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Evidence-Based Oncology January/February

Literature Review: Melanoma

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 (Table).

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 (Figure).

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.

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