Treating BRAFV600 mutation-positive advanced melanoma with atezolizumab, vemurafenib, and cobimetinib

The study evaluated whether the combination of atezolizumab (Tecentriq), vemurafenib (Zelboraf), and cobimetinib (Cotellic) or AVC can effectively treat patients with BRAF^V600 mutation-positive advanced melanoma (AM). The authors found that this combination was safe and effective as an initial treatment in such patients.

Unresectable AM cannot be surgically removed. Most such AMs carry abnormal genes (mutations), called V600, in the BRAF gene. As a result, cancer grows more aggressively. Vemurafenib inhibits the effects of BRAF mutation. A combination of vemurafenib and cobimetinib is effective in patients with such conditions. However, treatment responses are short-lived.

Atezolizumab has a lower but lasting response in AM therapy. The AVC combination was effective against BRAF^V600 mutation-positive AM in an early-phase clinical trial. Its efficacy in larger late-stage trials is unknown.

This trial included 514 patients with BRAF^V600 mutation-positive unresectable AM. Their cancer was previously untreated. 256 patients received AVC combination. 258 patients received vemurafenib and cobimetinib (VC) with a placebo in the control group. Treatment in both groups initiated with VC. After 4 weeks, the AVC group started receiving atezolizumab and the control group started a placebo. Patients were followed-up for 18.9 months on average.

Progression-free survival (PFS) denotes how long patients survive without cancer worsening. The average PFS was 10.6 months for the control group and 15.11 months for the AVC group. Atezolizumab was associated with a 22% improvement in PFS when compared to placebo. 

Mortality rates were 36% in the AVC grou[ and 43% in the control group. Patients in the atezolizumab group had 15% lower risks of mortality. Overall, 60% patients in the AVC and 53% in the control groups had survived for 2 years without any medical event. Treatment response lasted for 21 months in the AVC and 12.6 months in the control group, on average.

99% of each group reported treatment-related side effects. In the atezolizumab group, side effects that were reported more frequently compared to the control group were joint and muscle pain, fever, skin itch, thyroid dysfunction and elevated liver enzymes. Treatment was stopped due to side effects in 13% of the AVC group and 16% of the control groups.

The study concluded that initial therapy with AVC effectively improved PFS in patients with BRAF^V600 mutation-positive unresectable AM. 

This phase 3 trial is sponsored by Roche, the manufacturer of atezolizumab, vemurafenib, and cobimetinib and is still ongoing.