The broad-spectrum KIT inhibitor NB003 and activity in advanced gastrointestinal stromal tumors (GIST): Updated results from a phase 1 study (NCT04936178).

Abstract

11517 Background: NB003 is a novel potent and selective oral small-molecule tyrosine kinase inhibitor of KIT. It was designed to inhibit a broad spectrum of primary and acquired imatinib-resistant mutations in KIT. The abstract reports updated results from the escalation and expansion phases of the Phase 1 study in patients (pts) with advanced GIST. Methods: The Phase 1 study includes a dose-escalation phase where pts received oral NB003 (3mg to 40mg ) twice daily (BID) in 28-day cycles, followed by an expansion phase with the putative recommended Phase 2 dose (RP2D) (15mg or 20mg BID) in 6 cohorts, including cohorts for GIST pts based on prior standard-of-care (SOC) regimens (2 nd , 3 rd , 4 th , and ≥5 th -line). Efficacy was assessed by Modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1 every 2 cycles. Results: At the cut-off of Dec 23, 2024, 158 pts with KIT-mutant GIST were enrolled in the escalation and expansion phases (median follow-up of 9.9 months; range, 0.5–32.0). The 154 evaluable pts included 24 2 nd -line, 30 3 rd -line, 35 4 th -line, 56 ≥5 th -line pts and 9 others. The confirmed objective response rate (cORR) was 27.3% (95% CI:20.4, 35.0) in all, 40% (95% CI:22.7, 59.4) in 3 rd -line, 42.9% (95% CI: 26.3, 60.6) in 4 th -line, and 12.5% (95% CI:5.2, 24.1) in ≥5 th -line pts. Tumor responses were observed in pts with a broad spectrum of acquired resistance mutations, including those in the KIT ATP-binding site (exons 13/14) and the activation loop of the kinase domain (exons 17/18). The median progression-free survival (mPFS) was 9.2 months (95% CI:7.4, 11.3), not reached（NR) (95% CI:6.0, NE), 13.8 months (95% CI:9.2, NE), and 4.5 months (95% CI:3.8, 7.4), in all, 3 rd -line, 4 th -line, and ≥5 th -line pts, respectively. For ≥3 rd -line pts without prior ripretinib, the cORR was 41.2% (95% CI:29.4, 53.8) and the mPFS was NR (95% CI:9.5, NE). In all pts, the most frequent treatment-related adverse events (TRAEs) were asymptomatic CPK increased (80.4%), anaemia (75.9%), AST increased (71.5%), face oedema (65.2%), periorbital oedema (55.1%), neutrophil count decreased (48.7%), WBC decreased (48.7%), amylase increased (39.9%), lipase increased (38.6%), platelet count decreased (33.5%), and peripheral oedema (31.0%). The most frequent treatment-emergent SAEs were anaemia (13.3%), gastrointestinal haemorrhage (6.3%), pleural effusion (4.4%), pneumonia (3.2%), and tumour haemorrhage (3.2%). Conclusions: NB003 demonstrated a manageable safety profile, and showed encouraging clinical benefit in GIST pts, as evidenced by mPFS and cORR, across multiple lines of treatment and a broad spectrum of secondary resistance KIT mutations. The promising data from this phase 1 study supports further testing of NB003 in Phase 3 studies. Clinical trial information: NCT04936178 .