Adverse events (AEs) over time in patients (pts) treated with adjuvant dabrafenib plus trametinib (D + T) or placebo (Pbo) in the COMBI-AD trial

Background: 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. Methods: 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. Results: 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: 1251PAE occurrences per patient per 3-month exposurePreferred TermDabrafenib + Trametinib (n = 435)Placebo (n = 432)0 to3 to6 to9 to0 to3 to6 to9 to< 3 mo< 6 mo< 9 mo< 12 mo< 3 mo< 6 mo< 9 mo< 12 moPyrexia1.260.650.500.450.080.050.050.02Fatigue0.530.170.100.130.270.090.050.04Nausea0.490.140.080.090.200.070.060.05Headache0.500.170.130.120.270.100.090.07Chills0.550.290.210.140000Diarrhea0.320.110.090.100.140.080.060.05Vomiting0.320.130.090.080000Arthralgia0.300.120.070.070.090.050.060.05Rash0.260.070.100.080.080.040.030.02Cough0.140.040.030.010000 Open table in a new tab Conclusions: 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: NCT01682083. Editorial acknowledgement: Medical writing assistance was provided by Michael Demars, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation. Funding: Novartis Pharmaceuticals Corporation. Disclosure: 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.