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

Reference

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.