KEY TAKEAWAYS
- The Phase 3 study was conducted in 108 hospitals across 20 countries with patients having BRAFV600 mutation-positive melanoma.
- The primary aim was to evaluate the overall survival and safety outcomes of atezolizumab, vemurafenib, and cobimetinib.
- Patients were randomly assigned to receive either the triplet combination or placebo and were evaluated for safety and overall survival outcomes.
- The atezolizumab group showed a median overall survival of 39 months compared to the control group’s median of 25 months (range, 22% to 36%; HR, 0.84%; P=0.14).
- The most common side effects of any grade in the atezolizumab group were increased blood creatine phosphokinase, diarrhea, and pyrexia.
- The triplet combination of atezolizumab, vemurafenib, and cobimetinib was associated with improved overall survival in patients with BRAFV600 mutation
Patients with BRAFV600 mutation-positive melanoma who received first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) had better investigator-assessed progression-free survival than those who received placebo, vemurafenib, and cobimetinib (control group). Overall survival data were still preliminary at the time of the primary study, with a median follow-up of 18 months (IQR 10 months to 23 months). The second interim overall survival analysis was reported in this IMspire150 study. This phase 3 multicenter, randomized, placebo-controlled research was conducted in 108 academic and community hospitals across 20 nations. Patients were included if they were 18 years or older, had never had treatment for their melanoma, and had an unresectable stage IIIc or stage IV diagnosis. Patients received either vemurafenib (960 mg or 720 mg twice daily orally), cobimetinib (60 mg once daily), and atezolizumab (840 mg intravenously on day 1 and 15) in 28-day cycles (21 days on, 7 days off).
From cycle two onward, atezolizumab and a placebo were included in patients’ treatment plans. The randomization was conducted at a centralized location (Durham, NC, USA) utilizing a permuted block randomization scheme (block size = 4), an interactive web-based response system, and geographical region and baseline lactate dehydrogenase concentration as stratification factors. Safety was evaluated in all patients who received at least one dosage of study medicine based on actual treatment received, and overall survival was evaluated in the intention-to-treat population. Progression-free survival, as determined by the investigators, was the primary outcome. After about 270 overall survival events had occurred, investigators presented the results of the second interim analysis of overall survival. The trial is still active but is no longer recruiting participants. There were a total of 514 participants in the study, with half of them randomly assigned to either atezolizumab (n=256) or a placebo (n=258; median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) between January 13, 2017, and April 26, 2018. 273 individuals had passed away at the time the data was cut off (September 8, 2021).
This included 126 in the atezolizumab group and 147 in the control group. The atezolizumab group had a median follow-up time of 29.1 months (IQR 10.1-45.4), while the placebo group had a median follow-up time of 22.8 months (10.6-44.1). The atezolizumab group had a median overall survival of 39 months (95% CI 29 months to not estimable) compared to the control group’s median of 25 months (range, 22% to 36%; HR, 0.84%; P=0.14). Increased blood creatine phosphokinase (123 [53%] of 231 patients), diarrhea (116 [50%] of patients), and pyrexia (115 [50%] of patients) were the most common side events of any grade in the atezolizumab group. Diarrhea affected 157 (56%) of 280 patients in the control group, whereas an increase in blood creatine phosphokinase affected 135 (48%), and rash affected 119 (43%). Increases in lipase, blood creatine phosphokinase, and alanine aminotransferase were the most common adverse events of grade 3-4 (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group, respectively); 112 patients in the atezolizumab group (48%) and 117 patients in the control group (42%), respectively, suffered serious adverse events. Eight individuals in the atezolizumab group (3%) suffered adverse events of grade 5 compared to six patients in the control group (2%). Investigators determined that the triplet combination was responsible for two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group and that cobimetinib was responsible for one incident (pulmonary hemorrhage) in the control group.
Source: https://pubmed.ncbi.nlm.nih.gov/36460017/
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02908672
Ascierto PA, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Zhukova N, Schachter J, Yan Y, Caro I, Hertig C, Xue C, Kusters L, McArthur GA, Gutzmer R. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomized, phase 3 study. Lancet Oncol. 2023 Jan;24(1):33-44. doi: 10.1016/S1470-2045(22)00687-8. Epub 2022 Nov 29. PMID: 36460017.
