Background Regorafenib (R) has been approved as 3d line in mGIST patients (pts), with a median progression-free survival (mPFS) of 4.9 months (GRID study). R can alleviate the immunosuppressive GIST tumor micro environment by several mechanisms such as modifying the polarization of tumor-associated macrophages, reducing T regs infiltration. Thus, combining anti-PD1/PDL1 agents with anti-angiogenics appears promising in this population. Methods This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of R (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in pts with mGIST. The primary endpoint was the 6-month progression-free rate (6-month PFR) based on RECIST 1.1 criteria after central review. Secondary endpoints included: 6-month objective response, 1-year PFS, 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results Between November 2018 to July 2022, 50 pts were enrolled in 6 centers. Median age was 64 (range: 26-82). Median follow-up was 28.6 months (95% CI: 15.5 – 35.2). Median number of previous treatment lines was: 2 (range: 1-4). 42 (84%) pts experienced at least 1 dose modification or treatment interruption due to R and/or A. The most common grade 3/4 adverse events were: Palma-plantar erythrodysesthesia syndrome (18% of pts), hypertension (14%), diarrhea and maculopapular rash (12% each). No death was related to the treatment. Among the 46 assessable pts, 6-month PFR is 37% (N=17): 3 (6.5%) had partial response, 14 (30.4%) a stable disease, 23 (50%) a progressive disease, 6 were not evaluable. 24 (52.2%) had tumor shrinkage. Median PFS and OS are 5.5 months (95% CI: 3.6 – 7.5) and 19.5 months (95% CI: 13.7-33.5) respectively. 22% of pts are progression-free at one year. 6-month and 1-year OS rates are 93.5% (95% CI: 81.1-97.8) and 70.8% (95%CI: 55-81.9) respectively. Conclusions Regomune is the largest prospective study evaluating an approved TKI in combination with an IO agent in pts with advanced GIST. A subset of pts derived long term clinical benefit. Correlative studies will be presented at the meeting.< Leer menos