238 (PB118) - Phase II study of sunitinib in tumors with c-KIT mutations: results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol V

Abstract

Background: KIT mutations are common in gastrointestinal stromal tumors (GISTs) but are also found to a lesser degree in other tumor types such as mucosal melanomas, testicular seminomas or dysgerminomas. The NCI-MATCH study is a tumor agnostic platform trial enrolling patients to targeted therapies based on genomic alterations. Subprotocol V of the NCI-MATCH platform trial investigated sunitinib in patients with tumors harboring c-KIT mutations. Material & Methods: EAY131-V, is an open-label, single arm, phase 2 study. Eligible patients were those with a somatic c-KIT mutation on exons 9, 11, 13, and 14. Exclusions were mutations on exons 17, 18 which are reported to have resistance to sunitinib. Excluded tumor types were GIST, renal cell carcinoma, and pancreatic neuroendocrine tumors which have a known response to sunitinib. Patients received sunitinib 50 mg orally daily for 4 weeks with 2-week rest, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival (PFS) at 6 months, PFS, and toxicities. Results: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled, 9 were analyzable. Median age was 62 years (range 30–76), 77.8% received 2 lines of systemic therapy, while 22.2% received >3 lines. The most common tumor type was melanoma (44%), followed by squamous cell carcinoma of the lung or thymus (33%). There were 2 partial responses (PRs), both in squamous cell carcinomas, with an ORR of 22.2% (90% CI 4.1%–55%) and stable disease in 44%. Estimated 6-month PFS was 33.3% (90% CI 15.4%–72.4%). The 2 PRs had a PFS of 8 months and 10.8 months, respectively. Grade 3–4 toxicities at least possibly related to treatment occurred in 5 patients and included a thromboembolic event (n = 1), skin infections (n = 2), and lymphopenia (n = 2). This arm of the study was closed in 2022 based on low accrual, despite an amendment for additional actionable mutations. Prevalence of eligible c-KIT mutations after screening 5540 patients was estimated at 0.13%. Conclusions: In this study, sunitinib monotherapy for c-KIT mutations did not meet the primary endpoint for response, but in this small sample size a potential signal cannot be ruled out. Estimated rates of c-KIT mutations was lower than expected, impacting accrual to this arm. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180820, U10CA180794, UG1CA233302, UG1CA233180, UG1CA233341, and UG1CA189869. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No conflict of interest.