Adverse events (AEs) over time in patients (pts) treated with adjuvant dabrafenib plus trametinib (D 1 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 (2mg 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 3mo of treatment, the exposureadjusted 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<6mo [2.58]; 6 to<9mo [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 3mo (Table). Results were similar in pts who completed 12 mo of treatment. Conclusions: These results show that most AEs with adjuvant D + T occurred during the first 3mo 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. (Table Presented).