A final analysis of the phase 3 COMBI-I trial (NCT02967692), published in the Journal of Clinical Oncology, showed that adding the anti–PD-1 antibody spartalizumab to dabrafenib (Tafinlar) and trametinib (Mekinist; sparta-DabTram) was associated with longer overall survival (OS) than dabrafenib and trametinib alone in patients with BRAF V600-mutant unresectable or metastatic melanoma.

Final OS Results of COMBI-I

At the trial’s conclusion on August 21, 2024, the median duration of follow-up was 76.9 months (range, 73.7 to 83.3). A total of 127 patients (47.6%) had died in the sparta-DabTram arm compared with 151 patients (57.0%) in the placebo-DabTram arm. Median OS was 61.5 months (95% CI, 41.6 to not evaluable) with sparta-DabTram compared with 41.6 months (95% CI, 30.6-56.9) with placebo-DabTram, translating to a HR of 0.760 (95% CI, 0.598-0.966). The estimated OS rates at 60 months were 50.1% (437%-56.1%) for the sparta-DabTram arm vs 42.8% (5% CI, 36.6%-48.9%) for the placebo-DabTram arm. Treatment effect favored sparta-DabTram (HR less than 1) across most subgroups of patient and tumor characteristics that were examined.

Safety Findings

Adverse events (AEs) of any kind occurred in 99.3% of patients in the sparta-DabTram arm and 97.3% in the placebo-DabTram arm. Pyrexia was the most common AE overall and the most common treatment-related AE (TRAE), occurring in 65.9% of patients on sparta-DabTram vs 46.2% on placebo-DabTram; pyrexia also lasted longer with the triplet regimen (median 13.0 days vs 9.0 days) and tended to occur earlier. All-grade and grade 3 or higher TRAEs occurred in 98.5% and 57.3% of patients in the sparta-DabTram arm, respectively, compared with 88.6% and 36.7% of patients receiving the placebo-DabTram.

Serious AEs were reported in 56.2% vs 46.6% of patients, with pyrexia being the most common (17.2% vs 6.1%). Skin reactions were the most common AEs of special interest associated with spartalizumab, affecting 61.0% of the sparta-DabTram arm vs 47.0% of the placebo-DabTram arm. Other immune-mediated AEs of special interest, including colitis, pancreatic enzyme elevations, and endocrine and liver toxicities, occurred more frequently with sparta-DabTram.

Limitations and Post-Treatment Therapy

The study authors identified several limitations, including a high proportion of patients censored from the OS analysis because of study termination rather than a defined event, an imbalance in post-progression use of immune checkpoint inhibitors between arms, treatment discontinuations due to grade 3 or higher AEs, and nonadherence to protocol-specified dosing that may have been influenced by the onset of pyrexia. Post-treatment antineoplastic therapy was used in 46.1% of the sparta-DabTram arm and 50.6% of the placebo-DabTram arm, with immunotherapy, most often anti–PD-1 agents, used more frequently after progression in the placebo-DabTram arm (40.0%) than the sparta-DabTram arm (27.7%).

COMBI-I Trial Design

The randomized, double-blind, placebo-controlled trial enrolled 532 adult patients with histologically confirmed unresectable or metastatic BRAF V600-mutant cutaneous melanoma between September 13, 2017, and July 4, 2018. Patients received either intravenous spartalizumab at 400 mg every 4 week, plus oral dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily (n = 267), or the same dabrafenib/trametinib regimen with an intravenous placebo in place of spartalizumab, referred to as placebo-DabTram (n = 265).

The trial’s original primary end point, improved median progression-free survival (PFS) at 24 months, was not met (16.2 months vs 12 months; HR, 0.82; 95% CI, 0.66-1.03; P = .042).

Looking Ahead

The study authors noted that COMBI-I had the longest reported follow-up among trials evaluating an immune checkpoint inhibitor combined with BRAF and MEK inhibitors, with a clear separation of the Kaplan-Meier survival curves emerging after 6 months and sustained over time. The safety results in this final analysis were consistent with those from the trial's primary analysis, and no new safety signals were observed.

The authors concluded that the combination of sparta-DabTram suggested a trend toward a survival benefit over dabrafenib and trametinib alone in patients with BRAF V600-mutant metastatic melanoma, though they noted that the finding stems from a trial that did not meet its formal primary end point.

Reference

Ribas A, Robert C, Schadendorf D, et al. COMBI-I: long-term overall survival with spartalizumab plus dabrafenib and trametinib in BRAF V600-mutant advanced melanoma. J Clin Oncol. Published online August 12, 2026. doi:10.1200/JCO-26-00528