Phase 1 study of NB003, a broad-spectrum KIT/PDGFRα inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST).

11518 Background: NB003 is a potent and selective small-molecule tyrosine kinase inhibitor of KIT/PDGFRα. It was designed to inhibit a broad spectrum of primary and acquired imatinib-resistant mutations in KIT/PDGFRα. Methods: This is a first-in-human phase 1 study in patients (pts) with advanced GIST who progressed on or intolerant to imatinib and other SoCs. Pts received oral NB003 twice daily (BID). An accelerated titration followed by a Bayesian optimal interval (BOIN) design was used. After the MTD or MAD was determined, putative RP2D(s) were explored to establish the RP2D. The primary endpoint was safety and tolerability. Other endpoints included PK, efficacy and mutational status by ctDNA. Results: As of Jan 10, 2024, 42 pts (median age 55 y range 33–81; 69% male; 71.4% ECOG PS 1; 69% primary mutation in KIT exon 11; median 4 prior TKI therapies range 2–7) were treated in dose escalation phase. Seven dose levels (DL) were tested, including 3mg (1 pt), 6mg (1 pt), 12mg (3 pts), 20mg (15 pts), 30mg (15 pts), 35mg (4 pts), 40mg (3 pts). The most frequent treatment-related adverse events (TRAEs) were asymptomatic CPK increased (92.9%), anaemia (78.6%), AST increased, face oedema, WBC decreased (76.2% each), periorbital oedema (66.7%), neutrophil count decreased (64.3%), amylase increased (57.1%), lipase increased (52.4%), platelet count decreased (45.2%), oedema peripheral (38.1%). The most frequent Grade ≥3 TRAEs were anaemia (61.9%), asymptomatic CPK increased (59.5%), neutrophil count decreased (23.8%), WBC decreased (21.4%). TRAEs leading to treatment discontinuation were reported in 2 pts (fatigue, tumor haemorrhage) at 20mg DL, 2 pts (AST increased, WBC decreased) at 30mg DL and 1 pt (face oedema) at 40mg DL, respectively. DLTs occurred in 2 pts at 40mg DL (fatigue, face oedema) and 2 pts at 30mg DL (febrile neutropenia, rash maculo-papular, AST increased). In 42 treated pts, the confirmed ORR was 26.2% (11/42, 95% CI:13.9, 42.0) per mRECISTv1.1 by investigator assessment, DCR was 73.8% (31/42, 95% CI:58.0, 86.1). Most of the responses (7/11) are still ongoing. Tumor responses were observed in pts with a broad spectrum of acquired resistance mutations in both ATP-binding site and activation loop of the kinase domain of KIT based on predose ctDNA (including 3 pts with exon11/13, 3 pts with exon11/17, 2 pts with exon17, 1 pt with exon16, 1 pt with exon 9/17, 1 pt not detected). A correlation is observed between changes in the KIT mutation allele fraction (MAF) in ctDNA and changes in tumor size from baseline. Conclusions: In heavily pretreated pts with advanced GIST, NB003 demonstrated a manageable safety profile with encouraging antitumor activity across a broad spectrum of secondary resistance mutations in KIT. The RP2D was defined as 20mg BID based on overall safety and efficacy. Expansion cohorts in different lines of GIST are currently under enrollment. Clinical trial information: NCT04936178 .