Merrick I. Ross, MD: It has been an amazing year in looking at different adjuvant therapy trials. The first one that was published and then approved by the FDA was the CheckMate-238 trial, which was a randomized trial of ipilimumab, the current standard of care for adjuvant therapy in terms of immunotherapy, versus an anti—PD-1 drug, nivolumab. This was a randomized phase III trial for patients who had node-positive disease. The efficacy showed that nivolumab, the anti–PD-1 drug, was not only more effective than ipilimumab but it was also less toxic. It became a no-brainer to really switch from ipilimumab to nivolumab. The hazard ratios, in terms of efficacy, were not quite 50%. They were actually 0.65, or 65%. So, there was an absolute reduction of 35%, in terms of efficacy, in terms of looking at disease-free endpoints.

In terms of patients who have a BRAF mutation, they are eligible to receive a combination of the BRAF and MEK inhibitors. The trial that was published very recently was the COMBI-AD trial, which was a randomized trial versus a placebo control. It looked at the combination of the BRAF inhibitor and the MEK inhibitor in patients who had nodal involvement. This was a remarkably impressive trial, in terms of the results. I don’t think I’ve ever seen an adjuvant therapy trial that was as strongly positive as this one in any disease-state related to cancer. The hazard ratio for this was 0.38, I think—almost a 75% reduction in disease-free events versus placebo control. There was no crossover in this trial and we’re still waiting for the long-term survival outcomes, but this certainly became something that is very exciting for patients who have a BRAF mutation. In terms of toxicity, close to 20% of patients discontinued therapy because of toxicity, but these toxicities were not necessarily long-lasting. So certainly, this is a very effective therapy for patients, specifically for patients who have the BRAF mutation.

The KEYNOTE-054 trial, which was sponsored by the EORTC, was an anti—PD-L1 trial that looked at pembrolizumab versus placebo, as opposed to ipilimumab. The interesting thing about this trial was that patients who failed on trial and were randomized to the placebo control arm could actually cross over and receive pembrolizumab later. So, it was an interesting endpoint, in looking at the use of anti–PD-L1 drugs either early or late. In terms of the primary endpoint, which was disease-free survival, there was a clear difference. The hazard ratio was 0.58—again, almost a 50% reduction in events in patients who were treated with the pembrolizumab drug.

In terms of FDA approval, the BRAF/MEK combination is currently approved for patients who have BRAF-mutated tumors. Nivolumab, based on the CheckMate-238 trial, has also been approved by the FDA. The application for approval of pembrolizumab has been received and it would be a complete surprise if the FDA did not approve pembrolizumab in the adjuvant setting for patients with node-positive disease.

Transcript Edited for Clarity