Vemurafenib/Cobimetinib Shows Long-Term OS Benefit in BRAF+ Melanoma

The combination of vemurafenib and cobimetinib led to a 5-year overall survival rate of nearly 40% in patients with BRAF V600E–mutant metastatic melanoma who had not received prior therapy with a BRAF inhibitor.

Antoni Ribas, MD

The combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) led to a 5-year overall survival (OS) rate of nearly 40% in patients with BRAF V600E—mutant metastatic melanoma who had not received prior therapy with a BRAF inhibitor, according to updated phase I findings from the BRIM7 trial (NCT01271803) published in Clinical Cancer Research.1,2

Results showed that the median OS in patients who had not received a BRAF inhibitor was 31.8 months (95% CI, 24.5—not estimable), and the OS rate plateaued at 39.2% at years 4 and 5 of follow-up.

In those who previously received treatment with vemurafenib, the median OS was 8.5 months (95% CI, 6.7-11.1), and the OS rate plateaued at 14% at approximately 3 years of follow-up.

The 5-year OS results are significantly higher than the historical rate for patients with metastatic melanoma, which was 24.8% between 2009 and 2015, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results 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,” Antoni Ribas, MD, a professor in the Department of Medicine at University of California in Los Angeles Jonsson Comprehensive Cancer Center, stated in a press release. “The fact that a subgroup of patients were alive and well at the five-year follow-up mark after this combination treatment is remarkable.”

Early findings from the phase I trial showed that 87% of patients with BRAF V600E—mutant metastatic melanoma who received the vemurafenib/cobimetinib combination, and did not previously receive BRAF-targeted therapy, had a complete or partial response to the therapy.3

In the dose-finding, expansion phase Ib BRIM7 trial, investigators enrolled 2 cohorts of patients with advanced BRAF V600E—mutant melanoma: those who had not previously been treated with a BRAF-targeted agent and were referred to as BRAF inhibitor-naïve (n = 63), and a cohort of patients who had progressed on prior treatment with single-agent vemurafenib (n = 66).

Investigators noted that the relative proportion of patients with adverse prognostic factors in the BRAF inhibitor—naïve cohort was lower; 35% had an ECOG performance status of 1, 70% had stage IVc disease, and 46% had elevated lactate dehydrogenase levels. In the vemurafenib monotherapy cohort, the corresponding rates were 65%, 82%, and 62%, respectively.

In the dose-escalation phase, patients received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg daily for 14 days on/14 days off, 21 days on/7 days off, or continuously. The 2 regimens that were selected for dose expansion were vemurafenib at 720 and 960 mg twice daily, and cobimetinib at 60 mg daily for 21 days on/7 days off.

The primary endpoints were maximum-tolerated dose, dose-limiting toxicity, tolerability, pharmacokinetic profile, and the recommendation phase II and III dosing schedules. Secondary endpoints were antitumor activity as assessed by RECIST v1.1 criteria, duration of response (DOR), progression-free survival (PFS), and OS.

The median duration of follow-up was 28.0 months (range, 2.7-69.2) in the BRAF inhibitor—naïve cohort and 8.4 months (range 1.6-76.4) in those who previously received single-agent vemurafenib.

Additionally, the median PFS was 13.8 months (95% CI, 10.8—20.6) in the BRAF inhibitor–naïve cohort and 2.8 months (95% CI, 2.6–3.4) in the vemurafenib monotherapy–PD cohort.

Moreover, the best ORRs were 87% (95% CI, 77%-94%) and 15% (95% CI, 8%-25%) in the BRAF inhibitor—naïve and vemurafenib monotherapy cohorts, respectively. The median DOR was 14.3 months and 6.8 months in the BRAF inhibitor–naïve and previously received single-agent vemurafenib cohorts, respectively.

Regarding safety, treatment-related adverse events (AEs) were similar to those previously reported with this drug combination, and there was no increase in frequency and severity of AEs with the long-term follow-up. However, both cohorts did report increases in photosensitivity reactions and actinic keratitis due to longer-term exposure.

A limitation of the study, Ribas stated in the press release, was that some patients may have received PD-1 inhibitors after experiencing disease progression on vemurafenib/cobimetinib, and may have derived long-term benefit from the immunotherapy.

“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 added. “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.”


  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 [published online ahead of print November 15, 2019]. Clin Canc Research. doi: 10.1158/1078-0432.CCR-18-4180.
  2. Long-term Survival Rate for Subset of Patients With Advanced Melanoma Following BRAF- and MEK-targeted Treatment Combination Higher Than Historical Rate. American Association for Cancer Research. November 15, 2019. Accessed November 18, 2019.
  3. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15(9):954-965. doi: 10.1016/S1470-2045(14)70301-8.