Belvarafenib is active in BRAF- and NRAS-mutant tumors, but acquired ARAF mutations drive resistance

  • Major Finding: Belvarafenib is active in BRAF- and NRAS-mutant tumors, but acquired ARAF mutations drive resistance.

  • Concept: Belvarafenib blocks RAF dimer activity and does not cause paradoxical MAPK activation in RAS-mutant cells.

  • Impact: The distinct resistance profile of a pan-RAF inhibitor shows ARAF can compensate upon BRAF and CRAF inhibition.

Although RAF monomer inhibitors are approved for the treatment of BRAFV600E-mutant melanoma, these agents are ineffective in patients with NRAS-mutant melanoma and drive paradoxical MAPK pathway activation in RAS-mutant or non–BRAFV600E-mutant cells that can cause secondary skin squamous cell carcinoma (SCC). Yen, Shanahan, Lee, Hong, Shin, and colleagues present the preclinical characterization and phase I dose-escalation and dose-expansion results for belvarafenib, a potent inhibitor of BRAFV600E as well as wild-type CRAF, BRAF, and ARAF. Unlike RAF monomer inhibitors, belvarafenib bound both protomers of a RAF dimer, and it inhibited growth of both BRAF- and NRAS-mutant melanoma cells without induction of paradoxical MAPK activation in RAS-mutant cells. In first-in-human phase I dose-escalation and dose-expansion studies in BRAF- or RAS-mutant solid tumors, belvarafenib was tolerable and had a safety profile similar to RAF monomer inhibitors, except that secondary SCC was not observed. In the dose-expansion cohort, the confirmed overall response rate for belvarafenib monotherapy was 20% among patients with NRAS-mutant melanoma and 33% among patients with BRAF-mutant melanoma. Analysis of circulating tumor DNA identified mutations in the ARAF kinase domain arising before confirmation of progressive disease that were not detectable prior to treatment, suggesting that these mutations were driving belvarafenib resistance. Indeed, these mutations, which also arose in NRAS-mutant melanoma clones selected for belvarafenib resistance, conferred resistance to belvarafenib (and other RAF dimer inhibitors) in BRAF- and NRAS-mutant cells in an ARAF dimer– and kinase-dependent manner. However, these ARAF mutants retained sensitivity to MEK and ERK inhibition, and combination treatment of belvarafenib and the MEK inhibitor cobimetinib led to greater suppression of tumor growth in vivo than belvarafenib alone and did not lead to ARAF-driven resistance. These first insights into clinical resistance mechanisms of pan-RAF inhibitors reveal an unanticipated compensatory role for ARAF when BRAF and CRAF are inhibited and suggest that, like RAF monomer inhibitors, the efficacy and duration of response of RAF dimer inhibitors will benefit from deep suppression of MAPK signaling with combined MEK inhibition.

Yen I, Shanahan F, Lee J, Hong YS, Shin SJ, Moore AR, et al. ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. Nature 2021 May 5 [Epub ahead of print].

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