As reported in The Lancet Oncology by Paolo A. Ascierto, MD, of the Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Pascale, Naples, 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/cobimetinib in BRAF V600–mutant advanced melanoma.¹

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

In the double-blind trial, 514 patients with unresectable stage IIIC or stage IV disease from sites in 20 countries 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. Stage IV disease was present in 242 patients in the atezolizumab group and 240 in the control group. The current report is from the second, prespecified, interim overall survival analysis in the intention-to-treat population, which was planned after approximately 270 overall survival 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. Treatment was ongoing in 14% of patients in each 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. In landmark analyses, overall survival rates at 12 and 24 months were 76% (95% CI = 71%–81%) vs 76% (95% CI = 71%–82%) and 62% (95% CI = 55%–68%) vs 53% (95% CI = 47%–60%).

With the additional follow-up, the atezolizumab group continued to have significantly better investigator-assessed 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).  In landmark analyses, progression-free survival rates were 73% (95% CI = 67%–78%) vs 74% (95% CI = 69%–80%) at 6 months, 54% (95% CI = 48%–60%) vs 46% (95% CI = 39%–52%) at 12 months, and 44% (95% CI = 37%–50%) vs 32% (95% CI = 26%–38%) at 18 months.

At least one subsequent anticancer therapy was received by 48% of 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. Median duration of treatment was 9.2 months (IQR = 3.3–23.0 months) in the atezolizumab group and 8.9 months (IQR = 4.2–18.8 months) in the control group. The safety profile in the atezolizumab group was similar to that observed at primary analysis, with no new safety signals observed with additional follow-up.

The most common adverse events of any grade were increased creatine phosphokinase (53%), diarrhea (50%), and pyrexia (50%) in the atezolizumab group and diarrhea (56%), increased creatine phosphokinase (48%), and rash (43%) in the control group. Grade 3 or 4 adverse events occurred in 75% of the atezolizumab group vs 66% of the control group. The most common events in the atezolizumab group were increased lipase (23% vs 22% in 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 versus vemurafenib plus cobimetinib.” 

DISCLOSURE: The study was funded by F. Hoffmann–La Roche. Dr. Ascierto owns stock in PrimeVax; has held a consultant or advisory role for Bristol-Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis, Lunaphore, Seattle Genetics, ITeos Therapeutics, Medicenna, Bio-Al Health, ValoTx, Replimune, and Bayer; has received research funding from Bristol-Myers Squibb, Roche/Genentech, Array BioPharma, Sanofi, and Pfizer; and has received travel expenses from Merck Sharp & Dohme, Pfizer, Bio-Al Health, and Replimune.

REFERENCE

1. Ascierto PA, Stroyakovskiy D, Gogas H, et al: Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAF^V600 mutation-positive advanced melanoma (IMspire150): Second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol 29:S1470-2045(22)00687-8, 2022.