Sandra Horning, MD
Treatment with the combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) improved overall survival (OS) by 4.9 months compared with vemurafenib alone for patients with BRAF
mutation-positive advanced melanoma, according to findings from the phase III coBRIM study presented at the 2015 Society for Melanoma Research (SMR) Congress.
In the updated findings, the median OS was 22.3 months with the combination compared with 17.4 months with vemurafenib alone, representing a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.55-0.90; P
= .005). The 1- and 2-year OS rates with the combination were 74.5% and 48.3%, respectively.
“With about half of the people taking Cotellic and Zelboraf alive after two years, these data underscore the progress being made in cancer research toward better patient outcomes,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, the company developing the combination, said in a statement. “Five years ago, the survival rate for BRAF mutation-positive advanced melanoma was measured in months, and now we are measuring it in years.”
In the phase III coBRIM study, the MEK inhibitor cobimetinib plus the BRAF inhibitor vemurafenib was compared with single-agent vemurafenib in previously untreated patients with BRAF
V600E/K mutation-positive unresectable locally advanced or metastatic melanoma. Four hundred and ninety-five patients were randomized to continuous vemurafenib at 960 mg twice daily plus cobimetinib at 60 mg once daily on days 1-21 of a 28-day cycle (n = 247) or placebo (n = 248).
Patient demographics were well balanced across the two arms for age, ECOG performance status, geographic region, and disease stage. More than half of patients had stage IV, M1c melanoma. The primary endpoint for the study was progression-free survival (PFS), with secondary endpoints focused on OS, objective response rate (ORR), and duration of response.
According to earlier assessments, the median PFS with the combination of vemurafenib and cobimetinib was 12.3 versus 7.2 months for vemurafenib alone (HR, 0.56; P
<.001). The ORR with the combination was 69.6% compared with 50% for vemurafenib alone. The complete response rate in the combination arm was 15.8% versus 10.5% with vemurafenib and placebo (P
<.001). The median duration of response was 12.98 months versus 9.23 months, with cobimetinib and placebo, respectively.
The most frequently reported adverse events (AEs) of all grades reported in the cobimetinib arm versus the control arm included diarrhea (57% vs 28%), nausea (39% vs 24%), photosensitivity (28% vs 16%), increased ALT (24% vs 18%), increased AST (22% vs 13%), increased CPK (30% vs 3%), vomiting (21% vs 12%), and serous retinopathy (20% vs <1%).
Some AEs occurred at lower rates in the combination group, including hair loss (14% vs 29%), hyperkeratosis (10% vs 29%), joint pain (33% vs 40%), cutaneous squamous cell carcinomas (3% vs 11%), and keratoacanthomas (<1% vs 8%). Treatment-related discontinuation rates in the combination and control groups were similar at 13% and 12%, respectively. There were six deaths related to AEs in the cobimetinib arm and three in the control arm.
“The overall survival benefit for Cotellic and vemurafenib observed in the coBRIM trial further underscores the positive impact that the combination of these two therapies can have on the treatment of advanced BRAF V600 mutation-positive melanoma,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, the developer of cobimetinib, said in a statement.
On November 10, 2015, the FDA approved the combination of vemurafenib and cobimetinib as a treatment for patients with BRAF-positive metastatic or unresectable melanoma, based on an extension in progression-free survival in the phase III coBRIM study. An approval decision from the European Commission is anticipated before the end of 2015. The final OS data from the coBRIM study are being submitted to both regulatory agencies for potential label updates for the combination.
Clinical trials continue to assess vemurafenib plus cobimetinib for patients with melanoma, including a phase II study of the combination as a neoadjuvant therapy for patients with melanoma (NCT02036086). Additionally, a phase Ib study is exploring the combination with the PD-L1 inhibitor atezolizumab for BRAF-positive metastatic melanoma (NCT01656642).
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