by ecancer reporter Janet Fricker

Adding the MEK inhibitor cobimetinib to the BRAF inhibitor vemurafenib in patients with BRAFV600 mutated metastatic melanoma improved response rates and progression free survival, reported the phase 3 coBRIM study published in The New England Journal of Medicine.

Around 50% of metastatic cutaneous melanomas harbour a BRAF V600 mutation, and can be treated with the BRAF inhibitors such as vemurafenib and dabrafenib.

However, after median progression-free survivals of six to seven months acquired resistance often occurs with the most common mechanism of acquired resistance to vemurafenib being MAPK reactivation through MEK.

The combined inhibition of BRAF and MEK, it has been hypothesized, would improve clinical outcomes in melanoma patients by preventing or delaying the onset of resistance observed with BRAF inhibitors alone.

In preclinical models furthermore, MEK plus BRAF inhibition has been shown to prevent the development of acquired resistance.

Cobimetinib is an orally bio available, potent, and selective MEK inhibitor.

In the coBRIM study between January 2013 and January 2014, 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation positive melanomas were randomised 1:1 to receive vemurafenib and cobimetinib (n=247)or vemurafenib and placebo (n=248).

In the study, whose first author was James Larkin, patients were recruited from 135 sites in the US, Canada, Australia, New Zealand, Europe, Russia, Turkey and Israel, with the primary endpoint being progression-free survival assessed according to RECIST criteria.

Results showed that median progression-free survival was 9.9 months in the combination group versus 6.2 months in the control group (HR for death or disease progression, 0.51; 95% CI 0.39 to 0.68, P<0.001).

The rate of complete or partial response was 68% in the combination group versus 45% in the control group (P<0.001), including complete response in 10% of patients treated with combination therapy versus 4 % with vemurafenib alone.

The 9-month overall survival rate was 81.1% in the combination arm versus 72.5% in the vemurafenib arm (HR 0.65, p=0.046).

Notably, combination therapy reduced cutaneous squamous cell carcinoma from 11% to 3%, and keratocanthoma from 8% to 1%.

The combination of vemurafenib and cobimetinib was associated with a higher frequency of central serous retinopathy, gastrointestinal events, photosensitivity, elevated aminotransferase levels and increased creatine kinase levels than single-agent therapy.

Most of these events however were grade 1 or 2.

“The combination of vemurafenib and cobimetinib, as compared with vemurafenib alone, resulted in an improvement in progression-free survival and objective responses, with early evidence of improved overall survival and a somewhat increased toxicity profile, among patients with advanced BRAF-mutated melanoma,” write the authors.

Data from the pre specified interim analysis of overall survival, add the authors, was immature, reflecting the time of the planned analysis of progression-free survival, and did not cross the boundary pre specified in the statistical analysis plan.

“Nevertheless, these data are encouraging, although mature data are needed before definitive conclusions can be drawn,” write the authors.

Reference

J Larkin, P Ascierto, B Dréno, et al. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. NEJM.