Antitumor Activity Of Belvarafenib In Melanoma Brain Metastasis And Nras Mutation Melanoma Models.

Abstract Over the past decade, BRAF inhibitors, either alone or in combination with MEK inhibitors, have set a new milestone in the treatment of patients with BRAF V600 mutation melanoma, which accounts for about 50% of melanomas. More recently, anti-PD-(L)1 therapies such as nivolumab or pembrolizumab and atezolizumab have been approved as very useful treatments for patients with melanoma. Nevertheless, metastases to the brain in melanoma patients, which are highly aggressive and associated with poor outcomes, still require better treatment. Also, to date, no targeted therapy has been developed for patients with NRAS mutations, which account for about 20% of melanoma. Previously, we reported that belvarafenib (HM95573 or GDC5573) strongly inhibits the growth of various cancer cell lines harboring BRAF, NRAS or KRAS mutations and demonstrates remarkable anticancer efficacy in preclinical animal models. Belvarafenib, currently in Phase 1 clinical trials, is a potent and selective pan-RAF kinase inhibitor showing strong inhibition activities for BRAF WT, BRAF V600E and CRAF. Here, we present the results of preclinical model studies suggesting that belvarafenib could be effective in treating melanoma patients with metastases to the brain as well as NRAS mutation melanoma patients. First, belvarafenib was found to be able to accumulate in the brain of mice and rats following oral administration. The exposure of belvarafenib in the brain was similar to that in plasma (approximately 100% brain to plasma ratio). This level of brain penetration of belvarafenib differs significantly from currently approved BRAF inhibitors that are known to have low brain penetration. Belvarafenib showed excellent anti-tumor activity in an orthotopic brain tumor model using melanoma cells. Belvarafenib significantly increased the overall survival of mice implanted intracranially with BRAF V600E A375SM melanoma cells. Overall, our data demonstrated that belvarafenib has therapeutic potential to treat NRAS mutation melanoma patients. In fact, in the NRAS G13D K1735 murine melanoma cell syngeneic mice model, the combination of belvarafenib with atezolizumab (anti-PD-L1) significantly inhibited tumor growth and effectively induced infiltration of cytotoxic T-cells into tumor tissues. These effects of belvarafenib identified in the above preclinical studies need to be immediately warranted through appropriate clinical trials. Citation Format: Inhwan Bae, Yu-Yon Kim, Jisook Kim, Hyunjin Park, Taehyun Song, Joo-Yun Byun, Semi Lim, Young Hoon Kim, Young Gil Ahn, Kwee Hyun Suh. Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1474.