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Long-term Survival Rate for Subset of Patients With Advanced Melanoma Following BRAF- and MEK-targeted Treatment Combination Higher Than Historical Rate

PHILADELPHIA —  Almost 40 percent of patients with metastatic melanoma harboring BRAF V600E mutations who were treated with a combination of a BRAF-targeted and a MEK-targeted therapeutic and who had not previously been treated with a BRAF-targeted therapeutic were alive after five years of follow-up, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

According to the National Cancer Institute’s SEER data, the five-year survival rate for metastatic melanoma among patients diagnosed between 2009 and 2015 was 24.8 percent.

Early results from the BRIM7 phase I clinical trial evaluating the BRAF V600E inhibitor vemurafenib (Zelboraf) in combination with the MEK1 inhibitor cobimetinib (Cotellic) in patients with BRAF V600E metastatic melanoma have been previously reported. They showed that 87 percent of patients who received the combination and had not previously been treated with a BRAF-targeted therapeutic had a partial or complete response. This study provides extended follow-up results from the trial, including overall survival (OS) data.

“When this study was initiated, the treatments available yielded long-term benefit at four or five years for only about 10 percent of patients diagnosed with metastatic melanoma,” said Antoni Ribas, MD, professor in the Department of Medicine at University of California in Los Angeles and the Jonsson Comprehensive Cancer Center. “The fact that a subgroup of patients were alive and well at the five-year follow-up mark after this combination treatment is remarkable.”

Ribas is the AACR President-Elect for 2019-2020.

The researchers enrolled two cohorts of patients with advanced BRAF V600E-mutant melanoma. The first cohort, which had 63 patients, had not previously been treated with a BRAF-targeted therapeutic and were referred to as BRAF inhibitor-naïve; the second cohort, which had 66 patients, had progressed on prior treatment with vemurafenib monotherapy. The data cutoff for this follow-up study was May 25, 2018.

At the time of the extended follow-up, the median OS in the BRAF inhibitor-naïve cohort was 31.8 months; the OS rate plateaued at roughly four years of follow-up at 39.2 percent. The median OS for patients who had progressed on prior vemurafenib monotherapy was 8.5 months; the OS rate plateaued at 14 percent at roughly three years of follow-up. 

Treatment-related adverse events were similar to those previously reported with this drug combination. However, both cohorts had increases in photosensitivity reactions and actinic keratitis due to longer-term exposure.

“A subset of patients derived long-term benefit from this therapeutic strategy, indicating that targeted therapies are a viable option for patients with BRAF-mutant melanoma,” Ribas said. “With the goal of increasing the number of patients with long-term benefit, clinical trials investigating dual BRAF and MEK inhibition in combination with PD-1 or PD-L1 blocking antibodies are currently underway.” 

Some patients may have received PD-1 blockade treatments after experiencing progression during this clinical trial and may have derived long-term benefit from such immunotherapy treatments, representing a limitation of this study, Ribas noted.

This study was funded by F. Hoffmann-La Roche Ltd. 

Ribas reports institutional research grants from Genentech; honoraria for consultancy from Genentech, Roche, Chugai Pharmaceutical Co., Novartis, Amgen, Merck, and Bristol-Myers Squibb; and personal fees for advisory roles from Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime Therapeutics, FLX Bio, ImaginAb, Kite Pharma, Merus, Rgenix, Tango Therapeutics, and PACT Pharma.