Combination treatment with BRAF and MEK inhibitors, such as dabrafenib plus trametinib or cobimetinib plus vemurafenib is, however, effective, with 3-year OS rates of about 45%, and a subset of patients demonstrate long-term survival without acquired resistance to BRAF and MEK inhibition. Dr Sullivan noted that because the BRAF/MEK combination was demonstrated to be superior to single-agent BRAF inhibition by multiple trials, there is rarely a place for BRAF inhibitors alone.
“On the other end of the spectrum are patients with rapidly developing, severe symptoms who require rapid symptom management with the faster acting targeted therapy,” Dr Sullivan said.
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The algorithm recommends BRAF/MEK combination therapy for patients with a prognosis measured in weeks, with a consideration to switch to combination immunotherapy after about 1 month. The goal is to gain disease control quickly with the targeted therapy, and then to introduce checkpoint inhibition.
The authors of the algorithm acknowledge that this recommendation to switch from BRAF/MEK inhibitors to combination immunotherapy is not based on current data. Dr Sullivan differed from the recommendation, and said: “I think the concept that patients with less disease should receive immunotherapy and patients with more disease should receive targeted therapy is not supported by data and may be reversed.”
Ongoing trials, including those that combine immunotherapy with BRAF inhibitors or a triple combination of an anti-PD-1 antibody with BRAF and MEK inhibitors, may provide more options to clinicians and their patients.
Sequencing Therapies
Another unanswered question is how to optimally sequence therapies for patients with BRAF-mutated advanced melanoma.
Retrospective studies suggest that first-line treatment of BRAF-mutated disease with immunotherapy does not alter a patient’s response to a subsequent BRAF inhibitor.1 Another retrospective study found that patients had better outcomes if they received anti-PD-1 therapy before BRAF inhibitors. Data from large, randomized clinical trials are, however, not yet available to provide a definitive answer.
“There is no right answer at this point, and randomized trials are ongoing in an attempt to provide clarity to the issue,” Dr Sullivan said.
Resources for Clinicians
Given the challenges for treatment selection and sequencing for patients with advanced melanoma, particularly those who harbor a BRAF mutation, inter-colleague discussion of difficult cases is important for optimal treatment decisions.
“I think tumor boards — either in person or remote boards with participation by relevant experts — offer the best forum for these discussion,” Dr Sullivan said. He also noted that expert commentaries published in the literature or online may be helpful.
For clinicians in the community, especially those who do not have access to a tumor board, Dr Sullivan recommends creating “a relationship with a local, regional, or national expert that they can ‘bounce-off’ ideas and may present cases to for assistance.”
References
- Amaral T, Meraz-Torres F, Garbe C. Immunotherapy in managing metastatic melanoma: which treatment when? Exp Opin Biol Ther. 2017;17:1-16. 10.1080/14712598.2017.1378640
- Silva IP, Long GV. Systemic therapy in advanced melanoma: integrating targeted therapy and immunotherapy into clinical practice. Curr Opin Oncol. 2017 Sep 12. doi: 10.1097/CCO.0000000000000405 [Epub ahead of print]
