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
Grob, J. J.
Menzies, A. M.
Del Vecchio, M.
AffiliationDivision of Cancer Services, Princess Alexandra Hospital, University of Queensland, 199 Ipswich Road, Woolloongabba, Queensland 4102, Australia. Electronic address: email@example.com. Department of Medicine, Gustave Roussy, Paris-Saclay University, Villejuif, Orsay, France. Dermatology and Skin Cancer Department, Aix-Marseille University, Marseille, France. First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. Department of Dermatology, University Hospital of Bordeaux, Bordeaux, France. Tumor Biotherapy, N. N. Blokhin Russian Cancer Research Center, Moscow, Russia. Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. Department of Medical Oncology, Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. Medical Oncology, Melanoma Patient Network Europe, Uppsala, Sweden. Clinical Operations, Global Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. Analytics, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. Global Medical Affairs, Novartis Pharma AG, Basel, Switzerland. Unit of Melanoma Medical Oncology, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
MetadataShow full item record
AbstractBackground 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.
CitationAtkinson V, Robert C, Grob JJ, Gogas H, Dutriaux C, Demidov L, et al. 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. Vol. 163, European Journal of Cancer. Elsevier BV; 2022. p. 79–87.
JournalEuropean Journal of Cancer
- Patient-reported outcomes in patients with resected, high-risk melanoma with BRAF(V600E) or BRAF(V600K) mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial.
- Authors: Schadendorf D, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Lesimple T, Plummer R, Schachter J, Dasgupta K, Manson S, Koruth R, Mookerjee B, Kefford R, Dummer R, Kirkwood JM, Long GV
- Issue date: 2019 May
- Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
- Authors: Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV
- Issue date: 2021 Aug
- Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.
- Authors: Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM
- Issue date: 2017 Nov 9
- Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.
- Authors: Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L, Moschos SJ, Hogg D, Márquez-Rodas I, Del Vecchio M, Lebbé C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV
- Issue date: 2017 Jul
- Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF(V600)-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial.
- Authors: Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, Gusenleitner D, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Flaherty K, Larkin J, Robert C, Kefford R, Kirkwood JM, Hauschild A, Schadendorf D, Long GV
- Issue date: 2020 Mar