Combination Targeted Therapy of Avapritinib and Sunitinib for Patients with Refractory Advanced Gastrointestinal Stromal Tumors after Failure of Standard Treatments: Early Results from a Multi-Institutional Pilot Study.

11535 Background: The objective of this study was to explore the efficacy and safety of the combination of avapritinib and sunitinib in refractory GISTs. Methods: This was a multi-institutional prospective cohort study in part of a real-world trial (NCT05461664) exploring avapritinib in GIST patients (pts) after failure of standard treatments. From Jan 2022 to Sep 2023, participants were administered avapritinib at 100–200mg QD combined with sunitinib at 25–37.5mg QD continuously in 28-day cycles until PD or discontinuation. Clinical outcomes including ORR, survival and safety were assessed. Results: Twenty pts, generally heavily pretreated (65% with ≥4 prior TKIs, and 70% had progressed on ripretinib) were enrolled across seven participating centers. Median sum of target lesions was 27.0cm (range, 6.6–80.8). Among them, nine pts had primary KIT 11 mutation, 10 harbored KIT 9and one harbored KIT 17. Nine pts had KIT activation-loop (AL) mutations without KITATP-binding pocket (ABP) mutations ( KITALpos ABPneg), 2 had KIT ABP mutations without KIT AL mutations ( KITALneg ABPpos). ORR was 20% (4 PR), 15 pts (75%) had SD, one (5%) had PD with a CBR (PR+SD≥16w) of 75%, assessed via mRECIST v1.1. Tumor shrinkage was observed in 18 pts (90%), with a median best percent change in target lesions of -20.2% (range, -54.5% to 16.1%). With a median follow-up duration of 11.3 months (range, 2.3–20.9), 12 pts progressed, 3 were withdrawal, 7 were dead and 5 continued to receive combination therapy. Median PFS (mPFS) was 6.6 months (95% CI 5.8-7.4). Median OS was not reached. mPFS in pts with primary KIT 11 was similar compared to those with KIT 9. Regarding secondary KIT mutations, mPFS was numerically longer in KIT ALpos ABPneg pts compare to without (6.9 months VS 2.3 months, p=0.251). mPFS was significantly shorter in pts with KITALneg ABPpos than without (1.1 months VS 6.9 months, p<0.001). Three pts carrying KIT 16 L783V exhibited significantly longer mPFS than others (18.2 months VS 6.4 months, p=0.041). The dose of avapritinib (100–150 mg/d) and sunitinib (25–37.5 mg/d) could be tolerated. Common adverse events (AEs) were anemia, leukopenia, diarrhea, fatigue, periorbital and face oedema, and memory impairment. Common grade ≥3 AEs included leukopenia (30.0%), neutropenia (25.0%), anemia (20.0%), diarrhea (20.0%), and gastrointestinal hemorrhage (15.0%). Conclusions: The combination of avapritinib and sunitinib provided meaningful clinical benefit with an acceptable safety profile in pts with refractory GISTs, except for those harbored KITALneg ABPpos mutations. Clinical trial information: NCT05461664 .