COMBI-i’s invited discussant, Bartosz Chmielowski, MD, PhD, Associate Clinical Professor at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, said this study is one of three key trials in which checkpoint inhibitors were combined with BRAF and MEK inhibitors. “This is not the first clinical trial to address the important question of combination of immunotherapy and targeted therapy,” he noted. “Unfortunately, COMBI-i did not meet its primary endpoint based on the statistical design of the trial.”
KEYNOTE-022 evaluated pembrolizumab plus dabrafenib and trametinib in 120 patients with BRAF-mutant melanoma.1 Like COMBI-i, this trial was statistically negative for the primary endpoint of progression-free survival. Another similar trial was IMspire 150, which evaluated atezolizumab plus vemurafenib and cobimetinib.2 This study did meet its primary endpoint of progression-free survival.
“Where does the difference come from?” Dr. Chmielowski asked. The answer is unclear, as the Kaplan-Meier progression-free survival curves from all three studies essentially overlap each other. “This tells us there’s no clinical difference, no matter which of these three combination therapies is used,” he said. “Their difference is only based on the statistical design of the trial.”
He continued: “This also tells us that minimal differences in trial populations will result in significant changes in the statistical result.” For example, the patient population in COMBI-i may have had a better prognosis, as at baseline most patients had normal lactate dehydrogenase levels and few metastatic sites. It has been previously shown that these good-prognosis patients have a prolonged benefit from the targeted therapy alone. In the subset analysis, patients with more than three metastatic sites derived the greatest benefit from the spartalizumab regimen (hazard ratio = 0.63 vs 1.06 for fewer than three sites).
“One could also argue that not each BRAF/MEK inhibitor combination is equal. If a less effective targeted therapy is used one could expect a larger benefit from adding immunotherapy,” he said. In COMBI-i, the control arm performed better than expected, the investigators had noted.
Finally, Dr. Chmielowski wondered, “Are we asking the right question?” Treatment with BRAF inhibitors is associated with increased expression of melanoma antigens and increases in CD8-positive T-cell infiltrates. This means the better question might be whether targeted therapy could increase the efficacy of immunotherapy vs the opposite (whether immunotherapy might increase the efficacy of targeted therapy), as the current studies have asked. To answer this question, all patients in a study would receive anti–PD-1/PD-L1 antibody with or without the addition of BRAF and MEK inhibitors. This is the question being put forth in the STARBOARD trial of pembrolizumab with and without encorafenib and binimetinib.
DISCLOSURE: Dr. Chmielowski has served in a consulting or advisory role for Biothera, Deciphera, Epizyme, Ideaya Biosciences, Iovance Biotherapeutics, and Sanofi; has participated in a speakers bureau for Sanofi/Regeneron; has received institutional research funding from Advenchen Laboratories, Aeglea Biotherapeutics, Array BioPharma, Ascentage, Biothera, Bristol Myers Squibb, Compugen, Daiichi Sankyo, EMD Serono, Ideaya Biosciences, Idera, Immunocore, Incyte, Infinity Pharmaceuticals, Iovance, Karyopharm Therapeutics, Lilly, Macrogenics, Merck, Neon Therapeutics, PACT Pharma, RAPT Therapeutics, Rgenix, Tolero Pharmaceuticals, and Xencor; and has been reimbursed for travel, accommodations, or other expenses by Deciphera, Epizyme, Ideaya Biosciences, and Regeneron.
REFERENCES
1. Ascierto PA, Ferrucci PF, Fisher R, et al: Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nature Med 25:941-946, 2019.
2. Gutzmer R, Stroyakovskiy D, Gogas H, et al: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): Primary analysis of the randomised, double-blind, placebo-controlled, phase III trial. Lancet 395:1835-1844, 2020.
