As reported in The Lancet Oncology by Paolo A. Ascierto, MD, and colleagues, the second interim overall survival analysis of the phase III IMspire150 trial has shown a numeric but statistically nonsignificant improvement with the addition of first-line atezolizumab to vemurafenib and cobimetinib in patients with BRAF V600–mutant advanced melanoma.

The previously reported primary analysis of the trial, which showed a significant improvement in investigator-assessed progression-free survival with the addition of atezolizumab (median follow-up = 18.9 months) supported the July 2020 approval of atezolizumab plus vemurafenib/cobimetinib in this setting.

Paolo A. Ascierto, MD

Study Details

The double-blind trial included 514 patients with unresectable stage IIIC or stage IV disease from sites in 20 countries. Patients were randomly assigned between January 2017 and April 2018 to receive atezolizumab at 840 mg (n = 256) or placebo (n = 258) on days 1 and 15 plus vemurafenib at 960 mg or 720 mg twice daily and cobimetinib at 60 mg once daily for 21 days on and 7 days off in 28-day cycles. Atezolizumab and placebo were added to treatment at cycle 2. Overall survival was assessed in the intention-to-treat population, with the interim analysis planned after approximately 270 events had occurred.

Overall Survival

At data cutoff for the analysis (in September 2021), 273 patients had died, including 126 in the atezolizumab group and 147 in the control group. Median follow-up was 29.1 months (interquartile range [IQR] = 10.1–45.4 months) in the atezolizumab group and 22.8 months (IQR = 10.6–44.1 months) in the control group. Median overall survival was 39.0 months (95% confidence interval [CI] = 29.9 months to not estimable) in the atezolizumab group vs 25.8 months (95% CI = 22.0–34.6 months) in the control group (hazard ratio [HR] = 0.84, 95% CI = 0.66–1.06, P = .14). A late separation of survival curves favoring the atezolizumab group was observed. Overall survival at 12 and 24 months was 76% vs 76% and 62% vs 53%, respectively. 

With the additional follow-up, patients in the atezolizumab group continued to have significantly better progression-free survival. Median progression-free survival was 15.1 months (95% 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 (HR = 0.79, 95% CI = 0.64–0.97, P = .022). At least one subsequent anticancer therapy was received by 48% of patients in the atezolizumab group vs 54% of the control group, including immunotherapy in 32% vs 44%, targeted therapy in 27% vs 16%, and chemotherapy in 7% vs 9%. 

Adverse Events

The safety analysis population consisted of 511 patients, including 231 who received triplet therapy (atezolizumab group) and 280 who received control therapy (control group); 1 patient randomly assigned to the control group received atezolizumab and was included in the atezolizumab group and 26 patients randomly assigned to the atezolizumab group never received atezolizumab and were included in the control group. No new safety signals for atezolizumab were observed with additional follow-up.

Grade 3 or 4 adverse events occurred in 75% of patients in the atezolizumab group vs 66% of the control group. The most common in the atezolizumab group were increased lipase (23% vs 22% in the control group), increased creatine phosphokinase (22% vs 18%), and increased alanine aminotransferase (14% vs 9%). Serious adverse events were reported in 48% vs 42% of patients. Adverse events led to discontinuation of all study treatment in 15% vs 16%. Adverse events led to death in eight patients (3%) in the atezolizumab group and six patients (2%) in the control group. Two deaths in the atezolizumab group (due to fulminant hepatitis and hepatic failure) and one death in the control group (due to pulmonary hemorrhage) were considered related to study treatment.

The investigators concluded, “Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAF V600 mutation–positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination vs vemurafenib plus cobimetinib.”

Dr. Ascierto, of Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Pascale, Naples, is the corresponding author for The Lancet Oncology article.

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