Improved pyrexia-related outcomes associated with an adapted pyrexia adverse event management algorithm in patients treated with adjuvant dabrafenib plus trametinib: Primary results of COMBI-APlus

Eur J Cancer. 2022 Mar;163:79-87. doi: 10.1016/j.ejca.2021.12.015. Epub 2022 Jan 14.


Background: COMBI-AD demonstrated long-term benefit of adjuvant dabrafenib plus trametinib in patients with resected stage III BRAF V600E/K-mutant melanoma; however, 9% of patients permanently discontinued therapy due to pyrexia. COMBI-APlus evaluated whether an adapted pyrexia management algorithm reduces high-grade pyrexia and pyrexia-related adverse outcomes.

Methods: COMBI-APlus is an open-label, phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K-mutant melanoma treated with up to 12 months of adjuvant dabrafenib plus trametinib. Both drugs were interrupted for pyrexia (temperature ≥38°C) or the occurrence of pyrexia syndrome for suspected recurrent pyrexia. Treatment was restarted at the same dose once patients were symptom free for ≥24 h. The primary endpoint was the composite rate of grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent discontinuation due to pyrexia versus historical COMBI-AD control (20.0%; 95% confidence interval [CI], 16.3%-24.1%).

Results: At data cutoff (5 October 2020), COMBI-APlus met its primary endpoint of significant improvement in the composite rate of pyrexia (8.0% [95% CI, 5.9%-10.6%]), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalisation due to pyrexia, and 2.4% for discontinuation due to pyrexia. Estimated 12-month relapse-free survival was 91.8% (95% CI, 89.0%-93.9%). The most common adverse events were consistent with those in COMBI-AD, and 14.7% of patients permanently discontinued treatment due to adverse events.

Conclusions: The adapted pyrexia management algorithm appears to reduce the incidence of severe pyrexia outcomes, enables patients to manage pyrexia at home, and helps patients remain on treatment.

Clinical trial registration: NCT03551626.

Keywords: Adjuvant; BRAF V600–mutant melanoma; BRAF inhibitor; Dabrafenib; MEK inhibitor; Pyrexia; Targeted therapy; Trametinib.

Publication types

  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / therapeutic use
  • Algorithms
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Fever / chemically induced
  • Humans
  • Imidazoles
  • Melanoma*
  • Mutation
  • Neoplasm Recurrence, Local / drug therapy
  • Oximes
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridones
  • Pyrimidinones
  • Skin Neoplasms* / drug therapy


  • Adjuvants, Immunologic
  • Imidazoles
  • Oximes
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Proto-Oncogene Proteins B-raf
  • dabrafenib

Supplementary concepts

  • Melanoma, Cutaneous Malignant

Associated data