belvarafenib (RG6185)

Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.

Purpose: This study explores the potential of preclinical in vitro cell line response data and computational modeling in identifying optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Further, our analysis suggests the importance of drug dosing strategies to optimize synergy based on mutational context, yet highlights the real-world challenges of maintaining a narrow dose range. This approach establishes a framework for translational investigation of drug responses in the refinement of combination therapy, balancing the potential for synergy and practical feasibility in cancer treatment planning.

Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.

P1, N=65, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | N=128 --> 65

P1, N=128, Recruiting, Genentech, Inc. | Trial completion date: Sep 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2025

Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

Mechanistically, we identified distinct biochemical and transcriptional effects of RAF dimer and MEK inhibition in AML cells. We are characterizing these further and pursuing causes of resistance in primary Nras- and ­Kras-mutant mouse AMLs that relapsed after an initial response to treatment.

A literature review reported no renal adverse effects associated with pan-RAF agents.Belvarafenib is a novel agent; further research and time are required to determine its adverse effects incidence. However, clinicians must remain vigilant about the potential kidney adverse effects of this agent and consider a kidney biopsy to assess AIN in patients whose AKI does not respond promptly to discontinuing Belvarafenib and supportive care.

P1, N=128, Recruiting, Genentech, Inc. | Trial primary completion date: Nov 2024 --> Nov 2023

P1; Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

No new safety signals were found. Table: 661MO SC-A: BRAF fusion (N=15) SC-B: Point mutation (N=8) Best overall response CR 0 0 PR 9 (60.0) 0 SD 5 (33.3) 4 (50.0) PD 1 (6.7) 4 (50.0) ORR n (%) 9 (60.0) 0 95% CI 32.29, 83.66 0, 36.94 Disease control rate (PR+SD) n (%) 14 (93.3) 4 (50.0) 95% CI 68.05, 99.83 13.70, 78.80 mPFS month 13.7 2.1 95% CI 7.36, 18.23 1.61, 7.16 Conclusions The combination of Belva with Cobi showed promising anti-tumor activity as well as durable responses in patients with BRAF fusions regardless of cancer type.

Selective inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as Pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.