Dr. Rodabe N. Amaria
Question: In BRAF-mutant melanoma, what regimen should be used as first-line therapy in advanced disease?
Answer: The answer to this question has been controversial in the melanoma community since 2011, when the treatment landscape broadened to include BRAF-targeted therapy and immune checkpoint blockade for patients with advanced disease. Use of immunotherapy in patients with small burden or asymptomatic disease has often been favored in the first-line setting because of the potential for achieving durable benefit and possibly even cure. CTLA-4 and PD-1 blockade individually and in combination produce durable responses in subsets of treated patients, although we currently do not have enough information to predict which subsets will derive benefit. In a pooled analysis of outcomes of more than 1,800 patients treated with the CTLA-4 blocker ipilimumab, the 3-year survival rate was 22%.1 Treatment with the anti–PD-1 antibody pembrolizumab led to median overall survival (OS) of 31 months, with 12- and 24-month survival rates of 73% and 60%, respectively, in patients who were treatment naive.2 Additionally, combination ipilimumab and nivolumab is associated with response rates of 57% and 2-year survival rates of 75%, although the toxicity of this regimen can limit its broad applicability.3,4
I reserve first-line BRAF/MEK inhibition for patients with BRAF-mutant, symptomatic disease characterized by pain, potential for organ compromise, elevation in lactate dehydrogenase (LDH), or presence of brain metastases. This recommendation is based on evidence of rapid disease responses with symptomatic improvement often seen in a matter of days after treatment initiation. These medications can work well initially in patients with LDH elevation with 1-, 2-, and 3-year OS rates of 68%, 18%, and 5%, respectively.5 The use of BRAF/MEK inhibition in the first line can potentially debulk tumor mass to improve feasibility of immunotherapy in the second-line setting because immunotherapy is not as effective in patients with large tumor burden.6 BRAF-targeted therapy is safe and efficacious in central nervous system metastases. In the BREAK-MB trial, single-agent dabrafenib produced intracranial response rates of 20% to 29% in patients with prior surgery or radiation or for patients who had previously untreated brain metastasis.7
However, newer data put the dogma of immunotherapy for first-line treatment of patients who are asymptomatic in doubt. Combination BRAF/MEK inhibition can produce durable responses that rival those seen with immunotherapy, especially in patients with low disease burden and normal LDH. In an analysis of 78 patients who were BRAF-inhibitor naive and were treated with dabrafenib/trametinib, prolonged OS was seen with 20% of patients remaining progression free at 3 years. The best correlates of prolonged response were normal LDH and earlier-stage melanoma with fewer sites of metastatic disease at the time of treatment initiation.5 These data are echoed in a pooled retrospective analysis of 617 patients treated with dabrafenib/trametinib showing that patients with normal LDH and less than three sites of metastatic disease fared the best and had 1- and 2-year OS rates of 90% and 75%, respectively.8
Additionally, evidence suggests that ipilimumab/nivolumab may be appropriate in high-risk groups such as patients with symptomatic disease, high LDH, or brain metastases. Time to treatment response is usually about 8 to 12 weeks for single-agent checkpoint blockade; however, treatment responses with ipilimumab/nivolumab can be appreciated after just one dose of therapy. Ipilimumab/nivolumab does work in the population of patients with high LDH with median duration of response of 12.5 months.9 There is also evidence that single-agent anti–PD-1 can induce disease control in untreated or progressive brain metastases,10 and ipilimumab/nivolumab is being actively assessed in the CheckMate204 trial for untreated symptomatic and asymptomatic brain metastases (NCT02320058).
Ultimately, we do not currently have sufficient evidence to definitively answer the question of the optimal first-line therapeutic modality for patients with BRAF-mutated metastatic melanoma. However, two ongoing clinical trials are designed to answer this important question. NCT02224781 is a randomized phase III trial of up-front ipilimumab/nivolumab followed by dabrafenib/trametinib at progression versus the opposite approach. The primary objective of this trial is OS rate, defined as the proportion of patients alive after 2 years of follow-up. LDH levels and other clinical characteristics will be analyzed to assess how these may correlate with response and survival. A parallel trial (NCT02631447) is ongoing in Europe with three treatment groups: up-front BRAF/MEK (LGX818/MEK162) followed by ipilimumab/nivolumab at progression, the opposite approach, and a third cohort with 8 weeks of BRAF/MEK with a forced switch to combination immunotherapy and then BRAF/MEK at progression. These trials should provide the answer to this controversial question of which treatment modality is superior in the first-line setting for patients with BRAF-mutant metastatic melanoma.