Preliminary safety, pharmacokinetics, and clinical activity of RG6344 in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC).

3542 Background: RG6344 (RO7276389) is a novel paradox breaker and brain penetrant BRAF inhibitor (BRAFi) designed to overcome the MAPK paradoxical activity, a well-established liability of the first generation BRAF inhibitors. The BRAF V600E mutation, present in about 10% of mCRC patients, negatively impacts prognosis and response to standard therapies. Methods: Dose escalation of RG6344 is being conducted in participants with solid tumors harboring BRAF V600E mutation up to the protocol specified maximum daily dose, to define the maximum tolerated dose (MTD) and/or recommended Phase 2 dose and characterize safety, PK/PD, and clinical outcomes (ISRCTN13713551). Results: As of September 25, 2024, 51 patients with mCRC (27, 53% with prior BRAFi treatment; median number of treatments 3 [2-6]), including 4 patients with non-measurable brain lesions, have been treated with RG6344 in the monotherapy dose escalation part of the study. Patients received at least one dose of study drug as a single agent. MTD has not been reached up to the highest dose of 3600 mg/d. Of the 51 treated patients, Grade 3 treatment-related AEs (TRAEs) occurred in 8 patients (14.5 %), grade 4 TRAEs in 2 patients (3.6%; both laboratory findings) and no grade 5 TRAEs were reported. The most commonly reported TRAEs included diarrhoea (23.6%), nausea (21.8%) and fatigue (12.7%). 3 patients (5.5%) discontinued study treatment due to TRAEs. None of the typical BRAFi class toxicities, such as cutaneous squamous cell carcinomas (cSCCs), Palmar-Plantar Erythrodysesthesia (PPE) and keratoacanthoma, have been observed to date, highlighting the paradox breaking properties of this BRAF inhibitor. Linear and time-independent PK was demonstrated across the tested dose range, reaching Ctrough levels exceeding pERK inhibition > 80%. Strong and early ( i.e. FDG PET at 15 days) metabolic response of 74% (6 CMR, 30 PMR out of 49 evaluable patients) was observed on FDG PET. Association between metabolic responses and exposure was observed. Observed ORR (RECIST v1.1) was 25% in BRAFi-naive mCRC patients and 14.8% in BRAFi-experienced patients, DCR was 100% for BRAFi-naive patients and 62.9% for BRAFi-experienced patients, mPFS was 7.3 months and 3.6 months, respectively, in the ongoing study. Conclusions: RG6344 is well tolerated allowing unprecedented exposure for pERK inhibition and shows promising preliminary single-agent activity. Clinical trial information: ISRCTN13713551 .