Interim analysis of ABM-1310, a blood-brain barrier-penetrant BRAF inhibitor, in patients with BRAF V600-mutated solid tumors

Document Type

Conference Proceeding

Publication Date

5-29-2024

Publication Title

J Clin Oncol

Keywords

cobimetinib, triacylglycerol lipase, adult, adverse drug reaction, aged, antineoplastic activity, blood brain barrier, conference abstract, drug combination, drug dose escalation, drug exposure, drug therapy, drug withdrawal, electrocardiography, female, glioblastoma, human, male, maximum tolerated dose, melanoma, monotherapy, multicenter study, myalgia, nausea and vomiting, neutropenia, pancreas cancer, pharmacokinetics, phase 1 clinical trial, phase 4 clinical trial, pleomorphic xanthoastrocytoma, QT prolongation, rash, side effect, solid tumor, therapy, thyroid papillary carcinoma

Abstract

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 (100-200mgbid) + cobimetinib (60mgQD 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 6 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 ±hibitors) 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 6 MEK inhibitors.

PubMed ID

Not assigned.

Volume

42

Issue

16

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