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

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.”

References

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. https://bit.ly/2Xqp3PY. Accessed November 18, 2019.
3. 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. Lancet Oncol. 2014;15(9):954-965. doi: 10.1016/S1470-2045(14)70301-8.