(P 49) EFFICACY OF RIPRETINIB IN A MULTICENTER EXPANDED ACCESS PROGRAM IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS HARBOURING NON-KIT EXON 11 MUTATIONS.

Objective: There remains an unmet need for effective and well tolerated systemic therapy for metastatic gastrointestinal stromal tumors (GISTs) after disease progression on imatinib is challenging. Ripretinib is a novel tyrosine kinase inhibitor with a broad spectrum of activity against KIT and PDGFRA mutations. Patients harbouring KIT exon 11 mutation derive meaningful clinical benefit from ripretinib, but less is known about its activity in other mutational subtypes. We performed a retrospective analysis of advanced GIST patients harbouring primary mutations other than KIT exon 11 and enrolled in the European expanded access program between December 2019 and February 2023.

Methods: Primary efficacy endpoints included were Progression Free Survival (PFS), Overall Survival (OS) and Disease Control Rate (defined as complete remission + partial remission + stable disease) based on Response Evaluation Criteria in Solid Tumors (RECIST).

Results: Overall, 35 patients with advanced GIST and primary mutations other than KIT exon 11, received ripretinib at 14 European centers. Primary mutations were detected in 27 (77.2%) tumor specimens. 19 of them were in KIT (16 exon 9, 2 exon 13, 1 exon 17), 6 in PDGFRA (4 exon 18 D842V and 2 in exon 14) and 2 in SDH genes. Secondary KIT mutations were detected in 4 (11.4%) patients prior to ripretinib treatment (2 exon 13, 1 exon 14, 1 exon 18). Remaining 4 (11.4%) were KIT/PDGFRA/SDH wild type. Median age on commencing ripretinib was 61 (range 21-81) years and most patients were male (21, 60%). The most frequent primary sites were jejunum (17, 48.6%), stomach (9, 25.7) and duodenum (4, 11.4%). In 30 patients (85.7%) ripretinib was used as fourth or later line treatment. Only 9 patients (25.7%) required a dose reduction while 6 (17.1%) patients were escalated to ripretinib BID after disease progression. The Disease Control Rate (DCR) was 51.4% for the whole population and 66.7% for those patients whose ripretinib dose was escalated. In particular we observed 4 partial responses and 14 stable diseases in patients receiving standar dose of Ripretinib. After a median follow up of 15.4 (95% CI 9.1-NA) months, the median progression free survival was 4.3 (95% CI 3.2-6.2) in those patients receiving Ripretinib standard dose (150 mg QD) and 4.9 (95% CI 1.1-NA) in those who received dose escalation. Median overall survival was 12.2 months (95% CI 5.8-NA). Only 4 (11.4%) patients experienced grade 3 or greater (G ≥ 3) treatment related adverse events (TRAEs). The most common G ≥ 3 TRAEs were arthalgias/myalgias, skin toxicity and asthenia.

Conclusion: In the real world setting, ripretinib has durable benefit in metastatic GISTs harbouring non KIT exon 11 primary mutations. Ripretinib at a dose of 150 mg BD can be safely administered. Ripretinib is generally well tolerated with toxicity profile consistent with previous reports. Due to the small patient numbers, no conclusions can be drawn on the activity of ripretinib for each specific mutational subtype.