Adding spartalizumab to treatment with dabrafenib and trametinib did not improve progression-free survival (PFS) in patients with unresectable or metastatic BRAF V600-mutant melanoma, according to a phase 3 trial published in the Journal of Clinical Oncology.1

The phase 3 COMBI-i trial (ClinicalTrials.gov Identifier: NCT02967692) was designed to investigate whether the upfront combination of a PD-1 inhibitor, MEK inhibitor, and BRAF inhibitor could yield durable responses in patients with BRAF V600-mutant unresectable or metastatic melanoma. 

The trial was conducted in 3 parts. Results from part 1 (safety run-in; 9 patients) and part 2 (biomarker cohort; 27 patients) were previously reported.2 In that report, spartalizumab plus dabrafenib and trametinib produced an objective response rate (ORR) of 78% and had an acceptable safety profile, according to researchers.  


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In the current report, researchers disclosed results from part 3.1 This part included 532 patients who were randomly assigned to receive spartalizumab plus dabrafenib and trametinib (267 patients) or placebo plus dabrafenib and trametinib (265 patients). Baseline characteristics were well balanced between the arms.

At a median follow-up of 27.2 months, the median PFS was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (hazard ratio [HR], 0.82; 95% CI, 0.66-1.03; P =.042). The ORR was 69% in the spartalizumab arm and 64% in the placebo arm. 

As of the data cutoff (July 1, 2020), 34% of patients in the spartalizumab arm and 39% of those in the placebo arm had died (HR, 0.79; 95% CI, 0.59-1.05).

The researchers noted that overall survival (OS) could not be formally tested because the study’s primary endpoint of PFS was not met. However, the interim analysis showed that median OS was not reached in either treatment arm. The estimated 2-year OS rates were 68% in the spartalizumab arm and 62% in the placebo arm.

Patients in the spartalizumab arm had higher rates of adverse events (AEs) and dose modifications than patients in the placebo arm. Grade 3 or higher treatment-related AEs were observed in 55% of patients in the spartalizumab arm and 33% in the placebo arm.

AEs leading to dose modifications occurred in 88% of patients in the spartalizumab arm and 73% of those in the placebo arm. Pyrexia (64%), chills (19.1%), and diarrhea (10.5%) were the most common AEs leading to dose modifications in the spartalizumab arm.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600mutant metastatic melanoma,” the researchers wrote. 

Disclosures: This research was supported by Novartis Pharmaceuticals Corporation. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

References

  1. Dummer R, Long GV, Robert C, et al. Randomized phase III trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600-mutant unresectable or metastatic melanoma. J Clin Oncol. Published online January 14, 2022. doi:10.1200/JCO.21.01601
  2. Dummer R, Lebbe C, Atkinson V, et al. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: Safety run-in and biomarker cohorts of COMBI-i. Nat Med. 2020;26(10):1557-1563. doi:10.1038/s41591-020-1082-2