Phase 2 Study of Nivolumab plus Ipilimumab in Metastatic Uveal Melanoma

Previous studies of single-agent immunotherapy with checkpoint inhibitors (specifically anti–PD-1 agents) have not shown positive response rates in treatment of uveal melanoma.1 These studies on monotherapy with ipilimumab (IPI), tremelimumab, pembrolizumab, and nivolumab (NIVO) showed poor overall survival (OS) of 6.8 months, 12.8 months, 7.6 months, and 7.6 months, respectively.1 Combination therapy with NIVO plus IPI has been studied for the treatment of cutaneous melanoma and showed a higher overall response rate (ORR) than the single agents.

In a phase 2 study of NIVO plus IPI in patients with metastatic uveal melanoma, the investigators hypothesized that dual immunotherapy with checkpoint inhibitors would demonstrate improved clinical outcomes in metastatic uveal melanoma.1

To test this hypothesis, a single-arm, open-label study was performed at a single institution between 2015 and 2018.1 The inclusion criteria for the study were ≥18 years of age, with documented metastatic uveal melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1, and acceptable end-organ function.1 The exclusion criteria included metastatic cancer only in bones, a second primary malignancy within the past 2 years, a history of autoimmune disease, or current therapy with immunotherapies other than those being studied, cytotoxic chemotherapy, immunosuppressive drugs, or chronic systemic corticosteroids other than physiologic replacement doses.1

Patients (N = 35) were administered NIVO 1 mg/kg intravenously (IV) plus IPI 3 mg/kg IV every 3 weeks for 4 doses. Following the initial therapy, treatment was continued with NIVO 3 mg/kg IV every 2 weeks but was changed to 480 mg IV every 4 weeks. This treatment was continued for up to 104 weeks, or until disease progression, toxicity, death, or withdrawal of consent.1 The primary end point was ORR. Progression-free survival (PFS), median OS, and 1-year OS were the secondary end points.1

After a median follow-up of 13.0 months, patients had an ORR of 18% (95% confidence interval [CI], 7.0%-35.5%).1 One patient (3%) had a complete response (CR) and 5 patients (15%) had a partial response (PR).1 Stable disease (SD) was achieved in 33% of the patients; 6 of those patients maintained that response for ≥6 months, and 49% of the patients had disease progression.1 A total of 27 patients had liver metastases; 19% of those had a PR and 11% had SD for ≥6 months. In the other 6 patients who had extrahepatic metastases, 17% had a CR and 50% had SD for ≥6 months.1

There were 2 patients who had received treatment prior to the study with pembrolizumab monotherapy; of these, 1 patient had SD and 1 had disease progression on NIVO plus IPI.1 The patients who responded had a median time to response of 2.7 months. These responders had a median duration of response of 12.1 months with a median treatment duration of 3.9 months.1 For the patients who were responders, the median PFS was 5.5 months (95% CI, 3.4-9.5 months); the median OS was 19.1 months (95% CI, 9.6 months-not reached), and the 1-year OS was 56% (95% CI, 38%-71%).1

There were 29 (83%) patients with a treatment-related adverse event (TRAE). Grade 3/4 TRAEs occurred in 14 (40%) patients. Diarrhea, liver enzyme abnormalities, pruritus, and hypothyroidism were the most common TRAEs of any grade. Adverse events caused 10 patients (29%) to leave the study. There were no treatment-related deaths in the study.1

The researchers concluded that NIVO plus IPI exhibits antitumor activity in metastatic uveal melanoma. This study, combined with the Spanish GEM-1402 study, supports the use of the NIVO plus IPI combination for patients in this setting.1


  1. Pelster MS, Gruschkus SK, Bassett R, et al. Nivolumab and ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study. J Clin Oncol. 2021;39:599-607.

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