Background: There is currently no standard treatment after ripretinib beyond the fourth-line setting for refractory gastrointestinal stromal tumors (GISTs). A combination of tyrosine kinase inhibitors (TKIs) is rational to be potentially effective after failure of standard therapies. The objective of this study was to explore the efficacy and safety of avapritinib plus sunitinib in refractory GISTs. Methods: This was a prospective cohort study in part of a real-world trial (NCT05461664) exploring avapritinib in GIST patients (pts) after failure of standard treatments. Participants received avapritinib 100–200 mg once a day (QD) combined with sunitinib 25–37.5 mg QD continuously in 28-day cycles until disease progression (PD) or discontinuation from January 2022 to January 2023. Clinical outcomes including objective response rate (ORR), survival and safety were assessed. Results: A total of 11 pts with a median age of 57 years were enrolled. Median follow-up duration was 4.1 months (range, 1.4–12.8 months). Median sum of target lesions was 28.2 cm (range, 6.6–47.0 cm). Four pts had primary KIT exon 11 mutation, 6 had exon 9 and one had exon 17, secondary mutation KIT exon 13 was in 2 pts, exon 14 in one, exon 16 in 2 and exon 17 in 7 pts. Seven pts received more than 4 lines of prior TKIs, three received 3 and one had 2 lines of prior TKIs. One patient (9.1%) achieved partial response (PR) with 48.7% lesion length reduction, 9 (81.8%) had stable disease (SD) with 8 out of 9 pts achieving tumor shrinkage (median sum of lesion reduction of 20.8% [range, 9.8–27.3%]), and one (9.1%) had PD according to mRECIST1.1. Eight pts (72.8%) achieved PR, one (9.1%) had SD, and 2 (18.2%) had PD according to the Choi criteria. Until last follow-up, 4 pts progressed, one withdrew from the study and one discontinued treatment after surgery. Five pts were still receiving treatment, one exceeded 1 year with 26.3% lesion reduction in the seventh line setting. Progression-free survival and overall survival results were immature. ORR and lesion reduction trended favorably in those with KIT activation loop (AL) mutations, but this was not statistically significant. 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 anemia (54.5%), leukopenia (36.4%), diarrhea (36.4%), tumor hemorrhage (27.3%) and gastrointestinal hemorrhage (18.2%). Conclusions: The preliminary results from this study demonstrated meaningful clinical benefit with avapritinib plus sunitinib, achieving significant lesion reduction in refractory GISTs, especial those with KIT AL secondary mutations. Further studies are warranted to determine the optimal dosing regimen of two targeted drugs. Clinical trial information: NCT05461664.