With the regulatory approval of six agents (ipilimumab, vemurafenib, dabrafenib, trametinib, pembrolizumab, and nivolumab) for the treatment of metastatic and/or unresectable melanoma since March 2011, compared to approval of two agents (dacarbazine and high-dose interleukin 2 [HD IL2]) from 1976 to 2010, it is clear that a therapeutic revolution is underway, as described in the ONCOLOGY article by Bhatia et al. Despite this proliferation of available treatment options for melanoma, however, the great majority of patients diagnosed with metastatic melanoma still will die from their disease. As the melanoma research community strives to develop curative therapeutic approaches through innovative clinical and translational studies, two central and practical issues must be considered in order for us to make the best treatment decisions for our patients: molecular targeted therapy vs immunotherapy and sequential vs combinatorial regimens.
A decision to implement front-line molecular targeted therapy or immunotherapy only needs to be made for the 40% to 50% of patients with tumors harboring a BRAF V600 mutation, since specific targeted therapy options are not yet approved for other molecular subsets. In the absence of randomized data, initial treatment selection for BRAF-mutant patients is guided by retrospective analyses and anecdotal experience. In general, molecular targeted therapy is considered to be associated with rapid yet transient responses in most patients, and immunotherapy is associated with fewer though more durable responses that take longer to be realized.[3-7] Additionally, two retrospective analyses suggest that front-line immunotherapy prior to BRAF-targeted therapy is associated with better outcomes than those achieved by first-line BRAF-inhibitor therapy prior to immunotherapy.[8,9] While these concepts may hold true when comparing single-agent BRAF inhibitors (such as vemurafenib or dabrafenib) with single-agent ipilimumab, an anti–cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody, emerging evidence suggests that other strategies could be considered. First, newer agents targeting the programmed cell death 1 (PD-1) receptor, including pembrolizumab and nivolumab, are associated with a percentage of patients experiencing a reduction in tumor volume that is similar to the percentage seen with single-agent BRAF inhibitor therapy, as demonstrated by analysis of so-called waterfall plots.[10-13] Second, combined BRAF/MEK inhibitor therapy has emerged as the new standard molecular targeted approach for BRAF-mutant patients. This approach is associated with a median overall survival (OS) of approximately 2 years and 2-year progression-free survival (PFS) in 30% of patients—data that suggest targeted therapy may, indeed, be associated with durable benefit in a subset of patients. Needless to say, a randomized trial is necessary to determine whether BRAF-targeted therapy or immunotherapy is the best front-line approach for patients with metastatic BRAF-mutant melanoma. One such trial is the Intergroup EA6134 trial that will be comparing front-line dabrafenib plus trametinib (BRAF/MEK inhibitor combo) with the combination of ipilimumab plus nivolumab. In the meantime, either combined BRAF/MEK inhibitor therapy or immunotherapy is justifiable in the front-line setting.
As described above, combined BRAF-and-MEK–inhibitor therapy is the new standard targeted therapy approach in patients with metastatic BRAF-mutant melanoma. The initial data to support combination therapy came from three phase I/II trials that described high response rates and favorable side-effect profiles.[15-17] In fact, the data from the phase I/II trial with dabrafenib and trametinib led to FDA approval of the combination in January 2014. More recently, survival data have become available from three randomized phase III trials showing that dual BRAF/MEK targeting is superior to BRAF targeting alone.[18-20] Additionally, given the ineffectiveness of single-agent MEK inhibitors after BRAF inhibitors, there does not appear to be any justification to compare combined BRAF/MEK inhibitor therapy to a sequence of BRAF inhibitors followed by MEK inhibitors or even single-agent BRAF inhibitors followed by a BRAF/MEK inhibitor combination.[21,22]
It is still unknown whether combined immunotherapy, consisting of anti–CTLA-4 plus anti–PD-1 therapy, is better than sequenced anti–CTLA-4 prior to anti–PD-1 or anti–PD-1 followed by anti–CTLA-4. What is clear is that ipilimumab plus nivolumab is associated with unprecedented response rates and survival data, as approximately 50% of patients respond and upwards of 90% of patients are alive at 1 year.[23,24] Perhaps not surprisingly, the toxicity of dual CTLA-4 and PD-1 antagonism is quite high, with high-grade adverse events seen in over 60% of patients. With the high activity of both nivolumab and pembrolizumab following ipilimumab, the key issue will be to determine which patients are most appropriate candidates for combination anti–CTLA-4/PD-1 therapy and which are appropriate for either up-front single-agent anti-PD1 therapy or ipilimumab. It is anticipated that more concrete evidence will be available in the near future. Data are expected soon from a phase III trial comparing ipilimumab, nivolumab, and the combination of ipilimumab plus nivolumab (ClinicalTrials.gov identifier NCT01844505). In addition, results are anticipated from two phase II trials, one comparing the combination of ipilimumab plus nivolumab vs ipilimumab followed by nivolumab therapy following progression (NCT01927419), and the other randomizing patients to induction ipilimumab or nivolumab followed by induction therapy with the other agent (NCT01783938).
In early 2015, determining the optimal treatment regimen for a patient with metastatic melanoma remains challenging. In patients with BRAF mutations, more options are available, yet prospective data are lacking as to whether BRAF-targeted therapy or immunotherapy is better in the front-line setting. In BRAF wild-type patients, the major decision is between ipilimumab and chemotherapy, although previous data support ipilimumab as a first step and recent data have demonstrated the superiority of nivolumab compared with chemotherapy in the front-line setting.[10,25] Comparative data for ipilimumab vs anti–PD-1 therapy are lacking. In general, when faced with a patient with newly diagnosed metastatic BRAF-mutant melanoma, I (and many of my colleagues) tend to recommend up-front immunotherapy, to be followed at a later date by combined BRAF/MEK-targeted therapy. The exception to this approach is if the patient presents with a life-threatening, cancer-related issue that would limit his or her prognosis to a matter of days or a few weeks; in such a case, I would favor combined BRAF/MEK-targeted therapy as initial therapy, due to the associated rapid (within 1 to 3 days) improvement of symptoms. In patients without BRAF mutations, upfront immunotherapy is the obvious choice over chemotherapy, since ipilimumab and nivolumab have been shown to be superior to chemotherapy.[10,25] As always, given the number of key clinical and translational questions that need to be answered, enrollment into a clinical trial should always be considered in eligible patients.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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