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Supplements The Role of Immuno-Oncology in the Treatment of Advanced Melanoma

Current Landscape of Immuno-Oncology in Advanced Melanoma

Epidemiology of Advanced Melanoma

Melanoma is the most lethal type of skin cancer.1 In 2017, approximately 87,110 new cases of melanoma will be diagnosed and approximately 9730 deaths will occur due to the disease.2 Compared with individuals younger than 50 years, individuals 50 years and older consistently experience higher rates of melanoma. Incidence in this age group increased up to 3% each year from 2003 to 2014.2 Melanoma is more likely to spread than other skin cancers and, if caught after metastasis, is difficult to treat.1,2 The 5-year survival rate for patients with metastatic melanoma is 18%.2

Economic Burden of Advanced Melanoma

The financial burden of treating metastatic melanoma weighs heavily on patients and the healthcare system, and with each progressive stage of melanoma, treatment costs increase.1,3 Recently, a retrospective, longitudinal, open-cohort study in patients with metastatic melanoma (N = 834) measured the total all-cause per-patient-per-month (PPPM) direct healthcare costs and utilization for traditional and newer therapies.1 Study treatments included ipilimumab (n = 265), vemurafenib (n = 234), interleukin-2 (IL-2; n = 104), dacarbazine monotherapy (n = 24), dacarbazine combination therapy (n = 22), paclitaxel monotherapy (n = 44), paclitaxel combination therapy (n = 130), and temozolomide (n = 11).1 Average PPPM costs for the ipilimumab cohort were the highest at $35,472, followed by IL-2 ($34,850) and vemurafenib ($17,793). Temozolomide was the least costly ($10,879).1

Newer therapies in this study were more expensive. Ipilimumab and vemurafenib, approved in 2011, were the primary therapies for 60% of patients, and although the adjusted PPPM total costs were $18,337 higher with ipilimumab, this was mainly due to the expense of its administration in the outpatient setting. There were no significant differences observed in resource utilization (hospitalizations and emergency department visits) between ipilimumab and vemurafenib.1

Considerable toxicity associated with current treatments for metastatic melanoma may lead to higher healthcare resource utilization and related expenditures. A study reviewing the cost of managing grade 3 or 4 treatment-related adverse events (AEs) reported with FDA-approved or National Comprehensive Cancer Network–recommended monotherapies in patients with metastatic melanoma (N = 2998) found that serious AEs led to costly inpatient and outpatient procedures. The agents reviewed were dabrafenib, dacarbazine, IL-2, ipilimumab, temozolomide, trametinib, vemurafenib, and talimogene laherparepvec (T-VEC).4 Investigators performed a literature search to determine the most common grade 3 or 4 AEs with each drug, then interviewed oncologists specializing in melanoma to assess their treatment approaches for these AEs.4

In the outpatient setting, the most expensive treatment-related AEs were neutropenia, headache, peripheral neuropathy, cutaneous squamous cell carcinoma, and dyspnea. Treatment for neutropenia was the most » expensive, at $2088 per incident, and dyspnea was the least expensive, at $277.4 In the inpatient setting, the most expensive treatment-related AEs were acute myocardial infarction (MI), sepsis, acidosis, acute kidney failure, pneumonitis, neuropathy, thrombocytopenia, and oliguria/anuria. Hospitalization for acute MI was the most expensive, at an average of $47,069 per event. The lowest average inpatient costs were seen with nausea, at $14,043 per event.4

Although this study was conducted before the FDA approval of pembrolizumab and nivolumab, the investigators determined that the list of toxicities would not change if these agents were included and that the estimated costs would remain the same.4 In addition, costs for outpatient treatment were based on Medicare reimbursements, which are typically lower than payments from commercial health insurance plans, potentially underestimating the financial burden of managing these AEs.4

In another retrospective cohort study in patients with metastatic melanoma (N = 2621), incremental costs, defined as the differences in 30-day costs, linked to specific treatment-related AEs were also considerably high.5 This study evaluated patients receiving vemurafenib (n = 119), ipilimumab (n = 152), dacarbazine (n = 254), temozolomide (n = 847), high-dose IL-2 (n = 227), paclitaxel (n = 153), and interferon-α (n = 869).5 AEs were identified using each therapy’s package insert and consultation with a clinical expert and were grouped into 8 categories: cardiovascular, central nervous system and psychiatric, gastrointestinal (GI), hematologic and lymphatic, metabolic and nutritional, pain, skin and subcutaneous tissue, and other.5 Healthcare costs comprised the total amount paid to all providers for inpatient and outpatient services minus the cost of study drugs and other cancer therapies.5 Compared with patients who did not experience these AEs, adjusted costs were highest for “metabolic and nutritional disorders” ($7800 vs $16,936, respectively) and “hematologic and lymphatic disorders” ($7715 vs $16,165, respectively).5 To decrease the financial burden of new and existing treatments for metastatic melanoma, the prevention of these AEs may be important.4,5

Quality of Life

Regardless of stage, melanoma has significant impact on quality of life (QoL), and efficacy of therapy is an important factor in establishing healthcare priorities.6 Patients typically experience the lowest QoL upon receiving a diagnosis of melanoma, reporting higher levels of physical and emotional stress, lower levels of energy, and more pain, which affect social interactions. About one-third of patients with melanoma report significant levels of distress.7 Owing to the poor prognosis of metastatic melanoma, there is a lack of cost-benefit ratio information when comparing available treatment regimens.8 While new agents improve survival, they are also associated with new toxicities.7 Increasingly, studies are including health-related QoL assessments as part of their design.7

A pilot study was conducted in which patients with melanoma (N = 163) were asked to estimate the impact of the disease at stages other than their own.6 Investigators assessed the face validity of melanoma utilities (ie, trade-off of money, time, or risk of death to not have the disease), which decreased significantly with each subsequent stage.6 Patients with stage I melanoma reported higher QoL and overestimated the impact of a later-stage diagnosis, while patients with stage II and IV disease reported lower QoL and underestimated the impact of a stage I diagnosis.

Early diagnosis and treatment of melanoma, and remission status, result in better QoL. After 2 years of follow-up, patients who have undergone treatment for stage 0 to II melanoma have a health-related QoL similar to the general population.3,9 Patients with advanced melanoma whose disease is in remission report similar health-related QoL.9

Mutational Burden

The majority of patients with metastatic melanoma develop mutations in their disease that complicate treatment. Approximately 50% have BRAF-mutated disease. Other common mutations include the NRAS subtype (28%), NF1 subtype (14%), and KIT subtype (3%).10-12 The presence of a BRAF V600 mutation is key in guiding treatment decisions. The V600E mutation accounts for 74% to 86% of all BRAF mutations, while V600K mutations can occur in 10% to 30% of cases. The latter are mostly found in patients older than 65 years or in those with confirmation of prolonged UV exposure. Adequate data obtained with the BRAF inhibitors vemurafenib and dabrafenib warranted inclusion of the V600K mutation subpopulation in the regulatory approvals of both of these agents.13 FDA-approved targeted therapies for mutated melanomas currently exist only for those with BRAF mutations.13

NRAS-mutated melanomas are more commonly diagnosed in older patients and on sun-damaged skin and are typically located on the extremities. These mutations rarely co-occur with BRAF mutations.14 Several mechanisms of NRAS-targeted treatment have been tested in preclinical studies with little effect. Targeting the mitogen-activated ERK kinase (MEK) 1/2 pathway is the most developed approach, with second- and third-generation MEK inhibitors in phase 2 and 3 clinical trials.14

NF1 is another important mutation in melanoma and is found more often in older patients and patients with chronic sun exposure. These mutations result in increased RAS/mitogen-activated protein kinase (MAPK) pathway signaling, and preclinical evidence supports treatment with agents that target this pathway (eg, MEK inhibitors).15

KIT mutations occur in only 3% of melanomas, most commonly in acral and mucosal melanomas.12 KIT is a receptor tyrosine kinase that plays a role in melanocyte growth and can be mutated or amplified.12 It is difficult to assess because common markers in mutated KIT are easily missed when testing for hotspot mutations. Thorough testing involves complete sequencing of relevant exons, which creates challenges in identifying which patients should be screened.12 Case reports and phase 2 studies in patients with KIT-mutated melanoma have described responses to tyrosine kinase inhibitors, such as imatinib, sunitinib, and nilotinib.12

Targeted Therapies

Although dacarbazine was approved for metastatic melanoma in 1975, innovations in therapy over the next 30 years were limited to chemotherapies and IL-2.1 Recently, however, several new therapies have been approved, capitalizing on decades of research into the genomics of cancer and new understandings of the immune response.13

BRAF Inhibition

The treatment paradigm for melanoma with BRAF mutations has evolved.13 Single-agent, small-molecule BRAF inhibition has been enhanced by combination therapy with a MEK inhibitor.13

Vemurafenib, a first-in-class selective inhibitor of V600-mutant BRAF, was studied in a multinational randomized phase 3 trial in treatment-naïve patients with unresectable stage III or IV melanoma with BRAF V600E mutations.

Patients received either vemurafenib (n = 337) or dacarbazine (n = 338).16 Vemurafenib demonstrated an overall response rate of 48% compared with 5% for dacarbazine and progression-free survival (PFS) of 5.3 versus 1.6 months, respectively (hazard ratio [HR], 0.26; 95% CI, 0.20-0.33; P <.001).

The most common AEs with vemurafenib were cutaneous events, joint pain, and fatigue, and for dacarbazine, fatigue, nausea, vomiting, and neutropenia. AEs leading to dose interruption or adjustment occurred in 38% of patients receiving vemurafenib and 16% of patients receiving dacarbazine.13,16

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