Monday, August 15, 2016

coBRIM trial (cobimetinib wih vemurafenib) - updated results

I reported on this combo first back in 2014:  BRAF/MEK combo: vemurafenib with cobimetinib

Here in 2015 with the FDA approval:  Two new FDA approvals for the treatment of melanoma
And this was out of ASCO this year: ASCO 2016: cobimetinib and vermurafenib

Here is the latest update:
Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.  Ascierto, McArthur, Dréno, Chang, Ribas, et al. Lancet Oncol. 2016 Jul 29.  

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAFV600-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.  In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAFV600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with, number NCT01689519, and is ongoing but no longer recruiting participants.  Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months, the updated investigator-assessed median progression-free survival was 12·3 months for cobimetinib and vemurafenib versus 7·2 months for placebo and vemurafenib. The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months for cobimetinib and vemurafenib versus 17·4 months for placebo and vemurafenib. The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [less than 1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.  These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAFV600-mutant melanoma.

And as one would assume....progression free survival as well as median overall survival was greater when vemurafenib was combined with cobimetinib than when it was given with a placebo.  Perhaps a little surprising was the fact that side effects were higher in those receiving the cobimetinib and vemurafenib combo, as the BRAFi/MEKi combo's are generally shown to have greater efficacy than BRAFi given alone, but also produce FEWER side effects in previous studies.

Thanks, ratties. - c

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