A Data-informed Approach to First-line Treatment Selection

Data-driven clinical insights concerning the selection of effective first-line treatment options for patients with BRAF-mutated metastatic melanoma, with a focus on the DREAMseq trial.

Hussein Tawbi, MD, PhD: Regarding data addressing the first line treatment of patients with metastatic B-RAF mutated melanoma and what guides our treatment selection of targeted versus immunotherapy, until we had the recently reported phase three trial DREAMseq, we really did not have any head-to-head comparisons between those two treatment approaches. All of the treatments that I mentioned previously have been approved in the first line setting. Each of them has been approved in patients that are treatment naïve. Immunotherapy with PD-1 antibodies, immunotherapy with PD-1, CTLA-4 antibodies, PD-1 LAG-3 antibodies. Then any of the three B-RAF and MEK inhibitor combinations were all done in phase three trials that were in treatment-naïve patients. The sequencing data of what you should go with first was mostly limited to retrospective evidence from sometimes multi-center studies and occasionally single center studies talking about the outcomes of patients that have been treated with standard of care and switched from either our B-REF first to immunotherapy or vice versa. All of those data were not really very helpful in making a decision because as with most retrospective data, they weren't well controlled. There's a lot of biases involved in them, especially when you discuss, say, progression-free survival. DREAMseq was really incredibly valuable. It was a phase three trial that was ran through ECOG-ACRIN and across the entire country through the intergroup including SWAG and other cooperative groups. What that study asked is a very simple question in terms of how to treat patients in the first line. You took patients that are B-RAF mutated metastatic disease, treatment naïve, and by the way upfront they weren't expected to have brain metastasis either. But you decided you randomized them to either immunotherapy with combination of Ipilimumab and Nivolumab. Just to be clear, that is the high dose of Ipilimumab three milligram per kilogram with Nivolumab one milligram per kilogram for four doses of induction. Compare that to B-RAF and MEK inhibitor combination, in this case Dabrafenib and Trametinib. The choice for the first line was either ipi/nivo or Dabrafenib/Trametinib. Then at progression, the patients were expected to cross over. If they started B-RAF and MEK inhibitor, they would change to ipi/nivo. If they started with ipi/nivo, they would switch to Dabrafenib and Trametinib. The study was designed with a primary endpoint of overall survival at two years, which was really a very good time point to look at and a very important primary endpoint. Sure enough, the two-year overall survival had a 20% statistically significant difference in favor of Ipilimumab and Nivolumab. 20% difference in overall survival. If you started B-RAF and MEK inhibitors first and switched to Ipilimumab and Nivolumab, the overall survival is 52% at two years. If you started with Ipilimumab and Nivolumab first and then switched to B-RAF and MEK inhibitors, overall survival was 72% at two years. Again, not subtle difference. It's a major difference in survival. Therefore we feel that that study- randomized, controlled, well conducted- is incontrovertible evidence that you really should start those patients on Ipilimumab and Nivolumab, or at least immunotherapy as we had all suspected before the study started. But now we have phase three evidence to that effect.

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