resistance mutations have limited their long-term efficacy, recent advances have been made in the development of novel TKIs and combination strategies.

". . . since no single TKI can inhibit all of the known resistance mutations in KIT exons 13 and 17, one idea to improve TKI efficacy is to combine a type I TKI (ie, the investigational bezuclastinib) with a type II TKI (ie, sunitinib).”

— Jonathan C. Trent, MD, PhD

These tumors are rare, with an annual incidence of GIST estimated to be 0.7 cases per 100,000 people in the United States from 2001 to 2015. KIT mutations are, by far, the most common driver mutations, occurring in approximately 80% of patients with GIST. They typically occur in exons 11 or 9, but they are also found in exons 13 or 17. Further, approximately 5% of these tumors are driven by mutations in PDGFRA. Rare mutations have also been observed in BRAF and SDHx, as have fusions involving NTRK and FGFR1. Imatinib, the frontline standard of care for patients with KIT-positive GIST, was US Food and Drug Administration (FDA) approved in 2001. It is active against mutations in KIT exons 11 and 9 and most PDGFRA mutations. Two large phase 3 studies comparing different dosages of imatinib (ie, 400 mg/d vs 800 mg/d and 400 mg daily vs 400 mg twice daily) have reported a median overall survival ranging from 3.9 to 4.6 years and a median progression-free survival (PFS) of between 1.5 and 2.0 years.

Other KIT TKIs with FDA approval as later lines of therapy are sunitinib, regorafenib, and ripretinib. In the second-line setting, a phase 3 clinical trial reported a median PFS of 5.3 months with sunitinib. The phase 3 GRID study evaluating regorafenib in the third-line setting reported a median PFS of 4.8 months. Finally, in the fourth-line setting, the phase 3 INVICTUS trial evaluating ripretinib reported a median PFS of 6.3 months.

Beyond these KIT TKIs, novel TKIs are under investigation for GIST. For example, IDRX-42 appears promising based on initial efficacy and safety data from a phase 1 clinical trial. However, since no single TKI can inhibit all the known resistance mutations in KIT exons 13 and 17, one idea to improve TKI efficacy is to combine a type I TKI (ie, the investigational bezuclastinib) with a type II TKI (ie, sunitinib). The results from a nonrandomized phase 1b/2a study evaluating the combination of bezuclastinib (PLX9486) and sunitinib were promising, with a median PFS of 12.1 months. The randomized, open-label, phase 3 Peak study is comparing the combination of bezuclastinib and sunitinib with sunitinib alone in the second-line setting. In a summary of part 1 of the Peak trial, which was presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the 7 patients who were treated in the second line had a median PFS of 19.4 months and an objective response rate of 33.3%. Data analysis for the part 2 portion of the study is ongoing.

References

Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632. doi:10.1200/JCO.2007.13.4452

Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(7):923-934. Published correction appears in Lancet Oncol. 2020;21(7):e341.

Casali PG, Zalcberg J, Le Cesne A, et al; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, Australasian Gastrointestinal Trials Group. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017;35(15):1713-1720. doi:10.1200/JCO.2016.71.0228

Demetri GD, Garrett CR, Schöffski P, et al. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012;18(11):3170-3179. doi:10.1158/1078-0432.CCR-11-3005

Demetri GD, Reichardt P, Kang YK, et al; GRID Study Investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302. doi:10.1016/S0140-6736(12)61857-1

Patel N, Benipal B. Incidence of gastrointestinal stromal tumors in the United States from 2001-2015: a United States Cancer Statistics analysis of 50 states. Cureus. 2019;11(2):e4120. doi:10.7759/cureus.4120

Schöffski P, Heinrich MC, Trent JC, et al. StrateGIST 1: a first-in-human (FIH), phase 1 study of IDRX-42 in patients with metastatic gastrointestinal stromal tumors resistant to prior treatment with tyrosine kinase inhibitors (TKIs). J Clin Oncol. 2024;42(suppl 16):11501. doi:10.1200/JCO.2024.42.16_suppl.11501

Venkataraman V, George S, Cote GM. Molecular advances in the treatment of advanced gastrointestinal stromal tumor. Oncologist. 2023;28(8):671-681. doi:10.1093/oncolo/oyad167

Wagner AJ, Severson PL, Shields AF, et al. Association of combination of conformation-specific KIT inhibitors with clinical benefit in patients with refractory gastrointestinal stromal tumors: a phase 1b/2a nonrandomized clinical trial. JAMA Oncol. 2021;7(9):1343-1350. doi:10.1001/jamaoncol.2021.2086

Wagner AJ, Trent JC, Attia S, et al. Peak part 1 summary: a phase 3, randomized, open-label multicenter clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST). J Clin Oncol. 2024;42(suppl 16):11533. doi:10.1200/JCO.2024.42.16_suppl.11533

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Jonathan C. Trent, MD, PhD

Professor of Medicine
Associate Director for Clinical Research
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
Miami, FL