Sequence of therapies for advanced BRAFV600E/K melanoma

The treatment of BRAF-mutant advanced melanoma currently relies on targeted therapy and immunotherapy. Targeted therapy combines a BRAF and a MEK inhibitor (1-3), whereas immunotherapy is based on an anti-programmed death 1 (PD-1) antibody, either alone or combined with an anti-CTLA4 antibody (4). Patients who receive one of these options and have a progression can be treated with the other one.

A long-term debate has been established about the optimal sequence: should patients first receive targeted therapy or immunotherapy? Either modality has pros and cons. Targeted therapy achieves fast and profound responses, with less than 5% of patients refractory to the combination. Its tolerance is excellent, and the toxicity is usually easily manageable. But resistance usually appears after 12–18 months on therapy.

On the other hand, immunotherapy more commonly leads to durable responses, although responses are less common and 40% of patients are refractory to treatment. Moreover, the combination of the anti-PD-1 antibody nivolumab plus the anti CTLA-4 antibody ipilimumab produce high grade toxicities in more than 50% of patients, with some of them potentially fatal if medical management is not adequate (4,5).

Results from the DREAMseq study, a pharmaceutical independent clinical trial led by the ECOG-ACRIN research group, are very relevant for the clinical practice (6). It is the first phase 3 study to test the optimal sequence for advanced BRAFV600E/K mutant melanoma. Half the patients first received induction nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4), followed by nivolumab maintenance (Arm A); upon progression, patients were treated in arm C with dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor). This sequence was compared with the opposite, arms B and D. The primary end point of the study was the 2-year overall survival rate (OS2y). A total of 265 patients were included. The study demonstrated benefit in terms of OS2y for the arm starting with the combination of ipilimumab plus nivolumab, OS2y 72% vs. 51%, P=0.01 (6).

CITATION  Ann Transl Med. 2023 Mar 31;11(6):270.  doi: 10.21037/atm-23-165. Epub 2023 Feb 14.