Dose optimization of novel BRAF inhibitor FORE8394 based on PK and efficacy results.

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3106 Background: FORE8394 is a selective inhibitor of class 1 (V600) and 2 (activating non-V600) BRAF alterations that avoids paradoxical MAPK pathway activation. Consistent with the paradigm shift to optimal dosing vs identifying the maximal tolerated dose, integrated pharmacokinetic (PK), genomics, safety, and efficacy data, and exposure-response modeling were used to identify the recommended dose (RD). Methods: In a single arm phase 1/2a study, patients (pts) age ≥3 years with advanced solid or CNS tumors with BRAF alterations received FORE8394 900-3600 mg/day with or without the PK enhancer cobicistat (cobi) until progression. Efficacy pts had class 1 or 2 BRAF alterations & ≥1 post-baseline assessment (mITT); the BRAF V600 MAPKi naïve, non CRC subset provided a homogenous subset to also inform dose selection. PK was evaluated after single and repeated dosing. Results: To date, 110 pts (age range 4-86 years) received ≥1 dose of FORE8394; 58% had ≥2 prior lines of therapy, 25% had prior MAPKi. PK was independent of age or weight. Cobi increased FORE8394 exposure 2-3-fold. Exposure increased with dose, with less than proportional increase at doses >900 mg BID. Higher Cmax and trough levels were achieved with QD vs BID/TID. Objective (confirmed) responses were observed at all doses; however, objective response rate (ORR) was greatest (50%) at 900mg QD + cobi, with no further increases in ORR at higher doses. Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). Similarly, treatment-emergent adverse events (TEAEs) ≥Grade 3 (G3) increased at the higher doses. Only 1 pt discontinued FORE8394 due to treatment-related AE (G3 bilirubin; 3600 mg/day). Conclusions: Based on the entirety of safety, PK, and efficacy data, the optimal RD of FORE8394 in Phase 2 is 900 mg QD + cobi in pts ≥10 years old. This achieved targeted efficacious exposures with robust antitumor activity and favorable safety. This dose optimization is consistent with current guidelines, avoids higher exposure that may lead to higher toxicity and compromise dose intensity. QD dosing also allows for a convenient dosing regimen. A Phase 2 study at the RD is ongoing in pts with recurrent V600E BRAF-mutated primary CNS tumors and advanced solid or CNS tumors with BRAF fusions. Clinical trial information: NCT02428712 . [Table: see text]