Melanoma, an aggressive disease with a rapidly rising incidence rate, presents the oncology field with some of its greatest challenges and opportunities. Long considered one of the most difficult diseases to treat with pharmacotherapy, drug development within melanoma has lagged behind that of many other cancers, culminating in decades of limited progress. Developments in molecular biology, however, have led to an increased understanding of the molecular heterogeneity of melanoma in recent years, which has resulted in new insights into the roles of oncogenes, signaling pathways, immune checkpoints, and tumor-promoting events, accelerating the rate of discovery of therapeutic targets.
Melanoma, an aggressive disease with a rapidly rising incidence rate, presents the oncology field with some of its greatest challenges and opportunities. Long considered one of the most difficult diseases to treat with pharmacotherapy, drug development within melanoma has lagged behind that of many other cancers, culminating in decades of limited progress. Developments in molecular biology, however, have led to an increased understanding of the molecular heterogeneity of melanoma in recent years, which has resulted in new insights into the roles of oncogenes, signaling pathways, immune checkpoints, and tumor-promoting events, accelerating the rate of discovery of therapeutic targets. This has led to an influx of novel drugs in the past 4 years, transforming this previously stagnant market, and dramatically improved treatment options for patients. In particular, treatment algorithms have shifted toward more-targeted treatments for specific patient subsets. Evidence from the late-stage pipeline indicates that this trend is set to continue.
Melanoma is a type of cancer that originates in the pigment-producing melanocyte cells. Although tumors develop in melanocytes of the skin in over 90% of cases, melanoma can also occur in melanocytes found in the eye, the internal organs, and the mucosal membranes that line the gastrointestinal, respiratory, and urogenital tracts.1,2
The past several decades have seen the age-standardized incidence rate of cutaneous melanoma (skin melanoma) rise by approximately 4% to 6% per annum in many countries with predominately Caucasian populations.3 Changing patterns of sun exposure-including trends toward vacationing in sunny destinations and indoor tanning-have been proposed as contributing to this dramatic increase. Drug development within melanoma has therefore centered on cutaneous melanoma therapeutics. Indeed, all melanoma therapeutics approved to date are indicated for the treatment of this patient subset. Furthermore, as early-stage melanoma is highly curable with surgery, therapeutics are usually reserved for patients in the later stages of disease.
Prior to 2011, the melanoma market was dominated by chemotherapies and interferon therapies with poor benefit-to-risk ratios. In recent years, however, the market has been revolutionized by a number of breakthrough drug approvals, of which the approvals of Yervoy (ipilimumab, Bristol-Myers Squibb) and Zelboraf (vemurafenib, Genentech/Roche) marked the beginning in 2011. Yervoy is an immune checkpoint inhibitor that stimulates melanoma regression by boosting the immune response. Zelboraf is a targeted therapy only indicated for the treatment of approximately half of cutaneous melanoma patients with mutated BRAF, an oncogene protein product that promotes the proliferation and survival of melanoma by hyper-activation of the mitogen-activated protein kinase (MAPK) signaling pathway. By demonstrating unprecedented survival benefits over previously marketed therapies, Yervoy and Zelboraf rapidly became established as first-line therapies in BRAF-negative and BRAF-positive advanced cutaneous melanoma, respectively. More recent drug approvals include the targeted therapies Tafinlar (dabrafenib, GlaxoSmithKline) and Mekinist (trametinib, GlaxoSmithKline), which are also approved for BRAF-positive melanoma, as well as immune checkpoint inhibitors Opdivo (nivolumab, Bristol-Myers Squibb) and Keytruda (pembrolizumab, Merck).
These recent drug approvals have demonstrated strong clinical benefits over previously marketed therapies in terms of response rate and overall survival. Such advances, however, have come at a high cost. Bristol-Myers Squibb caused controversy on the launch of Yervoy by pricing the drug at approximately $120,000 for one course of therapy, while Merck’s recently approved Keytruda commands a monthly premium of approximately $12,500. Such high prices have, in some cases, presented a barrier to market penetration.
Despite the numerous advances within recent years, a recent report published by GBI Research confirmed that the current melanoma pipeline remains strong, diverse, and highly innovative. Over 95% of the 359 pipeline products were verified as novel, and approximately one third were found to be in phase 2 development or higher.4
Further analysis of the pipeline by molecular target revealed a strong presence of products targeting cytokines and antigens, key immune system mediators, demonstrating that manipulation of the immune response continues to be a fundamental therapeutic strategy within melanoma. Indeed, immunotherapies are well represented in late-stage development. One such candidate is seviprotimut-L, a shed-antigen vaccine in phase 3 development. Seviprotimut-L has a strong safety profile and has demonstrated potential in preventing disease recurrence in high-risk patients. As current treatment options for these patients are limited and highly toxic, seviprotimut-L may be able to address an important unmet need for safer therapies in melanoma.
Products targeting protein kinases were also conspicuous among the pipeline. Two such phase 3 candidates are selumetinib and binimetinib, both of which target MEK kinases, key constituents of the MAPK pathway. These products are the first drug candidates to demonstrate significant clinical benefits in patients with advanced uveal melanoma, a form of ocular melanoma, and a mutational subtype of cutaneous melanoma known as NRAS, respectively.5,6
Combination therapies among the pipeline, however, arguably hold the greatest potential for clinical benefits. One example is the BRAF/MEK inhibitor combination therapy Zelboraf/cobimetinib, which is in phase 3 development. The regimen has demonstrated superiority over Zelboraf monotherapy in terms of progression-free survival duration. It also appears to be superior to the Tafinlar/Mekinist combination therapy in terms of response rate and progression-free survival duration, but further clinical data will be required to validate this.7-10
In conclusion, the late-stage melanoma pipeline is strong with promising molecules demonstrating clinical benefits across a diversity of patient subsets. In particular, the pipeline holds potential to improve the treatment of patient subsets that currently have few or no approved therapeutic options available to them, such as uveal melanoma patients and NRAS-positive cutaneous melanoma patients, which reflects an enhanced understanding of melanoma as a heterogeneous disease. The treatment algorithms for melanoma will undergo further modifications in the near future as new competitive agents enter the market, driving the current trend for more specialized treatments for patient subsets.
1. McLaughlin CC, Wu XC, Jemal A, et al. Incidence of noncutaneous melanomas in the U.S. Cancer. 2005;103(5):1000–1007.
2. Mihajlovic M, Vlajkovic S, Jovanovic P, Stefanovic V. Primary mucosal melanomas: a comprehensive review. Inter J Clin Exp Pathol. 2012;5(8):739–753.
3. Whiteman D, Green A. Epidemiology of malignant melanoma. In: Dummer R, Pittelkow MR, Iwatsuki K, eds. Skin Cancer – A World-Wide Perspective. Berlin, Germany: Springer; 2011:13–26.
4. GBI Research. Melanoma Therapeutics in Major Developed Markets to 2020- Rising Prevalence and Evolving Treatment Algorithms to Drive Market Growth.GBIHC345MR. September 2014.
5. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harboring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249–256.
6. Goodwin P. MEK-inhibitor selumetinib called first effective treatment for advanced eye melanoma. Oncology Times. 2013;35(15):31.
7. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–1703.
8. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15(9):954–965.
9. Roche. [press release] Roche presents final phase 1b data on its investigational MEK-BRAF inhibitor combination therapy for metastatic melanoma at EADO 2014. Basel, Switzerland, May 7, 2014.
10. Roche. [press release] Roche’s investigational medicine cobimetinib, used in combination with Zelboraf (vemurafenib), helped people with advanced melanoma live significantly longer without their disease worsening. Basel, Switzerland, July 14, 2014.
Ms Chisholm is an associate analyst for GBI Research, based in the UK. Her research interests include pharmacogenomics, personalized medicine, and drug discovery and development. She holds a BSc in Natural Sciences from Durham University.