Could you please comment on the new data coming out for PD1 and BRAF/MEK inhibitors for use in the adjuvant setting? Do you expect the side effect profiles of the agents to be similar in the adjuvant vs metastatic settings?
Very exciting data released in Spain this past September at ESMO regarding what is known as the COMBI-AD trial. This was an adjuvant trial for patients with stage III BRAF-mutant melanoma; it was a double-blind trial randomizing 870 patients 1:1 to either dabrafenib + trametinib versus double placebo. Patients received treatment X 1 year.
Bottom line: The combination of dabrafenib (Tafinlar) + trametinib (Mekinist) reduced the risk of relapse or death by 53% compared with placebo. AMAZING!
Toxicity to some degree was seen in almost all of participants (97%). Of those, 41% was grade 3/4 compared to 88% and 14% with placebo, respectively. About 1/4 of stoped treatment as a result of toxicity (compared to 3% on placebo). The higher toxicity rate in this trial compared use of d+t in Stage IV trials is thought to be related to the fact that the majority of the participants did not develop progressive disease, therefore they received the full year of treatment. The longer patients receive treatment, the more likely they are to develop toxicity.
With regard to the adjuvant nivolumab, known as CheckMate 238- more exciting data! This was a randomized double-blind phase III trial comparing adjuvant nivolumab versus ipilimumab (remember this is now a standard, FDA approved adjuvant treatment). There were 906 patients with stages IIIB, IIIC, and IV resected melanoma]. Results showed a significant improvement in RFS (66.4%) compared to ipilimumab (52.7%). In fact, the trial was stopped early when it became clear that nivo was superior to ipi!
In addition, there was much less toxicity seen with nivo compared to ipi (14% vs 46% respectively); only 10% of patients receiving nivo stopped treatment due to toxicity, while 43% receiving ipi had to stop.