On July 30, the U.S. Food and Drug Administration (FDA) approved the PD-L1 inhibitor atezolizumab (Tecentriq) plus the MEK inhibitor cobimetinib (Cotellic) and the selective BRAF kinase inhibitor vemurafenib (Zelboraf) for the treatment of patients with advanced BRAF V600 mutation–positive melanoma.
The supplemental biologics license application for atezolizumab was granted Priority Review. The review was also conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology products among international partners.
IMspire150
The approval is based on results from IMspire150, a multicenter, double-blind, placebo-controlled randomized phase III study. The study compared the efficacy and safety of atezolizumab plus cobimetinib and vemurafenib to the combination of placebo plus cobimetinib and vemurafenib in patients with previously untreated BRAF V600 mutation–positive metastatic or unresectable locally advanced melanoma.
The primary endpoint of the study was investigator-assessed progression-free survival. Key secondary endpoints included progression-free survival per an independent review committee, overall survival, objective response rate, duration of response, and other safety and pharmacokinetic measures.
Five hundred and fourteen adult patients took part in the study. Random assignment was stratified by lactate dehydrogenase level and geographic region. Eligible patients were assigned to receive 28-day cycles of either atezolizumab plus cobimetinib and vemurafenib or placebo plus cobimetinib and vemurafenib. In cycle 1, all patients received once-daily oral cobimetinib at 60 mg plus twice-daily oral vemurafenib at 960 mg for 21 days, followed by twice-daily vemurafenib at 720 mg or 960 mg for 7 days in the experimental group or control group, respectively. Patients in the experimental group received vemurafenib at 720 mg for days 1–28 of each subsequent cycle. The lower 720-mg dose of vemurafenib in the experimental group was a safety measure to mitigate the risk of overlapping toxicities, while ensuring an efficacious dose of the agent. Treatment was continued until investigator-determined disease progression, unacceptable toxicity, death, or patient/physician decision to withdraw, whichever occurred first.
In the experimental arm, median progression-free survival was 15.1 months vs 10.6 months in the control arm (hazard ratio = 0.78, 95% confidence interval = 0.63–0.97, P = .025).
The safety profile observed in the triplet arm was consistent with the known safety profiles of the individual medicines. The most common adverse reactions (rate ≥ 20%) in patients who received atezolizumab plus cobimetinib and vemurafenib were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).
The recommended atezolizumab dose (following completion of a 28-day cycle of cobimetinib and vemurafenib) is 840 mg every 2 weeks with 60 mg of cobimetinib orally once daily (21 days on, 7 days off) and 720 mg of vemurafenib orally twice daily.
