A phase 2 multicenter, open-label, parallel cohort study to evaluate the efficacy, safety, and pharmacokinetic profile of ABN401 in patients with advanced solid tumors harboring c-MET dysregulation.

8641 Background: Vabametkib is a small-molecule, tyrosine kinase inhibitor (TKI) that is a highly selective type I inhibitor of c-MET kinase, for the treatment of solid tumors harboring c-MET gene dysregulation. Methods: Phase 2 trial is an open-label, global study designed to evaluate the safety and efficacy of vabametkib in patients with NSCLC harboring MET exon 14 skipping mutations confirmed by NGS. Patients received oral vabametkib at a dose of 800 mg once daily (QD) until disease progression or unacceptable toxicity. The primary endpoint was ORR as assessed by blinded independent central review. Secondary endpoints included pharmacokinetics, DoR, DCR, PFS and OS. Exposure–response relationships of vabametkib were evaluated in enrolled patients to explore the optimal dose and dosing regimen to support further clinical development. Results: Forty-two (42) efficacy patients enrolled and median age were 76 years; 78 years in treatment naive and 75 years in the prior treated patients. Median follow-up duration was 14.1 months overall; 14.6 months for treatment naive and 13.5 months for prior treated patients. BICR confirmed ORR was 55% overall, with comparable response rate in both treatment-naive patients (52%) and prior-treated patients (57%). The median DoR assessed by BICR was 14.5 months with 19.9 months in treatment naive patients and 11.7 months in prior treated patients. Median PFS by BICR was 8.8 months overall, with 10.2 months in treatment naive patients and 7.3 months in prior treated patients. TRAE were experienced in 89% patients, 11% patients experienced Grade ≥3 TRAEs and no Grade 4 TRAE was reported. The most common TRAEs included nausea (75%), diarrhea (34%), hypoalbuminemia (25%), rash (18%), vomiting (18%), peripheral edema (16%), fatigue (14%), and elevated ALT and AST (14%). The most common Grade ≥3 TRAE was pneumonitis (4.5%). TRAEs led to dose reductions in 22.7% of patients, most commonly due to rash (6.8%), nausea (4.5%) and stomatitis (4.5%). TRAEs resulted in dose interruptions in 36.4% of patients most frequently due to nausea (9.1%), vomiting (9.1%), rash (6.8%), and fatigue (4.5%). Median AUC inf values were highest in the PR group (2,946 ng·h/mL) compared to the SD (2,021ng·h/mL) and PD groups (988 ng·h/mL) with a statistically significant difference (p = 0.0347 by Kruskal-Wallis). PK simulation demonstrated BID dosing more effectively maintained EC 90 coverage than QD dosing; sustaining drug conc above EC 90 for 93% of the dosing interval and increasing AUC 0-24hr by 35.3% thereby increasing likelihood of achieving exposure observed in the PR patients. Conclusions: Alternative 350mg BID of Vabametkib had been selected to continue the clinical development. Clinical trial information: NCT05541822 .