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Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma

Lee, Clara I.a,d,*; Menzies, Alexander M.c,d,*; Haydu, Lauren E.c,d; Azer, Marya; Clements, Arthura,d; Kefford, Richard F.a,b,c,d; Long, Georgina V.b,c,d

doi: 10.1097/CMR.0000000000000110
ORIGINAL ARTICLES: Clinical research

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.

aWestmead Hospital

bWestmead Institute for Cancer Research, Westmead

cMelanoma Institute Australia

dSydney Medical School, The University of Sydney, Sydney, New South Wales, Australia

* Clara I. Lee and Alexander M. Menzies contributed equally to the writing of this article.

Correspondence to Georgina V. Long, MBBS, PhD, FRACP, Melanoma Institute Australia, 40 Rocklands Rd, North Sydney, NSW 2060, Australia Tel: +61 02 9911 7200; fax: +61 02 9954 9290; e-mail:

Received March 4, 2014

Accepted June 11, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins