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A study funded by F. Hoffmann-La Roche shows that almost 40% of patients with metastatic melanoma harboring BRAFV600E -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.[1]

Metastatic or advanced melanoma is a cancer that starts in the cells capable of producing a colored pigment called melanin and then has spread beyond its original location in the skin and may spread through the bloodstream or the lymph system.

The results of the study, which demonstrate that a subset of patients with advanced melanoma following a BRAF- and MEK-targeted treatment combination were higher than the historical rate, were published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).

Survival advantage
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%.

Early results from the BRIM7 phase I clinical trial evaluating the BRAF V600E inhibitor vemurafenib (Zelboraf®; Genentech/Roche) in combination with the MEK1 inhibitor cobimetinib (Cotellic®; Genentech/Roche) in patients with BRAFV600E -metastatic melanoma have been previously reported in The Lancet. They showed that 87% 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.[1][2]

Antoni Ribas, MD

Long-term benefit
“When this study was initiated, the treatments available yielded long-term benefit at four or five years for only about 10% of patients diagnosed with metastatic melanoma,” noted 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, who is the AACR President-Elect for 2019-2020, added.

Patient cohorts
The researchers enrolled two cohorts of patients with advanced BRAFV600E -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 included 66 patients, had progressed on prior treatment with vemurafenib monotherapy.

Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). 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 [95% confidence interval (CI), 24.5–not estimable]; the OS rate plateaued at roughly four years of follow-up at 39.2%. The median OS for patients who had progressed on prior vemurafenib monotherapy was 8.5 months (95% CI, 6.7–11.1); the OS rate plateaued at 14% 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 explained.

“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,” he said.

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.

Clinical trial
A Study of Vemurafenib and GDC-0973 (cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma – NCT01271803

Reference
[1] Ribas A, Daud A, Pavlick AC, et al. Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma . Clin Cancer Res. 2019;10.1158/1078-0432.CCR-18-4180. doi:10.1158/1078-0432.CCR-18-4180 [Pubmed][Article]
[2] Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study [published correction appears in Lancet Oncol. 2014 Sep;15(10):417]. Lancet Oncol. 2014;15(9):954–965. doi:10.1016/S1470-2045(14)70301-8

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