Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib forBRAFV600–Mutant Unresectable or Metastatic Melanoma

Abstract

PURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692 ). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients withBRAFV600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

“…[19][20][21] The trend toward greater survival benefit with sparta-DabTram vs placebo-DabTram in the subpopulation with detectable baseline ctDNA shedding complements Open access the previously reported greater PFS benefit in patients with measures of clinically higher tumor burden, such as greater number of metastatic sites or sum of lesion diameters. 11 In that analysis, there was also a predictive trend based on baseline LDH level (HR (LDH levels normal), 0.88; HR (LDH levels ≥1 to <2 × ULN), 0.78). 11 Notably, the predictive trend based on baseline ctDNA in the present analysis was even stronger (HR (no shedding), 1.01; HR (shedding), 0.75).…”

“…http://jitc.bmj.com/ Open access table S1). 11 Because biomarker results were not available from all patients at all time points, we summarize in table 1 the availability for each analysis. Most patients were represented, with biomarker results available from approximately 64%-90% (339 to 481 of 532 patients).…”

“…7 8 However, the results of three key clinical trials of such combinations have been reported at the time of this writing, showing only modest benefits vs targeted therapy alone. [9][10][11] While these data collectively do not support routine use of first-line checkpoint inhibitor plus targeted therapy combinations, biomarkers that identify patient subgroups more likely to benefit remain an intriguing possibility. The results from COMBI-i on July 3, 2022 by guest.…”

“…Only IMspire150 met its primary endpoint, and modest improvements in progression-free survival (PFS) occurred at the cost of increased toxicity; overall survival (OS) data from phase 3 studies are not yet mature. [9][10][11] Exploratory findings from COMBI-i parts 1 and 2 demonstrated on-treatment biomarker modulations, including increased expression of T-cell-inflamed signatures (TIS) and decreased mitogen-activated protein kinase (MAPK) pathway activity, in samples from patients treated with combination of the anti-programmed death receptor 1 (PD-1) monoclonal antibody spartalizumab, the BRAF inhibitor dabrafenib, and the MEK inhibitor trametinib (sparta-DabTram). The objective response rate with sparta-DabTram was 78% (28 of 36 patients), with 16 patients (44%) achieving a complete response.…”

PD-1 or PD-L1 Blockade Adds Little to Combination of BRAF and MEK Inhibition in the Treatment of BRAF V600–Mutated Melanoma

“…In the article that accompanies this editorial, 13 the addition of the anti–PD-1 antibody spartalizumab to combination dabrafenib plus trametinib in a randomized trial did not improve PFS, response rate, or 24-month OS in previously untreated patients with metastatic BRAF V600–mutated melanoma. Consistent with two previous randomized trials, the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi plus MEKi is not associated with a significant clinical benefit and should not be studied further in melanoma.…”