Cobimetinib/Vemurafenib Improves Survival in BRAF-Mutated Melanoma

A combination of cobimetinib and vemurafenib prolongs overall survival (OS) in melanoma patients with BRAF V600 mutations, according to a new study presented at the Society for Melanoma Research 2015 International Congress, held November 18–21 in San Francisco.

The coBRIM trial is a phase III, double-blind, placebo-controlled study that tested the BRAF inhibitor vemurafenib plus either placebo or cobimetinib-an oral, small-molecule, highly selective, allosteric inhibitor of MEK-in 495 previously untreated patients (median age, 55.5) with BRAF V600 mutation–positive unresectable locally advanced or metastatic melanoma.

Combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. A recently updated progression-free survival (PFS) analysis after 14.2 months of follow-up confirmed a clinically meaningful treatment benefit. The combination led to a median 12.3 months PFS vs 7.2 months for vemurafenib alone, said Victoria Atkinson, MD, of the Princess Alexandra Hospital in Queensland, Australia.

In a 28-day treatment cycle, vemurafenib was administered at 960 mg twice daily from days 1 to 28 and 60 mg cobimetinib or placebo was administered daily from days 1 to 21. The patient characteristics of the two groups were evenly matched, and the majority of the patients had good performance status, she noted.

Dr. Atkinson presented OS data after a median follow-up of 18.5 months. “The addition of cobimetinib to vemurafenib resulted in significant and meaningful OS benefit,” she said. The median OS for the combination was 23.3 months compared with 17.4 months with vemurafenib alone. The 2-year OS was 48% with the combination and 38% with vemurafenib alone.

“The benefit of the combination was seen in all subgroups assessed,” she said, including ECOG performance status, LDH level, and presence of V600E or V600K mutations.

Dr. Atkinson highlighted that OS was improved in patients with baseline normal LDH levels, with OS not reached for patients who received the combination and 23.3 months for the vemurafenib-alone group. A similar trend was found for patients with elevated LDH levels (OS of 14.8 months with the combination vs 11.2 months with vemurafenib alone). This is consistent with previous combination studies showing that patients with poor prognostic factors do worse, she said.

“The safety profile of cobimetinib plus vemurafenib was tolerable and manageable,” Dr. Atkinson said. “The combination was well tolerated, and there was not a large difference in grade 3/4 adverse events between the two groups.” The most common treatment-related adverse events with the combination were gastrointestinal, rash, and photosensitivity.

Heterogeneities in baseline activity of signaling pathways, as measured by Ki67 and PTEN status, did not affect OS with cobimetinib and vemurafenib, she added.

In conclusion, Dr. Atkinson said: “Cobimetinib and vemurafenib results in statistically significant and clinically meaningful improvement in OS vs placebo plus vemurafenib in advanced BRAF V600–mutated melanoma. OS was improved in all clinical and molecular subgroups evaluated.”

Cobimetinib in combination with vemurafenib is now approved for patients with unresected or metastatic BRAF V600E– or BRAF 600K–mutated melanoma in the United States and Switzerland.