TY - JOUR
T1 - Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers
AU - Schadendorf, Dirk
AU - Robert, Caroline
AU - Dummer, Reinhard
AU - Flaherty, Keith T.
AU - Tawbi, Hussein A.
AU - Menzies, Alexander M.
AU - Banerjee, Hiya
AU - Lau, Mike
AU - Long, Georgina V.
N1 - Funding Information:
This study was funded by Novartis Pharmaceuticals Corporation. The study was designed by the authors and the funder of the study. Data were collected by the study site staff and authors and monitored by the funder. The funder was also involved in data analysis, data interpretation, and writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.DS has received research grants from Novartis, Bristol Myers Squibb, and Amgen; received consulting fees from, travel support from, and had advisory relationships with Novartis, Bristol Myers Squibb, MSD, Roche, Incyte, Array, Pierre Fabre, Pfizer, Sanofi-Genzyme, Regeneron, 4SC, InFlarX, Neracare, Ultimovacs, Sun Pharma, Philogen, Amgen, Merck-Serono, Immunocore, Sandoz-Hexal; received honoraria from Novartis, Bristol Myers Squibb, Pierre Fabre, Sanofi-Genzyme and Merck-Serono; and held leadership or fiduciary roles with Dermatologic Cooperative Oncology Group (DeCOG), German Cancer Society, Hilfe-Stiftung, Deutsche Hautkrebsstiftung, NVKH eV and EuMelaReg. CR has received consulting fees from and had advisory relationships with Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, Amgen, Sanofi, Merck, MS and AstraZeneca. RD has had intermittent, project-focused consulting and/or advisory relationships with and received honoraria from Novartis, MSD, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalyn, Second Genome, Regeneron, Alligator, MaxiVAX SAand touchIME outside the submitted work. KTF has received grants from Novartis and Sanofi; received consulting fees from Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals and X4 Pharmaceuticals; has served on scientific advisory boards for PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, Lilly, Novartis, Genentech, Bristol Myers Squibb, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Debiopharm; had advisory relationships with Clovis Oncology, Strata Oncology, X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros and Vibliome; held leadership or fiduciary roles with Loxo Oncology, Clovis Oncology, Strata Oncology, Vivid Biosciences and Checkmate Pharmaceuticals; and holds stock or stock options with Loxo Oncology, Clovis Oncology, Strata Oncology, X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros and Vibliome. HAT has received institutional research support from Merck, Bristol Myers Squibb, Genentech, GlaxoSmithKline and Celgene and received consulting fees from Merck, Bristol Myers Squibb, Genentech, Eisai and Iovance. AMM has received consulting fees from Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre and QBiotics. HB holds stock or stock options with Bristol Myers Squibb and is employed with Novartis. ML is employed with Novartis. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array BioPharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics S.L., MSD, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. and Specialised Therapeutics Australia Pty Ltd and has received honoraria from Bristol Myers Squibb and Pierre Fabre.The studies in this analysis were sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015. The authors thank Parikshit Totawar (Novartis Pharmaceuticals Corporation) for assistance with safety reviews. The authors also thank the patients and their families for their participation, and they thank the study site staff and additional investigators for their contributions. Medical writing assistance was provided by Alana Reed, PhD (ArticulateScience LLC), and was funded by Novartis Pharmaceuticals Corporation.
Funding Information:
This study was funded by Novartis Pharmaceuticals Corporation . The study was designed by the authors and the funder of the study. Data were collected by the study site staff and authors and monitored by the funder. The funder was also involved in data analysis, data interpretation, and writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2021 The Authors
PY - 2021/8
Y1 - 2021/8
N2 - Background: Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non–small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials. Methods: Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively). Results: Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy. Conclusions: Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption. Trial registration: ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).
AB - Background: Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non–small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials. Methods: Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively). Results: Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy. Conclusions: Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption. Trial registration: ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).
KW - Adverse event
KW - BRAF V600–mutant melanoma
KW - BRAF inhibitor
KW - MEK inhibitor
KW - Pyrexia
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U2 - 10.1016/j.ejca.2021.05.005
DO - 10.1016/j.ejca.2021.05.005
M3 - Article
C2 - 34225229
AN - SCOPUS:85109441877
SN - 0959-8049
VL - 153
SP - 234
EP - 241
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -