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The advent of ipilimumab and the BRAF inhibitors (BRAFi) vemurafenib and dabrafenib has revolutionized the treatment of melanoma. Until a few years ago, the 1-year survival rate in the advanced melanoma population was only 25.5%.[1] However, treatment with these new agents has resulted in approximately half of patients still being alive at 1 year (46% with ipilimumab and more than 50% with vemurafenib). Moreover, the use of these drugs in novel combinations, such as combination tyrosine kinase inhibitors (TKIs) that block sequential or parallel steps in important oncogenic pathways or immune checkpoint blockers with complementary mechanisms of action appear likely to improve the clinical benefit even more than single-agent therapy.[2, 3]

The positive results observed in the pivotal clinical trials of ipilimumab and vemurafenib suggested the next logical step was combined ipilumumab and BRAFi treatment, but the phase 1 trial demonstrated increased toxicity (mainly liver and skin).[4] Because the alternative BRAF inhibitor dabrafenib causes a substantial incidence of fever and inflammatory symptoms, it is also not likely to be safely combinable with ipilimumab. Thus, sequential treatment may provide a better opportunity to potentiate these agents' efficacy. Emerging evidence from retrospective analyses of patient outcomes from clinical trials and Expanded Access Programs (EAPs) have shown that the sequence of first ipilimumab, then BRAFi is associated with superior outcomes than the reverse sequence,[5] and at our own institute, sequential treatment with ipilimumab and BRAFi showed a longer median overall survival (OS) than single-agent treatment.[6]

The experience reported in this issue by Ackerman et al[7] is consistent with the reported data that show longer survival among patients treated with immunotherapy first. Given that in Europe, the Committee for Medicinal Products for Human Use (CHMP) recently extended ipilimumab's indication to first-line treatment,[8] the main question now is which is the best sequence, ipilimumab followed by BRAFi or BRAFi followed by ipilimumab? In attempting to address this question, we need to take into account a number of important considerations. First, although the ipilimumab treatment course consists of just 4 injections, there are data favoring higher over lower doses[9] that were further explored in a recently completed phase 3 trial (data not yet analyzed). We also observed in a large review of the outcomes from the Italian EAP (855 patients from 55 centers treated with ipilimumab) that the 23% of patients who received 1 or 2 ipilimumab injections had significantly worse median OS compared with the 77% of patients who received 3 to 4 injections (1.7 versus 10.8 months).[10] Although the reasons for failure to complete the prescribed 4 treatments most likely included both severe immune-related adverse events as well as rapidly progressive tumor requiring alternative therapy, it is also likely that the mechanism of action of ipilimumab requires a particular minimum number of doses as well as time following therapy to exert its antitumor immune effects. Regarding the mechanism and kinetics of response to BRAFi, it is well known that a fraction of patients, generally identified as those who had the most unfavorable prognostic features prior to therapy, experience aggressive tumor growth and short survival following the development of BRAFi resistance and are too ill to benefit from immunotherapy.[5, 11, 12]

The data reported by Ackerman et al suggest that the response rates to BRAFi treatment are similar regardless of whether given before or after ipilimumab (66% and 57%, respectively, P = .31), indicating that the action of BRAFi is the same in both scenarios. Another important consideration is the potential effect of BRAFi treatment on the immune system. Vemurafenib has been reported to increase CD4+ and CD8+ T-cell tumor infiltrate, increase expression of melanoma-associated antigens, and decrease myeloid-derived suppressive cells in the tumor.[13-15] It was therefore believed that treating with BRAFi first might increase the infiltrate inside the tumor, thereby making subsequent ipilimumab treatment more effective. Although the Italian EAP data also showed that the response rate to ipilimumab was similar in patients who received ipilimumab before or after BRAFi (11% and 10%, respectively),[12] its mechanism of action does not lend itself to assessment by standard response criteria, and durable progression-free as well as overall survival has been accepted as a more reliable measure of its benefit. Thus, the Italian pooled data are in agreement with those of Ackerman et al in supporting a benefit for the sequence of ipilimumab first and BRAFi only after definitive failure of ipilimumab, which may require prolonged observation due to the delayed onset of benefit in some patients.[16] Ackerman and colleagues also suggest another interesting explanation for the lower efficacy of ipilimumab after BRAFi, which might be due to reduction of the tumor melanocytic antigen expression and T-cell infiltration at progression.

We believe that the currently available data continue to support the selection of patients with a poor performance status (> 2), including selected patients with untreated and/or symptomatic brain metastases, for initial therapy with BRAFi who will benefit from the very rapid symptom and radiographic responses achieved with these agents. This is particularly important for patients with symptomatic brain metastases requiring steroid for the control of symptoms and/or edema and not amenable to focal radiotherapy, because such patients rarely benefit from ipilimumab.[17] Although the predominant message in this commentary is to support the general principle of sequencing immunotherapy first and BRAFi therapy only after failure of immunotherapy, it should be pointed out that recent follow-up data from the initial studies of vemurafenib suggest that BRAFi failure may not be as inevitable as was originally believed, and that up to 20% to 25% of patients may remain alive at more than 2 years (K. T. Flaherty, oral communication, November 2013). Understanding the molecular biology of melanoma and its resistance to therapy is now the focus of research in many laboratories around the world, and single-agent BRAFi will soon be supplanted by combination TKIs that block sequential or parallel reactions to which melanoma is “addicted.” Similarly, promising data support the consideration of combination immune checkpoint blockade using antibodies with complementary mechanisms of action and mostly non overlapping toxicities, which have shown superiority over single-agent immunotherapy and are now under investigation in randomized trials for melanoma and other malignancies.

It is highly likely that standard therapy in the next few years for patients with BRAF activation mutations will consist of a brief cytoreductive exposure to combination mitogen-activated protein kinase pathway and AKT pathway inhibitors followed before progression by a switch to combined immune checkpoint blockade in order to achieve a form of “total therapy” analogous to that which has been so successful in pediatric malignancies.

CONFLICT OF INTEREST DISCLOSURES

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Dr. Ascierto has served as a consultant for Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline, and Novartis. He also received honoraria from Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline, and research funding from Bristol-Myers Squibb. Dr. Margolin has done ad hoc ad boards for Bristol-Myers Squibb, Roche-Genentech, and GlaxoSmithKline.

REFERENCES

  1. Top of page
  2. CONFLICT OF INTEREST DISCLOSURES
  3. REFERENCES