Final OS Analysis Confirms Cobimetinib/Vemurafenib Benefit in Melanoma

Combination therapy with cobimetinib (Cotellic) and vemurafenib (Zelboraf) reduced the risk of death by 30% compared with vemurafenib alone in patients with BRAF-positive advanced melanoma.

Josina Reddy, MD, PhD

Combination therapy with cobimetinib (Cotellic) and vemurafenib (Zelboraf) reduced the risk of death by 30% compared with vemurafenib alone in patients with BRAF-positive advanced melanoma, according to the final survival analysis of the phase III coBRIM study that has now been published in The Lancet Oncology.

The targeted combination improved median overall survival (OS) by 4.9 months versus single-agent vemurafenib (HR, 0.70; 95% CI, 0.55-0.90; P = .005). The OS rates for the combination at 1 and 2 years were 74.5% and 48.3%, respectively.

“Melanoma is one of the few cancers that has increased in incidence over the past 30 years, and until recently, people with advanced forms of the disease have had few treatment options. Five years ago, the survival of people with advanced melanoma was measured in months, and now we have medicines that are helping people live years,” Josina Reddy, MD, PhD, senior group medical director at Genentech, the company that manufactures the combination, said in an interview with OncLive.

“By understanding the biology of the tumor, we are learning how to best combine or sequence targeted medicines to improve outcomes for patients. The combination of Cotellic and Zelboraf was the first treatment to help people with a BRAF mutation live for a year without their disease worsening. The coBRIM overall survival results confirm the combination is an important treatment option for people with BRAF-mutant advanced melanoma,” added Reddy.

The phase III coBRIM study included 495 treatment-naïve patients with BRAF V600E/K—positive unresectable locally advanced or metastatic melanoma. Patient demographics were well balanced across the 2 arms, including disease stage, ECOG performance status, age, and geographic region. Over half of the patients had stage IV, M1c melanoma.

Patients were randomized to continuous vemurafenib at 960 mg twice daily plus placebo (n = 248) or cobimetinib (n = 247) at 60 mg once daily on days 1-21 of a 28-day cycle. The primary endpoint for the study was progression-free survival (PFS), with secondary outcome measures including OS, objective response rate (ORR), and duration of response.

Median OS was 22.3 months with the combination versus 17.4 months with vemurafenib alone. The median PFS was 12.3 months versus 7.2 months, respectively (HR, 0.58; 95% CI, 0.46-0.72; P <.0001).

The ORR with cobimetinib/vemurafenib was 69.6% compared with 50% for vemurafenib alone. In the combination arm, 15.8% of patients had complete responses versus 10.5% with single-agent vemurafenib. The median duration of response was 13 months versus 9.2 months, respectively.

“No new safety signals were observed with the longer follow-up,” said Reddy.

The most frequently reported grade 3/4 adverse events (AEs) in the combination arm versus the control group were gamma-glutamyl transferase increase (15% vs 10%), CPK increase (12% vs <1%), and ALT increase (11% vs 6%). Thirty-seven percent of patients in the cobimetinib/vemurafenib arm and 28% in the single-agent vemurafenib group experienced serious AEs. The most common serious AEs in the combination arm were pyrexia and dehydration, at 2% each. There were 5 deaths related to AEs in the cobimetinib arm and 3 in the control arm.

The FDA and European Commission approved the cobimetinib/vemurafenib combination in November 2015 as a treatment for patients with BRAF-positive metastatic or unresectable melanoma.

“This continues to be an exciting time to be involved in skin cancer research. Advancements with targeted therapies and immunotherapies both provide important treatment options for patients with advanced melanoma, as each person’s clinical situation is different,” said Reddy.

Ascierto PAA, McArthur GAA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial [published online July 29, 2016]. Lancet Oncol.

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