Ralf Gutzmer, MD
As reported inThe Lancet by Ralf Gutzmer, MD, of Medizinische Hochschule Hannover, Germany, and colleagues, the phase III IMspire150 trial has shown that the addition of atezolizumab to BRAF and MEK inhibitor therapy with vemurafenib and cobimetinib improved progression-free survival in the first-line treatment of unresectable BRAF V600–mutant melanoma.1
In the double-blind trial, 514 patients with unresectable stage IIIc to IV disease from sites in 20 countries were randomly assigned between January 2017 and April 2018 to receive 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (n = 256) or placebo, vemurafenib, and cobimetinib (n = 258). Randomization was stratified by lactate dehydrogenase (LDH) concentration and geographic region.
In cycle 1, all patients received twice-daily vemurafenib at 960 mg for 21 days plus once-daily cobimetinib at 60 mg, followed by either twice-daily vemurafenib at 720 mg in the atezolizumab group or at 960 mg for 7 days in the control group. Starting with cycle 2, patients in the atezolizumab group received the agent at 840 mg on days 1 and 15, twice-daily vemurafenib at 720 mg, and once-daily cobimetinib at 60 mg on a 21-days-on/7-days-off schedule. Patients in the control group received placebo (days 1 and 15), twice-daily vemurafenib at 960 mg, and once-daily cobimetinib at 60 mg on a 21-days-on/7-days-off schedule. The primary endpoint was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1.
In the atezolizumab vs control groups, median patient age was 54.0 vs 53.5 years (24% vs 23% ≥ 65 years), 59% vs 58% were male, and 95% vs 95% were White. Geographic region was North America for 5% vs 5%, Europe for 79% vs 79%, and Australia, New Zealand, or other for 16% vs 16%. Eastern Cooperative Oncology Group performance status was 0 for 76% vs 77% and 1 for 24% vs 22%. Disease stage was IIIC for 5% vs 6% and IV for 95% vs 93%. Overall, 33% vs 33% had elevated LDH, 57% vs 63% had M1C disease, 56% vs 56% had more than three lesions, 2% vs 3% had previously treated brain metastasis, 16% vs 12% had prior adjuvant therapy, and 63% vs 61% had PD-L1–positive disease (≥ 1% immune cells).
Median follow-up was at 18.9 months. Median progression-free survival was 15.1 months (95% confidence interval [CI] = 11.4–18.4 months) in the atezolizumab group vs 10.6 months (95% CI = 9.3–12.7 months) in the control group (hazard ratio [HR] = 0·78, 95% CI = 0.63–0.97, P = .025). Progression-free survival benefit was consistent among patient subgroups examined. With regard to stratification factors, hazard ratios were 0.85 (95% CI = 0.32– 2.27) for North America; 0.79 (95% CI = 0.62–1.00) for Europe; and 0.69 (95% CI = 0.37–1.27) for Australia, New Zealand, or other. Additional hazard ratios included 0.81 (95% CI = 0.58–1.14) for elevated LDH and 0.76 (95% CI = 0.57–1.01) for normal LDH, plus 0.80 (95% CI = 0.60–1.06) for PD-L1–positive disease and 0.76 (95% CI = 0.53–1.10) for PD-L1–negative disease.
Median progression-free survival as assessed by an independent review committee was also prolonged in the atezolizumab group (median = 16.1 months vs 12.3 months, HR = 0.85, 95% CI = 0.67–1.07, P = .16), although the difference did not achieve statistical significance.
At an interim analysis of overall survival, death had occurred in 36% of patients in the atezolizumab group vs 43% of patients in the control group (HR = 0.85, 95% CI = 0.64–1.11, P = .23). Estimated 2-year overall survival was 60% vs 53%. An investigator-assessed confirmed objective response was observed in 66.3% of patients vs 65.0% of patients, with a complete response observed in 15.7% vs 17.1%. Median duration of response was 21.0 months (95% CI = 15.1 months to not estimable) vs 12.6 months (95% CI = 10.5–16.6 months).
Common treatment-related adverse events of any grade (> 30%) in the atezolizumab and control groups were increased creatine phosphokinase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both groups), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), increased alanine aminotransferase (33.9% vs 22.8%), and increased lipase (32.2% vs 27.4%).
Treatment-related grade 3 or 4 adverse events occurred in 79% vs 73% of patients, with the most common in the atezolizumab group being increased lipase (20% vs 21% in control group), increased creatine phosphokinase (20% vs 15%), increased alanine or aspartate aminotransferase (13% vs 9%), and maculopapular rash (13% vs 10%).
Treatment-related serious adverse events occurred in 33% vs 29%. Adverse events led to discontinuation of all treatment in 13% vs 16% of patients and to death for seven patients in each group. Fatal adverse events in the atezolizumab group consisted of sepsis in two patients and cardiac arrest, pneumonia, septic shock, hepatic failure, and fulminant hepatitis in one patient each. Causes in the control group consisted of cardiac arrest, cardiac failure, left ventricular failure, cerebrovascular accident, hydrocephalus, gastrointestinal hemorrhage, and pulmonary hemorrhage in one patient each.
Immune-mediated adverse events occurred in 63% vs 51% of patients, with those occurring more commonly in the atezolizumab group (≥ 2% difference) consisting of increased aspartate aminotransferase, increased alanine aminotransferase, pneumonitis, increased amylase, dermatitis-acneiform, uveitis, hyperthyroidism, and acne.
The investigators concluded: “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.”
DISCLOSURE: The study was funded by F. Hoffmann–La Roche and Genentech. Dr. Gutzmer has received personal fees and nonfinancial support from Bristol Myers Squibb, Roche, and Merck Serono; grants, personal fees, and nonfinancial support from Amgen, Novartis, Pierre Fabre, and Sanofi Regeneron; personal fees from 4SC, Almirall Hermal, Merck Sharp & Dohme, and Sun Pharma; grants from Johnson & Johnson; and grants and personal fees from Pfizer. For full disclosures of the other authors, visit thelancet.com.
1. Gutzmer R, Stroyakovskiy D, Gogas H, et al: 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 III trial. Lancet 395:1835-1844, 2020.
Omid Hamid, MD
As investigators, we were always determined to find the drug to work with BRAF/MEK inhibitor combination therapy. It had come on like a storm and showed us that we could help even those with the most advanced metastatic melanoma, as long as it harbored the magical BRAF V600E...