In COMBI-AD (NCT01682083), adjuvant D + T led to a significant improvement in relapse-free survival vs Pbo in pts with resected BRAF V600–mutant stage III melanoma supporting recent US FDA approval in this indication. There were no new safety signals; however, a higher rate of permanent discontinuation due to AEs was observed compared with metastatic disease (26% [10% due to grade 3/4 AEs]); pyrexia (9%) and chills (4%) were most common. Here we further characterize AEs in COMBI-AD.
COMBI-AD was a randomized, double-blind, Pbo-controlled phase III trial comparing 12 mo of adjuvant D (150 mg twice daily) + T (2 mg once daily) vs Pbo in pts with resected BRAF V600E/K–mutant stage III melanoma. AEs were graded according to CTCAE v4.0. To assess AEs over time, exposure-adjusted AE rates (no. of occurrences/pt/3-mo exposure) were calculated over 3-mo intervals.
Although most pts in both arms experienced ≥ 1 AE, the majority of AEs reported were low grade (eg, pyrexia [% of pts in D + T arm]: grade 1 [29%], grade 2 [29%], grade 3 [5%], grade 4 [< 1%]). In the first 3 mo of treatment, the exposure-adjusted AE rate of any event in pts treated with D + T was 6.14 occurrences/pt/3-mo exposure. However, the AE rates declined substantially with increased time on treatment (3 to < 6 mo [2.58]; 6 to < 9 mo [1.80]; 9 to < 12 mo [1.65]). Similar results were observed in pts in the Pbo arm, albeit at lower rates. Adjusted AE rates for the 10 most common AEs observed in COMBI-AD in the D + T arm also declined after the initial 3 mo (Table). Results were similar in pts who completed 12 mo of treatment.Table: 1251P
AE occurrences per patient per 3-month exposure
|Preferred Term||Dabrafenib + Trametinib (n = 435)||Placebo (n = 432)|
|0 to||3 to||6 to||9 to||0 to||3 to||6 to||9 to|
|< 3 mo||< 6 mo||< 9 mo||< 12 mo||< 3 mo||< 6 mo||< 9 mo||< 12 mo|
These results show that most AEs with adjuvant D + T occurred during the first 3 mo of treatment and declined thereafter, highlighting the importance of AE management early during treatment to prevent premature discontinuations and allow patients to complete 1 year of adjuvant treatment.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Medical writing assistance was provided by Michael Demars, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation.
V.G. Atkinson: Consulting or advisory role: Bristol-Myers Squibb, MSD, Novartis, Merck Serono, Pierre Fabre; Honoraria: Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Merck Serono; Speakers’ bureau: Bristol-Myers Squibb, MSD, Novartis, Roche; Travel, accommodations, expenses: Bristol-Myers Squibb. A. Hauschild: Consultancy: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec; Research funding: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche; Honoraria: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Roche. M. Mandala: Research funding, Honoraria, Speakers bureau: Novartis, Roche. V. Chiarion Sileni: Consultancy: Bristol-Myers Squibb, MSD, Novartis, Pierre-Fabre, Merck Serono. J. Larkin: Consultancy and honoraria: Eisai, Bristol-Myers Squibb, MSD, GlaxoSmithKline, Kymab, Pfizer, Novartis, Roche, Genentech, Secarna, Pierre-Fabre, EUSA Pharma; Research funding: Bristol-Myers Squibb, MSD, Novartis, Pfizer. M.S. Nyakas: Honoraria (institution) for advisory board: Novartis, Incyte. C. Dutriaux: Consultancy: Bristol-Myers Squibb, MSD; Membership on board of directors or advisory committee: Bristol-Myers Squibb, Roche, Novartis, Merck Serono, MSD; Clinical trials investigator: Bristol-Myers Squibb, Roche, Novartis, Merck Serono, MSD, Amgen. A. Haydon: Honoraria: Novartis. L. Mortier: Research funding: Novartis. C. Robert: Advisory board: Merck, MSD, Novartis, Roche. J. Schachter: Honoraria: Bristol-Myers Squibb, MSD; Travel, accommodations, expenses: Bristol-Myers Squibb. D. Schadendorf: Personal fees: Amgen, Boehringer Ingelheim, Leo Pharma, Roche, Novartis, Incyte, Regeneron, 4SC, AstraZeneca, Bristol-Myers Squibb, MS, Pierre Fabre, Merck-EMD, Pfizer, Philiogen, Array; Patients' fees to institution: MSD, Roche, Novartis, Regeneron, Brisol-Myers Squibb, Merck-EMD, Philiogen. X. Feng, E. de Jong: Employee: Novartis. B. Mookerjee: Employment: Novartis; Stock ownership: Novartis, GlaxoSmithKline, AstraZeneca. R. Kefford: Membership on board of directors or advisory committees: Bristol-Myers Squibb, Amgen, Merck, Novartis, Teva; Conference travel: Bristol-Myers Squibb, Amgen. R. Dummer: Intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma outside the submitted work. J.M. Kirkwood: Consultancy: Bristol-Myers Squibb, Novartis, Array Biopharma, Merck, Roche, Amgen, Immunocore, Prometheus; Research funding: Merck. G.V. Long: Consultancy: Amgen, Bristol-Myers Squibb, Merck MSD, Novartis, Roche, Pierre-Fabre, Array; Honoraria: Bristol-Myers Squibb, MSD, Roche, Novartis, Incyte. All other authors have declared no conflicts of interest.