Immunotherapies for Melanoma: Worth the Cost?

Although melanoma, an aggressive malignant cancer of melanocytes, represents less than 5% of skin cancers, it accounts for approximately 75% of skin cancer-related deaths, according to the American Cancer Society. Advanced stage melanoma that has metastasized has historically been difficult to treat, with median overall survival times of 8-10 months and a 5-year survival rate of 10%. However, newer immunotherapies have demonstrated the ability to extend survival for this disease. 

Checkpoint Inhibitors

In 2011, the checkpoint inhibitor Yervoy (ipilimumab; Bristol-Myers Squibb) was the first immunotherapy to be approved by the FDA for the treatment of melanoma. Data from 10 prospective and two retrospective studies, including two phase 3 trials, revealed that patients receiving the drug had a median overall survival of 11.4 months; the 3-year survival rate was 22%.

Two other checkpoint inhibitors, Keytruda (pembrolizumab; Merck) and Opdivo (nivolumab; Bristol-Myers Squibb) were approved to treat melanoma in 2014. Ipilimumab targets the T cell protein CTLA-4, whereas pembrolizumab and nivolumab block the T cell protein PD-1.

The results with immunotherapies for melanoma have been impressive. New data presented by Caroline Robert, MD, PhD (Institut Gustave-Roussy, Paris, France) and colleagues at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting showed that 40% of patients were alive three years after starting pembrolizumab, with similar 36-month overall survival rates in both groups. At the American Association for Cancer Research Annual Meeting 2016, F Stephen Hodi, MD (Dana-Farber Cancer Institute, Boston, MA) and coworkers presented findings that nivolumab doubled the 5-year survival rate of patients with melanoma. 

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In 2015, the FDA approved the first therapy combining two of these immunotherapies, ipilimumab and nivolumab, for the treatment of advanced melanoma. The FDA based its approval of the combination treatment on findings from a clinical trial that showed the regimen significantly shrank tumors in 60% of melanoma patients vs 11% of patients receiving ipilimumab alone. Additionally, the regimen reduced the risk of disease progression by nearly 60%. 

Balancing Efficacy with Toxicity and High Costs

Pembrolizumab and nivolumab each have list prices of about $150,000 per year. Bristol-Myers Squibb has priced its ipilimumab and nivolumab combination therapy at $256,000 per year.

All of these treatment options are associated with different adverse events and, in some instances, considerable toxicity. A study presented by Neil T Mason, MD (H Lee Moffitt Cancer Center, Tampa, FL) and colleagues at the ASCO 2016 Annual Meeting used a model to estimate the total cost of treatment with ipilimumab, nivolumab, and pembrolizumab, including the cost of managing toxicities. They showed that all three drugs had similar estimated costs of managing toxicities, with nivolumab estimated to be the most costly. Ipilimumab was estimated to cost the most per patient, driven by the cost of the drug. However, toxicities made up a much larger proportion of the cost of care for nivolumab and pembrolizumab.

In a study published in the American Journal of Managed Care, researchers led by Daniel A Goldstein, MD (Candlewood Women Health Center, Danbury, CT) estimated the monthly cost of different immunotherapies for advanced melanoma (2015;21:S234-S241). Their analysis estimated an average sale price of $44,919.60 per month per patient for ipilimumab (3 mg/kg every 3 weeks); $12,498.76 per month per patient for nivolumab (3 mg/kg every 2 weeks); $47,697.10 per month per patient for nivolumab/ipilimumab (1 mg/kg every 3 weeks of nivolumab plus 3 mg/kg every 3 weeks of ipilimumab); and $991.32 or $74,934.88 per month per patient for pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, respectively).

Another study by Simon A Zeichner, DO (Winship Cancer Institute of Emory University, Atlanta, GA) et al comparing the cost effectiveness of different immunotherapies for melanoma concluded that single-agent nivolumab or pembrolizumab, followed by ipilimumab, are the most cost-effective immunotherapy-based treatment strategies in patients with unresectable stage III or IV melanoma (J Clin Oncol. 2016;34(suppl):abstr 6607).

Other immunotherapies

Aside from checkpoint inhibitors, cytokines, including alpha-interferon (IFN-alpha) and interleukin-2 (IL-2), are another type of immunotherapy that has been approved for the treatment of advanced melanoma. Because generic versions of these treatments are available, they are much less costly than newer immunotherapies. However, these treatments are associated with lower response rates as well as a number of serious toxicities.

The oncolytic virus Imlygic (talimogene laherparepvec; Amgen), also known as T-VEC, is approved by the FDA to treat melanomas in the skin or lymph nodes that cannot be removed with surgery. The virus is injected directly into the tumors, typically every 2 weeks. This treatment can sometimes shrink these tumors, but it has not been shown to shrink tumors in other parts of the body. It is also not clear whether this treatment extends survival. Side effects can include flu-like symptoms and pain at the injection site. The makers of T-VEC have estimated the treatment will cost on average $65,000.