Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies
CLINICAL CANCER RESEARCH(2024)
Abstract
Purpose: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. Patients and Methods: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following >= 1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; AL(pos)ABP(neg)), and other KIT mutations (OTHERS). Results: Sixty KIT AL(pos)ABP(neg) and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with >= 3 prior TKIs) were included. ORR was significantly higher in KIT AL(pos)ABP(neg) than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT AL(pos)ABP(neg) patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the >= 4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). Conclusions: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT AL(pos)ABP(neg) mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in >= 4 line settings.
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