As reported in The Lancet by Gutzmer et al, 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 first-line treatment of patients with unresectable BRAF V600–mutant melanoma.

Study Details

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 atezolizumab placebo, vemurafenib, and cobimetinib (n = 258). Randomization was stratified by lactate dehydrogenase (LDH) concentration and geographical 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 atezolizumab 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 on 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 according to Response Evaluation Criteria in Solid Tumors version 1.1.

In the atezolizumab vs control groups:

• Median age was 54.0 vs 53.5 years (24% vs 23% ≥ 65 years)
• 59% vs 58% were male
• 95% vs 95% were non-Hispanic 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 IV for 95% vs 93%
• 33% vs 33% had elevated LDH
• 57% vs 63% had M1C disease
• 16% vs 12% had taken prior adjuvant therapy
• 63% vs 61% had PD-L1–positive disease (≥ 1% immune cells).

Progression-Free Survival

Median follow-up was 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 patients in 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. Hazard ratios were 0.81 (95% CI = 0.58–1.14) for those with elevated LDH and 0.76 (95% CI = 0.57–1.01) for those with normal LDH, and 0.80 (95% CI = 0.60–1.06) for patients with 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 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 not achieve statistical significance.

At 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%. Investigator-assessed confirmed objective response was observed in 66.3% of patients vs 65.0% of patients, with complete response observed in 15.7% vs 17.1%. Median duration of response was 21.0 months (95% CI = 15.1 months–not estimable) vs 12.6 months (95% CI = 10.5–16.6 months).

Adverse Events

Common treatment-related adverse events of any grade (> 30% of patients) 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% of patients. Adverse events led to discontinuation of all treatment in 13% vs 16% of patients. Adverse events led to death in seven patients in each group. Causes of death 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.”

Ralf Gutzmer, MD, of Medizinische Hochschule Hannover, Germany, is the corresponding author for The Lancet article.

Disclosure: The study was funded by F. Hoffmann–La Roche and Genentech. For full disclosures of the study authors, visit thelancet.com.