Three-Pronged Treatment Approach to Advanced Melanoma With BRAF V600 Mutation

By: Celeste L. Dixon
Posted: Tuesday, March 12, 2024

Caution is necessary when combining inhibitors of heat-shock protein 90 (HSP90) with BRAF and MEK inhibitors in treating advanced BRAF V600–mutant melanoma because the agents have overlapping toxicities, according to the results of a small phase I study. Writing in Cancer, Zeynep Eroglu, MD, of Moffitt Cancer Center & Research Institute, Tampa, Florida, and colleagues characterized the tumor response rate to the combination of the BRAF inhibitor vemurafenib, the MEK inhibitor cobimetinib, and the HSP90 inhibitor XL888 as high, but the toxicities were significant.

Objective responses were observed in 19 of 25 patients (76%). “Treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells…, [but] the overall response rate [was] not substantially higher than would be expected with BRAF/MEK inhibition alone,” the team noted.

Initially, vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) were given with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly). “After two dose-limiting toxicities (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses,” they continued. Three dose-limiting toxicities (rash) were observed in 12 patients in the XL888 cohort given 60 mg, and this was determined as the maximum tolerated dose.

The frequent dose reductions may have contributed to the relatively low progression-free survival, they posited: The median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. “To overcome these observed limitations” and achieve better results in the future with similar triplets, wrote Dr. Eroglu and co-investigators, “novel combinatorial and dosing strategies are needed.”

Disclosure: For full disclosures of the study authors, visit acsjournals.onlinelibrary.wiley.com.

Cancer