title: Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma.
abstract: The combination of dabrafenib and trametinib (CombiDT) is an effective treatment for BRAF-mutant metastatic melanoma; however, over 70% of patients develop drug-related pyrexia, and little is known about this toxicity. We sought to examine the features and management of CombiDT pyrexia. The association between pyrexia and patient demographics, disease characteristics and outcome variables was assessed in patients treated with CombiDT at a single institution. The clinicopathological features of pyrexic events were analysed. Fourteen of 32 (44%) patients developed pyrexia (temperature≥38.5°C). Pyrexia was recurrent in 11/14 (79%). The median time to pyrexia was 38 days. Pyrexia was not associated with age, sex nor disease burden, and did not correlate with RECIST response, progression-free nor overall survival. Paracetamol, NSAIDs and/or dose reduction (DR) were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients (n=8), including two with multiple previous pyrexic events despite several DRs. In patients with previous DRs who commenced steroids (n=3), CombiDT doses were re-escalated without pyrexia. Pyrexia is a frequent and recurrent toxicity with CombiDT, with no predictive clinical characteristics. Pyrexia does not correlate with clinical outcome. Neither DR nor antipyretics are effective secondary prophylaxis, whereas corticosteroids are effective, prevent DR and enable re-escalation of CombiDT dosing.
authors: aWestmead Hospital bWestmead Institute for Cancer Research, Westmead cMelanoma Institute Australia dSydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors: Clara I
authors: CI
authors: Lee
authors: Alexander M
authors: AM
authors: Menzies
authors: Lauren E
authors: LE
authors: Haydu
authors: Mary
authors: M
authors: Azer
authors: Arthur
authors: A
authors: Clements
authors: Richard F
authors: RF
authors: Kefford
authors: Georgina V
authors: GV
authors: Long
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects* / Q000627:therapeutic use; D011728:Pyridones / Q000009:adverse effects* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D013696:Temperature; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D000082:Acetaminophen; C561627:dabrafenib