New Prescribing Options in Metastatic Melanoma | Page 1
Published Online: October 11, 2013
John A. Thompson, MD
Melanoma is currently the fifth-most common cancer diagnosis; however, the incidence of melanoma is increasing faster than that of any other form of cancer.1,2 The rate of invasive melanoma in the United States is increasing by 4% to 6% every year, with a 1 in 30 lifetime risk of developing either invasive or in situ melanoma in 2010.1 Surgical therapy for early-stage melanoma often yields long-term disease-free survival, but the prognosis is poor for patients with more advanced disease.
Until recently, there were few effective treatment options for patients diagnosed with unresectable stage III or IV melanoma.3 Dacarbazine was the only chemotherapy approved for treatment of metastatic melanoma, despite low overall response rates,4 while interleukin-2 (IL-2) was the only biologic therapy approved in this setting. Other chemotherapy agents including temozolomide, cisplatin, carboplatin, fotemustine, vindesine, and vinblastine have been evaluated as monotherapy or in association with IL-2 and/or interferon. These evaluations have not significantly improved upon overall survival (OS) or progression-free survival (PFS) associated with dacarbazine.5-8 The utility of high-dose IL-2 is limited by toxicity concerns, reliance on specialized treatment centers, and lack of proven impact on long-term survival.4,9
Advancements in understanding of the molecular pathways involved in the establishment and progression of melanoma have led to the development and recent approval of 2 new therapies with novel mechanisms of action for the treatment of melanoma. Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), was approved by the US Food and Drug Administration (FDA) in March 2011 for the treatment of patients with unresectable or metastatic melanoma; patients treated with this agent had improved OS compared with controls in 2 phase 3 trials of treatment-naive and previously treated patients with metastatic melanoma.10-12 Vemurafenib, a small-molecule BRAF inhibitor, was approved in August 2011 by the FDA for patients with metastatic melanoma and documented V600E mutation in BRAF.13 Ipilimumab and vemurafenib are recommended in the current National Comprehensive Cancer Network guidelines for consideration in appropriate patients as per the approved indication for each agent.14
CLINICAL DEVELOPMENT OF IPILIMUMAB
Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4, an important component of immune signaling.4 CTLA-4 is upregulated by T cells following activation via antigen-specific stimulation and functions to downregulate the antigen-specific T-cell response. Ipilimumab, through blockade of the inhibitory CTLA-4 pathway, augments antitumor T-cell responses (Figure 1).
The efficacy and safety of ipilimumab monotherapy have been demonstrated in several phase 2 and 3 studies conducted in patients with unresectable stage III or stage IV disease (Table 113-17). In the first phase 2 study, patients with previously treated melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 cycles followed by maintenance therapy (every 3 months). A best overall response rate (BORR) of 5.8% was achieved, with a median OS of 10.2 months (7.6-16.3 months). Adverse events (AEs) were most frequently attributable to the agent’s immunebased mechanism of action and thus were termed immune-related AEs (irAEs). The most common irAEs were in the skin and gastrointestinal (GI) tract, with 19% grade 3 and 3.2% grade 4. The incidence of grade 3/4 irAEs was skin, 3.2%; GI, 8.4%; liver, 7.1%; and endocrine, 1.3%. Treatment was discontinued due to drug-related AEs in 18.1% of patients.18 In a second phase 2 study, 217 patients with previously treated melanoma were randomized to receive ipilimumab 10 mg/kg (n = 73), 3 mg/kg (n = 72), or 0.3 mg/kg (n = 72) induction and maintenance therapy. The BORR was 11.1% for 10 mg/kg, 4.2% for 3 mg/kg, and 0% for 0.3 mg/kg. Again, the most common grade 3 to 4 adverse events were GI irAEs, occurring in 15% and 3% of patients who received 10 mg/kg and 3 mg/kg ipilimumab, respectively. Adverse events leading to treatment discontinuation occurred in 15%, 7%, and 3% of patients receiving 10 mg/kg, 3 mg/kg, or 0.3 mg/kg ipilimumab, respectively.19
A third phase 2 study evaluated whether addition of budesonide to ipilimumab would decrease the incidence of immune-related diarrhea. Previously treated and treatment-naïve patients with melanoma received ipilimumab at 10 mg/kg with budesonide (n = 58) or placebo (n = 57). Addition of budesonide did not affect the rate of grade >2 diarrhea. The BORR was 12.1% for ipilimumab and budesonide and 15.8% for ipilimumab and placebo, with a median OS of 17.7 and 19.3 months, respectively.15
Other phase 2 studies evaluated ipilimumab with or without gp100 vaccine, according to HLA-A*0201 status.16,17 The first study included previously treated and treatment-naïve metastatic melanoma patients (n = 139) and achieved a BORR of 17% and median PFS and OS of 2.9 and 15.7 months, respectively.16 The second study also included previously treated and treatment-naïve metastatic melanoma patients (n = 56) and achieved a BORR of 13%.17 Of note, response times exceeded 50 months for some patients achieving a partial response, and in patients achieving a complete response, some responseslasted more than 53 months.16 Results from phase 2 studies led to evaluation of ipilimumab safety and efficacy in phase 3 studies.
PHASE 3 REGISTRATION TRIALS
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