Which first-line therapy is appropriate for BRAF-mutated metastatic melanoma?

In about 50% of metastasized melanomas, a BRAF mutation is found, in these cases, targeted therapy can be applied. But immunotherapeutics have also revolutionized melanoma treatment in the last ten years.

The "agony of choice" for attending physicians

In about 50% of metastasized melanomas, a BRAF mutation is found, in these cases, targeted therapy can be applied. But immunotherapeutics have also revolutionized melanoma treatment in the last ten years.

Various options are available for the first-line therapy of melanoma. They were presented and discussed at a symposium during the annual meeting 2019 of the ASCO (American Society of Clinical Oncology) on the basis of the available study data.

There are now numerous therapeutic options for the treatment of metastatic melanoma. Modern therapy with immunotherapeutics and BRAF/MEK inhibitors began in 2011 with the introduction of ipilimumab, followed by vemurafenib, dabrafenib, trametinib and the combination of dabrafenib with trametinib. The first PD1 inhibitors with pembrolizumab and nivolumab became available in 2014, followed by a combination of nivolumab plus ipilimumab in 2015. In the same year, Talimogen laherparecvec and Cobimetinib (with vemurafenib) were approved. 

Encorafenib was approved with binimetinib in 2018. According to Leslie Fecher, Rogel Comprehensive Cancer Center, University of Michigan, Leslie Fecher, Ann Arbor, Michigan, USA, these modern substances have significantly improved the survival of patients with stage IV melanoma. The survival curves of modern therapeutics are usually similar - so that the practitioner is spoilt for choice.

The determination of the biomarker PD-L1 alone is only of limited use; according to Fecher, it is not required for the selection of first-line therapy. The ideal biomarker is multidimensional and dynamically captures the tumor, its microenvironment and the immune status of the patient.

Combination or sequence?

Targeted substances and immunotherapeutics have greatly improved the treatment of metastatic melanoma. Despite the substantial improvements in overall survival, some patients do not respond to initial therapy or rapidly develop resistance leading to recurrence. This led to new therapeutic strategies, especially combinations.

The discussion as to whether BRAF/MEK inhibitors should be combined as sequence therapy with immunotherapeutics or directly can only be conducted for patients with BRAF-mutated melanomas. All patients with metastatic melanoma without BRAF mutation are offered immunotherapy in the first line.

Potential combinations in melanoma, according to Paolo Ascierto, head of the melanoma department at the National Tumor Institute, Naples, Italy, include immunotherapy plus radiotherapy, immunotherapy plus targeted therapy, immunotherapy plus immunotherapy and immunotherapy plus chemotherapy. In the further course, he concentrated on the combination of immunotherapy plus targeted therapy. This is a rational combination because MEK/BRAF inhibitors induce a high response that occurs rapidly and lasts rather shorter, while the tumor responds more slowly to immunotherapy, but the response lasts longer.

Studies combining the therapeutic principles of BRAF inhibition, MEK inhibition, and PD-1 or PD-L1 blockade showed longer progression-free survival, stronger and longer response, but toxicity was higher. According to Ascierto, high-risk patients, in particular, could benefit from such a regime. Further information is expected from ongoing Phase III studies.

According to Ryan J. Sullivan, Massachusetts General Hospital Cancer Center, Boston, USA, there are no prospective data on sequence therapy. However, two retrospective analyses suggest that response and outcomes to ipilimumab are better when given before targeted therapy than when administered afterward. However, a recent analysis also showed that a BRAF-MEK regime after PD1-based therapy is quite toxic. In 68 of 81 regimens dose modifications were necessary, in the median it took 14 days until dose modification and 31% of patients had to be hospitalized due to side effects.

What to do?

The therapy decision must be based on patient characteristics. Here, Anna C. Pavlick, NYU Perlmutter Cancer Center, New York, USA, mentioned factors such as anamnesis (autoimmune diseases or other comorbidities), organ functions (especially heart), mutation status, presence of brain metastases, LDH levels, progression speed, tumor load, performance status as well as the patient's wishes and lifestyle. Her take-home message was:

The Stage IV melanoma consult in 2019: What Biomarker and treatment approaches are appropriate in setting). Educational Symposium, 2019 ASCO Annual Meeting, Chicago, May 31 to June 4, 2019.