Looking at Approved Agents in Metastatic Melanoma

Axel Hauschild, MD, PhD: Dirk, can you briefly explain the differences so far in the efficacy and tolerability of the 3 approved regimens for BRAF/MEK inhibitors? At least in Europe and in the United States, we have 3 different opportunities that are approved and reimbursed. In some other countries, they are approved but not reimbursed so far. Encorafenib/binimetinib is the latest development.

Dirk Schadendorf, MD: Yes. If one looks at the clinical trials, cross-trial comparisons are always difficult. In all the clinical trials, vemurafenib was a comparator, so you have a certain indirect way of comparing that. If one looks at the 2-year, 3-year PFS [progression-free survival] and also overall survival rates, it’s clear that all 3 combinations are quite effective and similar in controlling the disease over time. The major difference is the safety profile of the different combinations. 

Axel Hauschild, MD, PhD: Yes. 

Dirk Schadendorf, MD: What’s your experience…?

Axel Hauschild, MD, PhD: Yes. It’s dabrafenib/trametinib. If you would count 1 adverse event that is very obvious, it’s fever and chills. For the Roche combination of cobimetinib/vemurafenib, it is sun sensitivity and direct reactions to the skin, typically. There are no particular adverse events with encorafenib/binimetinib, but the treatment discontinuation rates for all the 3 are almost the same. This is what is most important for me. Therefore, I can only say that I believe the efficacy might be slightly different. There is difference in the tolerability, and this might also drive our decisions. 

Dirk, I was personally very disappointed in the year 2020 because the triplets didn’t show the results I expected. When I talk about triplets, it’s BRAF plus MEK inhibitors plus or minus PD-1 or PD-L1 antibody.

The atezolizumab trial from Roche showed 4.5 months of an absolute difference in PFS and 4.2 months for the COMBI-I trial from Novartis, which looks very much the same. The Roche trial made it to FDA approval, and the Novartis trial failed because it was not statistically significant. What about your expectations of these clinical trials? Would you share my opinion that this was a disappointing year for the triplets?

Dirk Schadendorf, MD: Absolutely. The hope we’ve had and what we have played for the last 5 years was that we have different modes of action, and if you would combine them, it would make deep and quick responses from targeted therapy now very durable. That didn’t turn out. The response rates are the same if we compare targeted therapy to the triplet therapy. The PFS curves were completely overlapping in the first 6 to 8 months. Whether this has a long lasting or as much benefit at the end is quite questionable. The toxicity is also quite increased.

Axel Hauschild, MD, PhD: Yes.

Dirk Schadendorf, MD: I don’t really see a new standard of care using triplets.

Transcript Edited for Clarity