Literature Review: Melanoma

Evidence-Based Oncology, January/February, Volume 19, Issue SP1

The Economic Value of Ipilimumab as a Second-Line Treatment in Patients With Advanced Melanoma

In early 2011, ipilimumab, an anti-CTLA- 4 monoclonal antibody with antitumor activity, was approved by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma. Ipilimumab was compared with the gp100 vaccine in a clinical trial and patients survived a median of 3.7 months longer than those receiving the vaccine. In another trial, ipilimumab with dacarbazine was compared with dacarbazine in previously untreated patients with advanced melanoma. The investigators found that combination therapy yielded higher survivals at 1, 2, and 3 years.

Ipilimumab is an expensive treatment that is associated with positive clinical outcomes. Researchers from the United States and United Kingdom (and from Bristol-Myers Squibb, the manufacturer of ipilimumab) sought to evaluate the cost-effectiveness of ipilimumab compared with best supportive care in previously treated patients with advanced (unresectable or metastatic) melanoma.

Progression-free and overall survival data were used from a phase III trial of ipilimumab to model stable disease, progression, and death. Clinical outcomes, quality of life, and healthcare utilization were included in the analyses. The Markov model considered only the direct costs in patients with an average age of 55 years having advanced melanoma. A discount rate of 3% was utilized for both costs and outcomes.


Because no previous clinical trial with another therapy demonstrated a prolongation of survival, best supportive care was defined as disease management without active chemotherapy. The researchers acknowledged that this may provide a conservative cost benefit for ipilimumab, as most patients usually receive some type of chemotherapy that increases treatment costs of advanced melanoma. Both the incremental costeffectiveness ratio (ICER) and incremental cost utility ratio (ICUR) were estimated in the model. They included direct costs associated with pharmaceuticals, clinical management, and costs associated with toxicity-related events ().

The model used ipilimumab clinical data from a trial comparing the agent with gp100, dacarbazine, interleukin-2, and temozolomide. Ipilimumab demonstrated benefits in both progressionfree survival and overall survival.

Those in the ipilimumab group demonstrated a mean gain of 1.88 life-years and 1.14 quality-adjusted life-years (QALYs) compared with patients receiving basic supportive care. The drug costs were higher in the ipilimumab group. They estimated the incremental cost-effectiveness ratios to be $78,000 per life-year gained and $129,000 for the incremental cost per QALY gained.

Based on their sensitivity analysis, and assuming a willingness-to-pay threshold of $113,000 per QALY, the researchers estimated a 6% chance that ipilimumab would be considered costeffective. However, if the threshold were raised to $146,000/QALY, ipilimumab would be considered cost-effective in better than 95% of the scenarios.

The investigators explained that the differences between the ICER and ICUR were expected, owing to the definitions utilized for disease progression from stable disease to progressive disease in the model. Using the costs of alternative therapies that have no shown benefit in survival would increase the cost-effectiveness of ipilimumab, as this therapy has been proved to improve survival.

Source: Barzey V, Atkins MB, Garrison LP, et al. Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis. J Med Econ. 2013;16(2):202-212.

Combined BRAF and MEK Inhibition in Melanoma Improves Cytogenic Response

Vemurafenib is a valuable treatment in patients with advanced melanoma who have the BRAF V600E mutation. However, roughly half of patients treated with vemurafenib have progression-free survivals of about 7 months before melanoma activity recurs. An international group of researchers from multiple centers sought to determine if a combination of investigational BRAF and MEK inhibitors might produce a more durable response.

This investigation was part of a larger study that determined the pharmacokinetic activity, clinical activity, and safety of oral dabrafenib (a BRAF inhibitor) and trametinib (an MEK or MAPKkinase inhibitor). The trial of interest was an open-label, randomized, phase II trial that included 162 patients with advanced melanoma who were therapy- naïve or received no more than 1 chemotherapy regimen (excluding any prior treatment with BRAF or MEK inhibitors).

The patients were randomly assigned treatment with either 150 mg dabrafenib bid monotherapy (54 patients; median age, 50 years) or 150 mg dabrafenib bid plus 1 daily dose of trametinib 1 mg (combination 150/1 therapy) (54 patients; median age, 49 years) or 2 mg (combination 150/2 therapy) (54 patients; median age, 58 years). Each of the 3 study groups in this phase had similar poor prognostic attributes including brain metastases, M1c disease, and high lactate dehydrogenase levels. The frequency of cutaneous squamous-cell carcinoma (including keratoacanthoma) was 19% for the dabrafenib monotherapy group, 2% for the combination 150/1, and 7% for the combination 150/2 group (P = .004 and P = .09, respectively).


The median follow-up time was 14.1 months (range, 10.8-17.6 mo) at the time of the planned efficacy analysis. The researchers calculated progression- free survivals (PFSs) of 9.4 months for the combination 150/2 patients, 9.2 months for the combination 150/1 patients, and 5.8 months for monotherapy patients. An independent review committee assigned a hazard ratio for progression or death of 0.55 (95% confidence interval, 0.33 to 0.93; P = .02) for those receiving the 150/2 combination ().

After 12 months, 41% of patients in the 150/2 group were still experiencing PFS compared with only 9% of monotherapy patients (P <.001). When investigators stratified patients according to BRAF V600E mutation or V600K mutation, they did not find any difference in outcome.

Seventy-six percent of the patients in the combination 150/2 group experienced a complete or partial response compared with 54% in the monotherapy group (54%; P = .03). The median overall survival rate, acknowledged the authors, could not be analyzed, because it had not yet been reached.

At 1 year, 79% of the patients in the 150/2 group and 70% in the monotherapy group were alive. When the disease progressed in patients currently receiving monotherapy with the BRAF inhibitor, 80% crossed over to the 150/2 combination therapy group.

The side effect of rash was higher in the monotherapy group (36%) versus the combination 150/1 and 150/2 populations (20% and 27%, respectively). However, the combination groups had a more widespread MEK-inhibitorassociated acneiform dermatitis than the monotherapy subjects (11% for 150/1, 16% for 150/2, 4% for monotherapy treatments).

Adverse events that were seen more frequently in the combination 150/2 group were pyrexia (all grades, 71%) and chills (all grades, 58%). In addition, other adverse events that occurred more frequently in the combination 150/2 group than in the monotherapy patients were fatigue (53% of patients), nausea (44%), vomiting (40%), and diarrhea (36%).

The investigators conclude that this combination of BRAF-MEK inhibitors is at least partly successful in mitigating the resistance in advanced melanoma to BRAF inhibition alone that occurs over time. Dabrafenib and trametinib given to patients at their full singleagent doses proved to be safe and effective when combined, the clinicians stated. This trial, they concluded, supports the effectiveness of using a combination regimen of BRAF-MEK inhibitors for treating patients with advanced melanoma.

Source: Flaherty KT, Infante JR, Daud D, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694-1703.

The Effect of Ipilimumab on Health-Related Quality of Life in Patients With Unresectable Advanced Melanoma

Patients diagnosed with melanoma are typically affected psychologically. Treatment usually causes impaired physical functioning and fatigue. Researchers summarized health-related quality of life (HRQOL) during the 12-week ipilimumab induction period in previously treated patients diagnosed with advanced stage III or IV melanoma.

Patients in the study were randomized to receive 1 of 3 treatments: ipilimumab plus gp100 vaccine, gp100 vaccine plus placebo, or ipilimumab plus placebo. The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORT QLQ-C30) was utilized to assess HRQOL. This tool entails global health status, and physical, emotional, role, cognitive, and social functioning. Higher scores are indicative of better functioning. Differences in scores were subgrouped into 4 categories (eg, “no change” [0-5 points], “a little” [5- 10 points], “moderate” [10-20 points], and “very much” [>20 points]). A score differential of 0 to 10 points was interpreted as no or minimal impact on patient HRQOL.

The researchers reported that after 12 weeks, most patients reported that changes to HRQOL outcomes were no greater than minimal. The only statistically significant difference in score was for constipation, in a comparison of the ipilimumab plus gp100 and the gp100 alone groups. Scoring indicating “moderate” function and global health status score were role function in the ipilimumab alone group and role function and global health in the gp100 group. Symptom scoring rating a “moderate” were fatigue in the ipilimumab plus gp100 group; fatigue, sleep disturbances, and appetite loss in the ipilimumab alone group; and fatigue, pain, sleep disturbances, appetite loss, and constipation in the gp100 alone group.

Patients older than 65 years tended to have more “moderate” changes in health status than the patients younger than 65 years. The greatest differences, albeit moderate, were observed for role function, social function, global health, dyspnea, sleep disturbance, appetite loss, and diarrhea. It is difficult to fully appreciate the importance of the findings owing to the small sample size of the >65 years group, as the mean age was 55.6 years to 57.4 years across all of the study groups.

Treatment within all 3 treatment groups resulted in minimal changes in HRQOL. Therefore, the authors conclude that HRQOL changes should not be a concern for those patients with advanced melanoma and their physicians considering ipilimumab treatment.

Source: Revicki DA, van den Ertwegh AJM, Lorigan P, et al. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012;10:66.

Is Daily Sunscreen Use Cost-Effective for Preventing Skin Cancer?

Exposure to ultraviolet radiation is an important risk factor for the development of skin cancers. A major study previously demonstrated the benefit of sunscreen as an effective strategy, both clinically and economically, for reducing the burden of squamous-cell carcinoma. However, the study did not investigate the long-term benefit of using sunscreen to prevent melanoma, the least prevalent but more often fatal skin cancer.

To evaluate the economic effects of sunscreen use to prevent melanoma, investigators evaluated data from the Nambour Skin Cancer Prevention Trial conducted in Queensland, Australia, from 1992 to 2006. In this trial, the intervention group was encouraged to apply daily a sunscreen with an SPF rating of at least 15, which was provided free of charge at designated study clinics. The study group was instructed to apply the sunscreen daily to their head, neck, arms, and hands, and the control group was instructed to apply sunscreen at their discretion. The decision model tracked multiple cohorts to examine the health and cost outcomes of participants with different profiles. Key measures included time since diagnosis, costs, number of melanomas, QALYs, and life-years lived.

All participants were melanoma free at the start of the data collection period. Individuals who developed melanoma and were diagnosed and treated were characterized further by whether they remained in remission, had a recurrence, were diagnosed with additional tumors or distant metastases, or died, as well as by an age-specific all-cause mortality risk.

Health outcomes in the model included QALYs, counts of melanomas and squamous-cell carcinoma, and melanoma-related deaths. Resources and costs included both those of government health providers (monitoring participants, cost of sunscreen, diagnosis, treating, and following suspicious skin lesions) and household members (time and out-of-pocket costs for applying sunscreen, attending clinic visits, and a discounted lifetime cost following a diagnosis of melanoma. The cost of melanoma was taken from a previous study and inflated to 2010 prices.

According to the investigators, the data analysis showed that daily sunscreen use was significantly associated with prevention of invasive melanoma. Self-reported time spent outdoors, time in the shade, and wearing a hat were not significant predictors of melanoma occurrence between the daily and discretionary users of sunscreen.

The ICER was calculated based on a willingness-to-pay threshold of AU$50,000 (approximately US$52,000) per QALY gained.

A discounted incremental cost per QALY gained from daily use of sunscreen was AU$42,600 for melanoma. If squamous-cell carcinoma was also included, the ICER per QALY was lower, at AU$40,900. The model showed that the use of daily sunscreen would prevent 168 squamous-cell carcinomas, 33 melanomas, and 4 melanoma-related deaths at an additional cost of AU$808,000 to society in population with an average age of 49 years. Additional or fewer cases would be dependent upon the age when daily sunscreen is initiated.

The researchers found that daily sunscreen use was cost-effective for individuals aged between 38 and 64 years. The likelihood that daily sunscreen use is cost-effective for melanoma was 64%.

Promoting frequent sunscreen use is likely to be cost-effective for preventing melanomas and squamous-cell carcinomas. The effect on basal-cell carcinomas and the known protective effect of sunscreen use on actinic keratosis was not included; thus, the cost-effectiveness is most likely underestimated. This analysis supports that not only is sunscreen use effective and safe, it is also cost-effective.

Source: Hirst NG, Gordon LG, Scuffham PA, et al. Lifetime cost-effectiveness of skin cancer prevention through promotion of daily sunscreen use. Value in Health. 2012;15:261-268.

Payer PerspectiveBasing Coverage Decisions on Weak Comparators in Advanced MelanomaJames T. Kenney, RPh, MBA

Payers have become intensely interested in managing oncology drugs over the past few years, and health plans have increasingly deployed utilization management techniques in an attempt to control the drug spend in this growing market. Over 900 compounds are in some phase of clinical development for the treatment of cancer,1 representing a significant future clinical and budgetary impact on pharmacy programs.

The prevalence of advanced melanoma is increasing among the general population; however, it still represents a small proportion of the overall health plan patient population.2 With a 5-year survival of only 15.2%, there is significant room for improvement in treating metastatic melanoma.2,3

Traditional treatments for metastatic melanoma have not been found through clinical trial data to be particularly effective in improving overall survival (OS). One of the products more recently approved for the treatment of metastatic melanoma (in 2011), ipilimumab, has been found to improve OS in a pivotal clinical trial using an unapproved vaccine as a comparator. Health plans prefer an approved comparator to evaluate the potential benefits of a new compound. Even with this caveat, the lack of strong evidence to support older treatments increases the likelihood that ipilimumab will be granted coverage status, with limited but reasonable restrictions focused on its targeted mechanism of action.

This is not an unusual situation. Health plans typically cover pharmaceuticals for cancer with limited restrictions under the pharmacy or medical benefit, based on the lack of clinical data to support alternative treatments. The ability to manage cancer treatments is driven by the opportunity to trade off therapies with established guidelines or comparative clinical data. If the health plan’s clinical team can offer specific and credible alternative drugs for a specific cancer, then the cost of the product and the total treatment costs will be considered as part of the coverage decision.

Most health plans do not use QALYs or ICERs to make formulary decisions. The formulary process primarily focuses on the core clinical parameters from the pivotal clinical trials, including OS, progression-free survival (PFS), and overall response rate (ORR). However, the cost-effectiveness analysis of ipilimumab by Barzey and colleagues4 presents an interesting case for coverage based on the cost per QALY and ICER, using best supportive care as the comparator. The modeling focused on direct costs, including severe adverse events that can significantly affect costs, and incorporated the OS and PFS data. The results suggest the effectiveness of ipilimumab in patients compared with best supportive care to be 99%.

A cost per QALY in excess of $100,000 will not resonate with health plans, owing to the relatively short time horizon for the clinical benefit of the product (just shy of 2 years).

As additional agents are approved by the FDA, payers will have better comparators for the evaluation of OS, PFS, or ORR in advanced melanoma and be ready for any opportunity to promote utilization management tools in support of guidelines and the most costeffective care pathway.

Because virtually all cancer agents are approved for coverage by health plans, with varying tools to encourage appropriate use, the willingness-to-pay discussion by Barzey et al4 does not typically occur at the health plan level. The finding of a durable benefit in 20%4 of the patients will support the argument to provide access to the medication, and plans will not be overly restrictive, despite the lack of reasonable clinical comparators. The long-term survival benefit supports reasonable access for the product while plans monitor future drug approvals that may better target and treat metastatic melanoma.

Health plans will continue to evaluate new agents and strive to promote the most costeffective options supported by solid clinical evidence. Although the analysis yields results in the range that is perceived to be acceptable to payers, most payers do not use these data in support of formulary decisions. At the end of the day, a new agent that demonstrates an OS benefit in metastatic melanoma will be covered by most plans.

Mr Kenney is pharmacy operations manager at Harvard Pilgrim Health Care in Wellesley, MA.


1. Medicines in Development: Cancer. Pharmaceutical Research and Manufacturing Association 2012. Accessed December 18, 2012.

2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010 [published correction appears in CA Cancer J Clin. 2011;61(2):133-134]. CA Cancer J Clin. 2010;60(5):277-300.

3. Surveillance, Epidemiology and End Results (SEER) Stat Fact Sheets: Melanoma of the Skin. National Cancer Institute website. Published 2012. Accessed December 19, 2012.

4. Barzey V, Atkins MB, Garrison LP, Asukai Y, Kotapati S, Penrod JR. Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis [published online October 31, 2012]. J Med Econ. 2013;16(2)202-212.