The FDA has approved a new indication for atezolizumab (Tecentriq®, Genentech) in combination with cobimetinib (Cotellic®, Genentech) and vemurafenib (Zelboraf®, Genentech and Daiichi-Sankyo) for the treatment of BRAF V600-mutated advanced melanoma. The approval was granted under a supplemental Biologics License Application (sBLA) with priority review.
The approval was based on data from the double-blind, international phase 3 IMspire150 trial (NCT02908672), for which 514 patients with unresectable stage IIIc/IV BRAF V600-mutated melanoma were randomized in a 1:1 ratio to receive 28-day cycles of vemurafenib, a BRAF inhibitor, and cobimetinib, a MEK inhibitor, in conjunction with either the PD-L1 inhibitor atezolizumab or identical intravenous placebo, added from Cycle 2 onward. The primary end point was investigator-assessed progression-free survival.
At the time of the primary analysis, completed with a median follow-up of 18.9 months, patients in the atezolizumab group experienced significantly longer progression-free survival compared with those in the control group (15.1 vs 10.6 months).
"Immune checkpoint inhibitors and BRAF and MEK inhibitors have significantly improved treatment outcomes in patients with BRAF V600 mutation-positive metastatic melanomas," wrote the study investigators in their June publication in The Lancet, led by first author Ralf Gutzmer, MD, Professor in the Department of Dermatology and Allergy of the Skin Cancer Center Hannover at Hannover Medical School, Hannover, Germany. "Although BRAF and MEK inhibitors are associated with high objective response rates, most responses are short lived. Immune checkpoint inhibitors provide more durable responses, but response rates are relatively lower. Because of these complementary clinical characteristics, the combination of the two approaches is appealing."
Adverse events of any grade occurring in over 30% of patients across both the atezolizumab and control arms included increase in blood creatinine phosphokinase (51.3% with atezolizumab vs 44.8% with placebo), diarrhea (42.2% vs 46.6%), rash (49.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), and increases in alanine aminotransferase (33.9% vs 22.8%) and lipase (32.2% vs 27.4%). Additional adverse events affecting at least 20% of patients in the atezolizumab arm included nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%). Treatment discontinuation due to adverse events occurred in 13% of patients in the atezolizumab arm, compared with 16% in the control arm.
"In this study, the proportion of patients in the control group with grade 3 or 4 adverse events was higher than that reported in the coBRIM study evaluating an identical regimen," noted Dr. Gutzmer and colleagues. "The increased frequency of grade 3 or 4 events in IMspire150 was probably the result of protocol-mandated monitoring of laboratory abnormalities and class-effect adverse events that were not routinely assessed in other clinical trials, including coBRIM… Notably, in the current study, lipase and amylase increases were not associated with clinically significant adverse events, such as pancreatitis, and abnormal liver function tests and creatine phosphokinase elevations were largely asymptomatic. The addition of atezolizumab only slightly increased the prevalence of treatment-related grade 3 or 4 adverse events (79%) versus control (73%) and did not escalate typical BRAF plus MEK inhibitor-associated adverse events."
"The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF V600 mutation-positive advanced melanoma," concluded the investigators.
For More Information
Gutzmer R, Stroyakovskiy D, Gogas H, et al (2020). Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 395(10240):1835-1844. DOI:10.1016/S0140-6736(20)30934-X
Clinicaltrials.gov (2020). A study of atezolizumab plus cobimetinib and vemurafenib versus placebo plus cobimetinib and vemurafenib in previously untreated BRAFv600 mutation-positive patients with metastatic or unresectable locally advanced melanoma. NLM identifier: NCT02908672.
Ascierto PA, McArthur GA, Dréno B, et al (2016). Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol, 17(9):1248-1260. DOI:10.1016/S1470-2045(16)30122-X
Image credit: Sriram Subramaniam. Courtesy of the National Cancer Institute