COMBI-i Trial: No Statistical Benefit to Adding Spartalizumab to Dabrafenib/Trametinib in Melanoma

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Patients with unresectable or metastatic melanoma harboring BRAF V600 mutations did not benefit from the addition of the anti–PD-1 antibody spartalizumab to dabrafenib and trametinib in the COMBI-i trial, which was presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1

“The triplet of spartalizumab, dabrafenib, and trametinib did not significantly improve investigator-assessed progression-free survival, compared with the doublet of dabrafenib and trametinib with placebo,” said Paul D. Nathan, MBBS, PhD, of Mount Vernon Cancer Centre in Northwood, United Kingdom, during his presentation. “Additional analyses are ongoing and planned to better understand these results, and further overall survival follow-up may provide additional insights.”

According to Dr. Nathan, preclinical data suggest that the combination of an anti–PD-1 antibody with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib may enhance antitumor activity compared with the doublet alone. Additionally, in phase II and phase III trials, the use of immune checkpoint inhibitors with targeted therapy have been shown to improve outcomes. Early clinical findings also showed that the triplet of spartalizumab, dabrafenib, and trametinib may boost durable responses. These findings led to the COMBI-i study.

COMBI-i Details

The global phase III COMBI-i trial enrolled 532 patients, randomly assigning them to spartalizumab at 400 mg intravenously every 4 weeks plus dabrafenib at 150 mg orally twice daily and trametinib at 2 mg orally once daily, or placebo plus dabrafenib and trametinib. All patients had untreated BRAF V600–mutant melanoma that was unresectable or metastatic. Approximately 60% of patients had stage IV M1c disease, about 40% had an elevated lactate dehydrogenase (LDH) level, and 45% had disease at three or more organ sites.

The primary endpoint was investigator-assessed progression-free survival. This analysis was based on a minimum follow-up of 24 months, with 312 events occurring; the statistical threshold was P = .02497 (1-sided).

At a median follow-up of 27.2 months, the addition of spartalizumab to dabrafenib and trametinib did not significantly improve progression-free survival, which was 16.2 months with the triplet and 12.0 months in the placebo arm (hazard ratio [HR] = 0.82; P = .042). At 24 months, 44% of the spartalizumab arm was progression-free compared with 36% of the control arm.

Of note, Dr. Nathan said, “The performance of patients receiving the doublet was superior to that which we have seen historically with the COMBI-d and COMBI-v studies.”

He added: “In the preplanned subset analysis, there were some interesting trends in favor of the immunotherapy-containing triplet.” He singled out benefits with the triplet as opposed to the doublet in terms of higher LDH levels (HR = 0.72), more sites of metastasis (HR = 0.63), increasing bulk of disease (HR = 0.52), and higher tumor mutational burden (HR = 0.70).

Overall survival was not formally tested because the primary endpoint was not statistically significant. That said, median survival was not reached across treatment arms (HR = 0.785, 95% confidence interval [CI] = 0.589–1.047).

Objective responses were achieved in 68.5% of the spartalizumab arm, of which 19.9% were complete responses vs 64.2% of the placebo arm, of which 17.7% were complete responses. Median duration of response was not reached with spartalizumab and was 20.7 months without spartalizumab.

Treatment-related adverse events of grade ≥ 3 occurred in 54.7% of patients receiving the triplet and 33.3% of those treated with the doublet. Adverse events leading to discontinuation of all study drugs were seen in 12.4% and 8.0%, respectively. The greater use of dose interruptions and reductions among patients treated with spartalizumab resulted in a slightly lower relative dose intensity. 

DISCLOSURE: COMBI-i was funded by Novartis Pharmaceuticals Corporation. Dr. Nathan has served in a consulting or advisory role for 4SC, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, Ipsen, Merck, MSD, Novartis, Pfizer, and Pierre Fabre; has participated in a speakers bureau for Bristol Myers Squibb, Merck, MSD, and Novartis; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and MSD.


1. Nathan P, Dummer R, Long GV, et al: Spartalizumab plus dabrafenib and trametinib in patients with previously untreated BRAF V600-mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. ESMO Virtual Congress 2020. Abstract LBA43. Presented September 19, 2020.

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