Dabrafenib plus trametinib improves relapse-free survival time in melanoma
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Patients with a stage III melanoma mutation treated with dabrafenib plus trametinib had longer restricted mean survival times compared with placebo, according to an analysis of a phase 3 trial presented at Maui Derm for Dermatologists.
“Kaplan-Meier and Cox regression analyses have been used to assess adjuvant treatment effects based on time-to-event analyses,” John M. Kirkwood, MD, and colleagues wrote in the poster. “Unfortunately, these statistical methods do not account for nonproportional hazards and the fact that some patients never experience relapse.”
To circumvent the limitations of other methods, Kirkwood and colleagues used restricted mean survival time and cure-rate modeling to analyze data from COMBI-AD, a double-blind, randomized phase 3 trial. The trial enrolled 870 adults who had a cutaneous stage IIIA, IIIB or IIIC BRAF V600E or V600K mutation that was completely resected 12 or fewer weeks before randomization. Researchers randomly assigned 438 patients to receive 150 mg dabrafenib twice daily plus 2 mg trametinib once daily and 432 patients to receive placebo. The study’s primary endpoint was relapse-free survival time. Median duration of follow-up was 60 months for the treatment group and 58 months for the placebo group.
Overall, patients in the treatment group had improved restricted mean survival times (41.5 months; 95% CI, 39.4-43.6) vs. placebo (28.7 months; 95% CI, 26.3-31.2), which researchers wrote “suggest[s] that on average, over a 60-month period, patients treated with dabrafenib plus trametinib gain an additional 12.8 months of remaining relapse free vs. placebo.”
Patients with stage IIIB (dabrafenib plus trametinib, 41.2 months; 95% CI, 37.7-44.7 vs. placebo, 29.0 months; 95% CI, 25.4-32.6) and stage IIIC (dabrafenib plus trametinib, 38.0 months; 95% CI, 34.6-41.3 vs. placebo, 22.8 months; 95% CI, 18.9-26.8) had the greatest differences in restricted mean survival time at 12.2 months (95% CI, 7.2-17.2) for stage IIIB and 15.1 months (95% CI, 10.0-20.3) for stage IIIC, respectively.
Patients with stage IIIA (dabrafenib plus trametinib, 50.4 months; 95% CI, 46.7-54.2 vs. placebo, 42.2 months; 95% CI, 36.4-47.9) had an 8.2 month (95% CI, 1.4-15.1) restricted mean survival time difference.
There was a 16% cure rate difference between patients in the treatment group (51%; 95% CI, 46-56) and the placebo group (35%; 95% CI, 30-40). The greatest cure rate differences occurred in patients with stage IIIB (dabrafenib plus trametinib, 54%; 95% CI, 46-62 vs. placebo, 33%; 95% CI, 26-40) at a 21% absolute difference and stage IIIC (dabrafenib plus trametinib, 43%; 95% CI, 35-51 vs. placebo, 28%; 95% CI, 21-36) at a 15% absolute difference. For patients with stage IIIA (dabrafenib plus trametinib, 63; 95% CI, 49-77 vs. placebo, 52%; 95% CI, 33-71), there was an 11% absolute difference.
“Results from [restricted mean survival time] and cure-rate modeling analyses suggest that treatment with dabrafenib plus trametinib leads to durable [relapse-free survival] benefit compared with placebo,” the researchers wrote. “These analyses provide insights into long-term clinical benefits of adjuvant therapy with dabrafenib plus trametinib; overall survival analysis is currently ongoing.”