Interim analysis of ABM-1310, a blood-brain barrier-penetrant BRAF inhibitor, in patients with BRAF V600-mutated solid tumors.
Authors: Piha-Paul Sarina A. , De La Fuente Macarena Ines , Iwamoto Fabio , Nagpal Seema , Weise Amy M. , Zhu Jay-Jiguang , Chandra Sunandana , Chen Chen , Fu Yali , Yang Zandong , Tsai Katy K. 
Published: June 2024

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Background: ABM-1310 is a novel, small-molecule BRAF inhibitor with preclinical evidence of high blood-brain barrier penetration. Here we report interim results from a Phase 1 study of ABM-1310 in patients (pts) with BRAF V600 mutations (NCT04190628). Methods: This multicenter, open-label, two-part study enrolled adult pts with advanced BRAF V600-mutated solid tumors, including those with recurrent or metastatic solid tumors or primary CNS tumors. Pts who failed previous BRAF ± MEK inhibitor treatment were eligible. In the dose-escalation (Part 1), pts received either ABM-1310 monotherapy (25–250 mg bid) continuously or ABM-1310 (100–200 mg bid) + cobimetinib (60 mg QD on d1–21) q28d. Escalation followed a “3+3 design” with dose-limiting toxicities assessed during Cycle 1. Part 2 was cohort expansion (ABM-1310 150–200 mg bid). Primary objectives were maximum tolerated dose (MTD) of ABM-1310 ± cobimetinib. Secondary objectives included safety, tolerability, pharmacokinetics, and anticancer activity. Results: As of 28 Nov 2023, 51 pts (36 male; median age 56 years; 38 pts refractory to BRAF ± MEK inhibitors) were enrolled. Of these, 74.5% (38/51) experienced treatment-related adverse events (TRAEs). The most frequent (≥10%) TRAEs were skin rash (n=15) and asymptomatic electrocardiogram QT prolongation (AQTP, n=18), most (97.4%) of which were grade (G) 1–2. Nine pts (17.6%) had G3 TRAEs including AQTP, rash, neutropenia, nausea, vomiting, lipase increased and myalgia. There were no treatment-related early discontinuations, G4 AEs, or treatment-related deaths. Among 28 efficacy-evaluable pts who received any dose of ABM-1310 monotherapy, the ORR was 21.4% and disease control rate (DCR) was 60.7%, including 6 partial responses (PR) (glioblastoma multiforme n=2, pleomorphic xanthoastrocytoma n=2, papillary thyroid carcinoma [PTC] n=1, and pancreatic cancer [PC] n=1). Eleven pts had stable disease (SD). Among 16 efficacy-evaluable pts treated with ABM-1310 + cobimetinib, the ORR was 12.5% and DCR was 68.8% including 2 PR (1 each with melanoma and PTC) and 9 SD. Among 10 pts with primary CNS tumors treated with ABM-1310 monotherapy, the ORR was 40% (4 PR, 4 SD), and the median PFS was 4.6 months. In 6 pts with PTC, the ORR was 33.3% (2 PR, 4 SD), and the median PFS was 6.0 months. In 4 pts with PC treated with ABM-1310 monotherapy, the ORR was 25% (1 PR for >6 months; pt remains on study treatment). The MTD for ABM-1310 either as monotherapy or in combination with cobimetinib was 200 mg bid. Preliminary assessment of ABM-1310 drug exposure vs. dose showed a linear dose-proportional relationship. Conclusions: ABM-1310, either alone or in combination with cobimetinib, was well tolerated without new or unexpected side effects or safety issues. Preliminary efficacy of ABM-1310 was seen in pts with BRAF V600-mutated solid tumors, including those who were refractory to prior BRAF ± MEK inhibitors. Clinical trial information: NCT04190628 .