Abstract CT017: A phase I study evaluating safety, pharmacokinetics, and clinical activity of the novel, paradox breaker BRAF inhibitor RG6344 in patients with BRAF V600-mutant solid tumors

Abstract Background: Clinical benefit of first generation BRAF inhibitors (BRAFi) as monotherapy is limited due to paradoxical feedback activation of downstream MAPK or EGFR; combinations with MEK inhibitors (in melanoma) or EGFR antibodies (in colorectal cancer [CRC]) have become a standard of care in BRAF V600-mutant tumors. RG6344 (RO7276389) is a novel brain penetrant paradox breaker BRAFi designed to address the limitations of approved BRAFi. Methods: Dose escalation of RG6344, as a single agent and in combination with standard dose of cobimetinib, is being conducted in participants with solid tumors harboring a BRAF V600E mutation up to the protocol specified maximum daily dose. The objectives were to define the maximum tolerated dose (MTD), the recommended Phase 2 dose and additionally to characterize safety, PK/PD, and clinical outcomes (ISRCTN13713551). Results: As of December 5, 2024, 66 patients (56% with prior BRAFi treatment), including 7 patients with non-measurable brain lesions, have been treated with RG6344 in the monotherapy dose escalation part of the study and 12 patients in the combination part with cobimetinib including 5 patients with measurable and one with non-measurable brain lesions. Eleven melanoma, 51 CRC, 4 patients with other cancers received at least one dose of study drug as a single agent (dose escalation in combination still ongoing and not reported). One dose limiting toxicity event of grade 3 rash maculo-papular was reported. MTD has not been reached up to the highest daily dose of 3600 mg. Grade 3 treatment-related AEs (TRAEs) occurred in 11 patients (16.6 %), grade 4 TRAEs in 2 patients (3%; both laboratory findings) and no grade 5 TRAEs were reported. 2 patients (3%) discontinued study treatment due to TRAEs. None of the known BRAFi class toxicities, such as cutaneous squamous cell carcinomas, including Palmar-Plantar Erythrodysesthesia (PPE) and keratoacanthoma, have been observed to date. Linear and time-independent PK was demonstrated across the tested dose range, reaching Ctrough levels exceeding PK-derived pERK inhibition >90%. Exposure -response (metabolic responses measured with FDG-PET) relationship was observed. Objective response rate (ORR) was 25% in a total of 64 evaluable patients across tumor types and doses including patients with brain metastases and/or refractory to or relapsing on prior BRAFi treatment. Conclusions: RG6344 is well tolerated allowing unprecedented exposure for pERK inhibition and shows promising preliminary activity. Citation Format: Maria Vieito, Elisa Fontana, Catherine Han, Eduardo Castanon, David J Pinato, Oliver Bechter, Irene Moreno, Rikke L Eefsen, Ruth Plummer, Reinhard Dummer, Hans Prenen, Giulia Pretelli, Gabriel Schnetzler, Piergiorgio Pettazzoni, Abiraj Keelara, David Dejardin, Andreas Roller, Ernesto Guarin, Elisa Cinato, Tomi Fakolade, Nino Keshelava, Ting Liu, Nick Flinn, Nicole A. Kratochwil. A phase I study evaluating safety, pharmacokinetics, and clinical activity of the novel, paradox breaker BRAF inhibitor RG6344 in patients with BRAF V600-mutant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT017.