Phase I study of ABM-1310 as monotherapy and in combination with cobimetinib for BRAF-mutated advanced solid tumors: safety, efficacy, and dose expansion

Background: ABM-1310 is an investigational, orally bioavailable BRAF V600 inhibitor with high blood–brain barrier (BBB) penetration. Patients and methods: This first-in-human, phase I trial evaluated patients with BRAF V600-mutated advanced solid tumors, including brain metastases (≤3 cm) and primary central nervous system (CNS) tumors. Patients received ABM-1310 monotherapy [25-250 mg twice a day (b.i.d.); Parts A/C] or in combination (ABM-1310 : 100-200 mg b.i.d.; cobimetinib 60 mg once a day, days 1-21 of each 28-day cycle; Part B). Primary endpoints included safety, tolerability, and maximum tolerated dose (MTD); secondary endpoints included pharmacokinetic (PK) profile and antitumor activity per RECIST v1.1 or Response Assessment in Neuro-Oncology criteria. Results: Fifty-three patients were enrolled (36 monotherapy, 17 combination). Median age was 55 years; 68% were male, 72% had ≥3 prior treatment lines, 92.5% had BRAF V600E mutations, 75% of patients had received prior BRAF plus MEK inhibitor therapy, and 7.5% had BRAF inhibitor monotherapy. Common tumor types included melanoma (47%), glioblastoma (17%) and thyroid cancer (13%). The most frequent treatment-related adverse events were QT prolongation and rash. Dose-limiting toxicities (DLTs) occurred in 6/37 patients (16.2%), all at doses ≥150 mg. All DLTs involved asymptomatic electrocardiogram QT prolonged, with two cases presenting co-occurring toxicities: one with rash and one with renal failure—establishing the MTD at 200 mg b.i.d. Among 50 efficacy-evaluable patients, the objective response rate (ORR) was 12% and disease control rate (DCR) was 64%. Median progression-free survival was 4.96 months (2.07-8.31) and median overall survival was 24.48 months 11.6-not estimable. In patients with primary CNS tumors (n = 13), ORR was 23.1% and DCR 76.9%. PK analyses showed dose-proportional exposure and moderate accumulation. Conclusions: ABM-1310 showed a favorable safety profile and encouraging intracranial activity. These findings support continued evaluation for CNS tumors and in cancer patients with prior BRAF inhibitor exposure.