Background: First-line DabTram has shown long-term efficacy in pts with BRAF V600–mutant unresectable or metastatic melanoma in the Phase III COMBI-d and COMBI-v trials. Data from the Phase III COMBI-i trial comparing spartalizumab plus DabTram vs placebo plus DabTram (pbo-DabTram) demonstrated efficacy in the pbo-DabTram arm, consistent with historical data. Pyrexia (single preferred term [PT]) is the most common adverse event (AE) reported with DabTram (pooled COMBI-d [data cutoff: Jan 12, 2015] and COMBI-v [data cutoff: Apr 17, 2014]: any grade, 54.2%; grade ≥ 3, 5.4%; serious pyrexia AEs leading to hospitalization, 11.8%). A new pyrexia management algorithm was implemented in the COMBI-i trial to improve pyrexia-related outcomes. We report pyrexia-related outcomes in pts treated with pbo-DabTram in the control arm of COMBI-i part 3. Methods: COMBI-i (NCT02967692) part 3 is a double-blind, Phase III trial in which pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma were randomized 1:1 to receive spartalizumab (400 mg intravenously every 4 weeks) plus Dab (150 mg orally twice daily) and Tram (2 mg orally once daily) vs pbo-DabTram. In the adapted pyrexia management algorithm, both Dab and Tram are interrupted promptly at the first symptom of pyrexia or its associated prodrome (ie, chills, rigors, night sweats, or influenza-like symptoms). Treatment at the same dose level is restarted upon the improvement of symptoms if pts are symptom free for ≥ 24 hours. Pyrexia incidence rates presented are for the single PT of pyrexia. Results: At data cutoff (July 1, 2020), median follow-up was 27.2 mo for all pts enrolled in COMBI-i part 3 (N = 532). In the DabTram control arm, 52.7% (139/264) and 3.0% (8/264) of pts had any-grade and grade ≥ 3 pyrexia, respectively. Serious pyrexia AEs were reported in 6.1% (16/264), which led to hospitalization in 5.3% (14/264). Pyrexia led to dose interruption of both Dab and Tram in 39.0% (103/264), with 1.5% (4/264) permanently discontinuing both agents. Median relative dose intensity was 97.8% for Dab and 97.7% for Tram. Conclusions: Pyrexia-related outcomes, including grade ≥ 3 pyrexia (3.0% vs 5.4%) and serious pyrexia AEs leading to hospitalization (5.3% vs 11.8%), were improved in pts treated with DabTram in COMBI-i part 3 compared with historical data from COMBI-d/v. The adapted algorithm offers a simplified approach for managing pyrexia, thereby reducing the incidence of severe pyrexia while maintaining consistent efficacy with DabTram. Clinical trial information: NCT02967692