The Future of Systemic Therapy of Melanoma: Combinations, Predictive Biomarkers

February 15, 2015

While the last several decades saw a lack of progress in treatment outcomes in this setting, the outlook has recently changed dramatically, driven by a deepening understanding of melanoma biology and host immunology.

In the United States, it is estimated that 73,870 persons will be diagnosed with cutaneous melanoma in 2015, and that 9,940 will die from this disease.[1] The high death rate from melanoma approximates the incidence of metastatic disease, illustrating the challenges in controlling stage IV melanoma. However, while the last several decades saw a lack of progress in treatment outcomes in this setting, the outlook has recently changed dramatically, driven by a deepening understanding of melanoma biology and host immunology.[2,3] This progress at the molecular level has been translated in record time into the clinic, with the approval of new molecularly targeted agents (BRAF and MEK kinase inhibitors) and immune checkpoint modulators (cytotoxic T-lymphocyte antigen 4 [CTLA-4]– and programmed death 1 [PD-1]–blocking antibodies) that have resulted in unprecedented improvements in disease control and in the survival of patients with metastatic melanoma.

The finding, in the late 1990s, that high-dose bolus interleukin-2 (IL-2) could produce durable responses in about 5% of patients provided the first evidence that metastatic melanoma could potentially be cured with immunotherapy. Ipilimumab was the first immunotherapeutic agent to demonstrate an overall survival benefit in a randomized phase III trial in metastatic melanoma.[4] In a recent analysis of 1,861 melanoma patients treated with ipilimumab in clinical trials, 22% lived 3 years or longer.[5] Targeting PD-1 and its ligand (PD-L1) in clinical trials followed a similar path, leading to approval by the US Food and Drug Administraion (FDA) of two potent and highly selective humanized monoclonal antibodies (mAbs), pembrolizumab and nivolumab.[6,7] These agents have demonstrated an unprecedented rate of durable responses as monotherapy, ranging from 20% to 40%. In addition, combination immunotherapy appears very promising. An impressive 2-year survival rate of 79% was recently reported in an update of the nivolumab-ipilimumab phase I combination trial,[8] and combinations pairing anti–CTLA-4 and anti–PD-1 mAbs with other immunotherapy agents have demonstrated significant results, leading to randomized trials.[9-11]

However, there is an important qualification to this good news. While these therapeutic antibodies can potentially control and even eliminate cancers, manipulation of the effects of immunologic checkpoints can lead to serious immune-mediated adverse events involving the targeting of self-tissues. At present, we have no way to predict which patients will be among the roughly one-quarter to one-third who will benefit, and which will be among the two-thirds who could be spared the adverse events and high cost due to lack of predicted efficacy. Thus, there is a critical need for therapeutic and toxicity predictive biomarkers. In fact, this is one of the most important areas of current melanoma research. Extensive efforts in biomarker studies are underway, and preliminary data are very promising with respect to gene expression signatures,[12,13] exome sequencing studies,[14] and CD8 expression within the tumor microenvironment.[15] Similar efforts are underway to identify markers for predicting which patients are more likely to suffer from treatment-limiting immune-related toxicities.

Driver BRAF mutations are found in 40% to 50% of patients with metastatic melanoma. To date, three small-molecule oral targeted therapies that inhibit mutant BRAF kinase or downstream MEK kinase have been approved by the FDA and shown to be effective therapies for patients with BRAF-mutant metastatic melanoma: vemurafenib, dabrafenib, and trametinib (with these last two approved both as monotherapies and as the BRAF-MEK inhibitor combination dabrafenib/trametinib).[2] Initial response rates of about 50% with BRAF inhibitor monotherapy (with median response durations of 6–7 months) were significantly improved to about 60% to 70% (with a median response duration of about 9 months) with the combination of a BRAF and a MEK inhibitor.[16-18]

The damper on this exciting development is the fact that resistance ultimately develops in the majority of patients treated with these targeted agents. Resistance mechanisms have been well characterized and are best classified as MEK-dependent and independent.[19] Strategies for overcoming this difficulty that are currently being investigated include the optimization of mitogen-activated protein kinase (MAPK) pathway inhibition (targeting ERK, CDK4/6 as monotherapy and in combinations) and the use of combinations that target alternate pathways implicated in mediating resistance (PI3K, AKT). Another strategy that shows promise for mitigating the problem of resistance to targeted agents involves combining targeted therapy with immunotherapy (including interferon, IL-2, anti–CTLA-4, anti–PD-1/PD-L1). This strategy is based on the hypothesis that the high response rates seen with BRAF/MEK inhibitors can be transformed into high rates of durable response with immunotherapy.[20] Combination studies involving the aforementioned immunotherapeutic agents are underway.

Nonetheless, while there are still significant obstacles to be overcome before the benefits from new therapies are maximized, the future of systemic therapy of melanoma remains quite bright, and as noted in the article in this issue by Bhatia and colleagues, we are “on the road to cure.”

Financial Disclosure:Dr. Tarhini serves on advisory boards for Bristol-Myers Squibb, Genentech, and Merck; and he receives research grant support from Bristol-Myers Squibb, Merck, and Novartis.


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10. Tarhini AA, Cherian J, Moschos SJ, et al. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol. 2012;30:322-8.

11. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312:1744-53.

12. Tarhini AA, Edington H, Butterfield LH, et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One. 2014;9:e87705.

13. Tarhini AA, Lin Y, Lin HM, et al. Immune related melanoma gene expression profile predicts neoadjuvant ipilimumab clinical benefit. AACR Annual Meeting; Apr 5–9, 2014. San Diego, CA. Abstr 2911.

14. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-99.

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16. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-16.

17. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-65.

18. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30-9.

19. Salama AK Flaherty KT. BRAF in melanoma: current strategies and future directions. Clin Cancer Res. 2013;19:4326-34.

20. Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges.
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