Updates in Pharmacotherapy for Melanoma

Angie Amado, PharmD Candidate 2019; Sonia Amin Thomas (Sonia Patel), PharmD, BCOP


US Pharmacist. 2018;43(6):HS2-HS9. 

In This Article


Although both anticytotoxic T lymphocyte–associated protein 4 (CTLA4) (ipilimumab) and anti–PD-1 (nivolumab and pembrolizumab) agents are checkpoint immunotherapies, they are not considered to have the same mechanism of action because they target different molecules. Adjuvant ipilimumab was FDA-approved for a prolonged high-dose regimen: 10 mg/kg every 3 weeks for four doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. For treatment of unresectable or metastatic disease, the recommended ipilimumab dosage is much lower (3 mg/kg) and the treatment duration much shorter (every 3 weeks for a total of four doses), consistent with the dosing regimen in the phase III trials discussed below.[17]

Two phase III trials in patients with unresectable stage III or IV melanoma support the use of ipilimumab for advanced disease.[18,19] Ipilimumab is approved for treatment of unresectable or metastatic melanoma, including treatment-naïve and previously treated disease.[5] However, single-agent ipilimumab monotherapy is no longer an NCCN-recommended first-line option, based on CheckMate-067, which showed improved outcomes with anti–PD-1 monotherapy or nivolumab/ipilimumab combination therapy versus ipilimumab monotherapy.[5] FDA-recommended dosing regimens indicate that, for all three approved regimens containing anti–PD-1 agents, treatment should continue until disease progression or unacceptable toxicity.[20]

Because of a lack of data on long-term anti–PD-1 treatment, the optimal treatment duration is unknown. In the absence of unacceptable toxicity, it is common practice to continue until maximal response is seen. Although there is not a standard definition, maximal response is commonly defined as lack of additional tumor regression on at least two consecutive scans taken at least 12 weeks apart.[5]

Treatment-related AEs occur in a high percentage of patients treated with anti-CTLA4 or anti–PD-1 agents, and grade 3- or 4-related AEs occur in up to 20% of those receiving single-agent therapy and approximately 50% of those receiving ipilimumab monotherapy or nivolumab/ipilimumab combination therapy.[18] As with nivolumab, treatment-related AEs are autoimmune in nature. Close monitoring for potentially lethal immune-related AEs (irAEs) in patients receiving ipilimumab is essential. Ipilimumab is associated with a variety of irAEs, and the frequency and severity of these toxicities increase with increasing doses.[21] The most common AEs are cutaneous toxicities (rash, pruritus, and vitiligo), gastrointestinal toxicities (diarrhea/colitis), and fatigue.[5] The most common high-grade toxicities observed in clinical trials were endocrinopathies (e.g., hypophysitis, hypo- or hyperthyroidism) and hepatitis (e.g., elevated alanine aminotransferase/aspartate aminotransferase).[17] With the exception of endocrinopathies, immune-related AEs resolved when they were managed by withholding ipilimumab and administering corticosteroids.[22]