1333PAdverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting

• Published in: Annals of oncology Vol. 30; no. Supplement_5
• Main Authors: Grob, J J, Atkinson, V G, Robert, C, Schadendorf, D, Nathan, P, Davies, M A, Kefford, R, Dummer, R, Kirkwood, J M, Flaherty, K T, Ribas, A, Burgess, P, Gasal, E, Long, G V, Hauschild, A
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01-10-2019
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdz255.022

Abstract
Background
In a pooled analysis of COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials, D+T led to long-term disease control in many pts and 5-y survival in approximately one-third of pts with BRAF V600–mutant unresectable or metastatic melanoma. In pts with resected BRAF V600–mutant stage III melanoma in COMBI-AD (NCT01682083), adjuvant D+T significantly improved relapse-free survival (RFS) with 3- and 4- year RFS rates of 59% and 54%, respectively. A higher rate of permanent discontinuation due to AEs was observed in the adjuvant setting in COMBI-AD (26%) than in the metastatic setting in COMBI-d/v (15%).
Methods
Analyses were performed using pt-level pooled data from COMBI-d and COMBI-v (phase III randomized trials comparing D+T with D+ placebo [PBO] or vemurafenib in unresectable or metastatic BRAF-mutant melanoma) and COMBI-AD (phase III, randomized, double-blind, PBO-controlled trial comparing adjuvant D+T with PBO in resectable stage III melanoma). In COMBI-d/v, pts were treated until disease progression; in COMBI-AD, pts were treated for 12 mo with adjuvant D+T. AEs were graded using CTCAE v4.0 and assessed over time using exposure-adjusted rates (occurrences/pt/3-mo exposure) calculated over 3-mo intervals.
Results
All-cause AE rates were 98% (548/559) in the metastatic and 97% (422/435) in the adjuvant setting. Grade (G) ≥ 3 AE rates were 57% (319/559) in COMBI-d/v and 41% (180/435) in COMBI-AD. Pyrexia was the most common AE in COMBI-d/v (any-grade [58%]; G ≥ 3 [6%]) and COMBI-AD (any-grade [63%]; G ≥ 3 [5%]). There were no treatment (tx)-related deaths in COMBI-d/v or COMBI-AD. In the first 3 mo of tx, the exposure-adjusted AE rates for any event in pts treated with D+T in the metastatic and adjuvant setting were 7.54 and 6.14, respectively. AE rates decreased with increased time on tx: 3 to < 6 mo (3.93 [COMBI-d/v]; 2.58 [COMBI-AD]); 6 to < 9 mo (3.22; 1.80); and 9 to < 12 mo (2.94; 1.65).
Conclusions
In the metastatic and adjuvant settings, there was a trend toward decreased AEs with longer tx duration. The rate of G ≥ 3 AEs was lower in the adjuvant vs metastatic setting suggesting that increased AE-related discontinuations in COMBI-AD are unlikely due to excess toxicity.
Clinical trial identification
NCT01584648 NCT01597908 NCT01682083.
Editorial acknowledgement
Allison Lytle, PhD, from ArticulateScience LLC, funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
J.J. Grob: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pfizer. V.G. Atkinson: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Roche/Genentech; Travel / Accommodation / Expenses: OncoSec. C. Robert: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Array; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Merck. D. Schadendorf: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Immunocore; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Honoraria (self), Advisory / Consultancy: 4SC; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy: Mologen; Advisory / Consultancy: Sanofi/Regeneron; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: Merck; Honoraria (self): Sysmex; Honoraria (self): Grünenthal Group; Honoraria (self): Agenus; Honoraria (self): Array BioPharma; Honoraria (self): AstraZeneca; Honoraria (self): LEO Pharma; Honoraria (self): Pfizer; Honoraria (self): Philogen; Honoraria (self): Regeneron; Honoraria (self): Mologen. P. Nathan: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Immuncore; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Merck. M.A. Davies: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (self): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Vaccinex; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Syndax; Advisory / Consultancy: NanoString Technologies; Advisory / Consultancy: Array BioPharma; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (self): Oncothyreon; Research grant / Funding (self): Myriad Genetics; Research grant / Funding (self): Sanofi. R. Kefford: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: TEVA; Travel / Accommodation / Expenses: Bristol-Myers Squibb. R. Dummer: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Intermittent, project focused : Novartis; Advisory / Consultancy, Intermittent, project focused : Merck Sharp & Dhome; Advisory / Consultancy, Intermittent, project focused : Bristol-Myers Squibb; Advisory / Consultancy, Intermittent, project focused : Roche; Advisory / Consultancy, Intermittent, project focused : Amgen; Advisory / Consultancy, Intermittent, project focused : Takeda; Advisory / Consultancy, Intermittent, project focused : Pierre Fabre; Advisory / Consultancy, Intermittent, project focused : Sun Pharma; Advisory / Consultancy, Intermittent, project focused : Sanofi; Advisory / Consultancy, Intermittent, project focused: Catalym . J.M. Kirkwood: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Research grant / Funding (institution): Immunocore; Advisory / Consultancy: Iovance; Advisory / Consultancy: Elsevier; Advisory / Consultancy: Checkmate Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Prometheus Laboratories. K.T. Flaherty: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncoceutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Aeglea Biotherapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Loxo; Advisory / Consultancy: Roche; Advisory / Consultancy: Asana Biosciences; Advisory / Consultancy: Incyte; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy: Tolero Pharmaceuticals; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options: FOGPharma; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tvardi; Advisory / Consultancy: Takeda; Advisory /