As reported in the Journal of Oncology by Reinhard Dummer, MD, and colleagues, the phase III COMBI-i trial has shown no significant progression-free survival benefit with the addition of the anti–PD-1 antibody spartalizumab to dabrafenib and trametinib in patients with no prior systemic treatment for BRAF V600–mutant unresectable or metastatic melanoma.

Reinhard Dummer, MD

Study Details 

In the double-blind trial, 532 patients from sites in 29 countries were randomly assigned between September 2017 and July 2018 to receive spartalizumab at 400 mg every 4 weeks (n = 267) or placebo (n = 265) plus dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily, with treatment continuing until disease progression or unacceptable toxicity.

The primary endpoint was investigator-assessed progression-free survival. Significance was determined by stratified log-rank test at an overall one-sided 2.5% level.

Progression-Free Survival

At data cutoff (July 2020), median follow-up was 27.2 months (interquartile range = 25.4–29.0 months). Median progression-free survival was 16.2 months (95% confidence interval [CI] = 12.7–23.9 months) in the spartalizumab group vs 12.0 months (95% CI = 10.2–15.4 months) in the control group (hazard ratio [HR] = 0.82, 95% CI = 0.66–1.03, P = .042; one-sided, nonsignificant). Estimated 24-month rates were 44% vs 36%.  

Median progression-free survival was 26.6 months vs 15.4 months among 138 vs 126 patients with PD-L1 expression ≥ 1% (HR = 0.76, 95% CI = 0.54–1.07) and 12.0 months vs 10.3 months among 98 vs 115 with expression < 1% (HR = 0.84, 95% CI = 0.60–1.18).   

Among patients who discontinued study treatment, 38% vs 40% of received subsequent anticancer therapy, most commonly checkpoint inhibitors. PD-1 inhibitor monotherapy was received by 11% vs 22%.

Overall survival was not formally tested since the primary endpoint was not met. At interim analysis, death had occurred in 34% of patients in the spartalizumab group vs 39% in the control group (HR = 0.79, 95% CI = 0.59–1.05). Estimated 24-month rates were 68% vs 62%. Objective response rates were 69% vs 64%, with complete response in 20% vs 18%.

Adverse Events and Dose Intensity

Among treatment-related adverse events of any grade, pyrexia (66%), chills (29%), diarrhea (24%), and nausea (24%) were the most common in the spartalizumab group and occurred at a higher rate vs the control group. Grade ≥ 3 treatment-related adverse events occurred in 55% of patients in the spartalizumab group vs 33% of the control group. Treatment-related adverse events led to discontinuation of any study drug in 32% vs 14% of patients and to all three study drugs in 12% vs 18%. Dose intensity of both dabrafenib and trametinib was lower in the spartalizumab group (87% vs 98%). Full doses of dabrafenib and trametinib were received by 32% and 55% of patients in the spartalizumab group vs 54% and 74% in the control group.

Treatment-related death occurred in two patients in the control group (due to pancreatitis and cerebrovascular accident) and in no patients in the spartalizumab group.

The investigators concluded, “The study did not meet its primary endpoint; broad first-line use of spartalizumab plus dabrafenib/trametinib is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.”

Dr. Dummer, of the Department of Dermatology, University of Zürich Hospital, is the corresponding author for the Journal of Clinical Oncology article. 

Disclosure: The study was supported by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit ascopubs.org.