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

Ipilimumab/Nivolumab Combination Therapy

Two randomized trials demonstrated that combination therapy with ipilimumab and nivolumab significantly improved response and PFS compared with ipilimumab monotherapy in patients with previously untreated unresectable stage III or IV disease.[14,22] Further follow-up is needed to determine whether nivolumab/ipilimumab combination therapy improves OS compared with single-agent ipilimumab. In patients with BRAF-mutant tumors, however, subgroup analyses in CheckMate-067 and -069 showed improved efficacy with nivolumab/ipilimumab combination therapy versus ipilimumab monotherapy regardless of BRAF-mutation status.[14] Both trials also showed substantially increased toxicity with immune checkpoint combination therapy versus monotherapy.

Based on these results, the FDA-recommended dosing regimen for nivolumab/ipilimumab combination therapy is nivolumab 1 mg/kg followed by same-day ipilimumab 3 mg/kg, every 3 weeks for four doses, and then single-agent nivolumab 3 mg/kg every 2 weeks until disease progression or toxicity.[17,23] Safety results from randomized phase II and III trials showed that combination therapy with nivolumab and ipilimumab was associated with higher rates of toxicity compared with single-agent ipilimumab or nivolumab.[14,20] Ipilimumab/nivolumab combination therapy also demonstrated an increase in total number of patients with treatment-related AEs of any grade and notably increased the occurrence of grade 3 or 4 AEs and AEs leading to treatment discontinuation (36 vs. 8; 15%).[20] Of all toxicities commonly observed with immune checkpoint inhibitors, grade 3 and 4 AEs occurred more frequently with combination therapy than with either monotherapy. Many high-grade or refractory irAEs have been successfully managed with high-dose oral or IV corticosteroids, and immunosuppressants have been beneficial in some particularly challenging cases of gastrointestinal and hepatic irAEs.[24]

Although the nivolumab/ipilimumab combination regimen is an NCCN first-line recommendation (category 1), selection of anti–PD-1 monotherapy or nivolumab/ipilimumab combination therapy should be made based on the consideration that although the combination provides somewhat better PFS, it is associated with a much higher risk of serious immune-mediated toxicities.