Phase 2 Trial of Nivolumab plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: Spanish Multidisciplinary Melanoma Group (GEM-1402)

Previous studies have shown that single checkpoint inhibitors were not successful in the treatment of patients with metastatic uveal melanoma (MUM). However, the combination of nivolumab (NIVO) plus ipilimumab (IPI) has demonstrated efficacy in metastatic cutaneous melanoma, particularly in tumors with low PD-L1 expression.1 Based on that success, the Spanish Multidisciplinary Melanoma Group performed the GEM-1402 study to investigate the efficacy of NIVO plus IPI in first-line treatment for MUM, specifically looking at 12-month overall survival (OS) in patients with MUM who were not eligible for liver resection.1

This was a phase 2 multicenter study conducted from 2016 to 2017 at 10 centers in Spain with a database lock of July 2019. The patients had Eastern Cooperative Oncology Group performance status ≤1 with treatment-naïve, histologically confirmed, progressive systemic MUM.1 The treatment in the study was NIVO intravenously (IV) 1 mg/kg plus IPI IV 3 mg/kg every 3 weeks for 4 doses. Patients then received NIVO IV 3 mg/kg every 2 weeks. This dosing was continued until there was clinical or objective disease progression (PD), unacceptable toxicity, or patient withdrawal from the study.1 Response to therapy was measured with computed tomography or magnetic resonance imaging every 6 weeks for 12 months, and then once every 12 weeks until discontinuation of treatment or PD, whichever was later.1

The primary end point of the study was 12-month OS, and secondary end points were investigator-assessed response rate and safety.1 Liver toxicity was especially followed, in addition to treatment-related adverse events (TRAEs) and other adverse events.1

Objective response was seen in 6 of the 52 patients (11.5%; 95% confidence interval [CI], 2.9-20.2) with 1 complete response and 5 partial responses, all occurring in the first 9 months of treatment and continued for 15.6 months (95% CI, 1.6-33.8). The most common outcome was stable disease in 51.9% of patients (95% CI, 38.3-65.5) that was maintained for a median of 3.8 months (95% CI, 0.1-21.5). The disease control rate was 63.5% (95% CI, 50.4-76.5).1

Median OS was 12.7 months (95% CI, 7.1-18.3); the 12- and 24-month OS rates were 51.9% (95% CI, 38.3-65.5) and 26.4% (95% CI, 14.2-38.6), respectively.1 Median progression-free survival (PFS) was 3.0 months (95% CI, 2.0-4.1), and 28.8% of all patients were progression-free at 6 months (95% CI, 16.5-41.1) and 19.2% were progression-free at 12 months (95% CI, 8.5-29.9).1

Radiologically significant growth of the patients’ target lesions was seen in 80.8% (95% CI, 70.1-91.5) of patients with PD.1

Of the 38 patients who had died by the time of the database lock, 32 were due to PD, 2 due to TRAEs, and 4 due to other causes.

Cytokine analysis was performed, with a possible association found for OS with expression of interleukin (IL)-1b (P = .022), IL-2 (P = .083), IL-6 (P = .027), IL-8 (P = .05), and vascular endothelial growth factor-A (P = .023), but the finding was not conclusive when the factors were all assessed together.1 DNA analysis was also performed on 41 of the baseline tumor samples. No significant differences were detected for association of mutations in GNAQ, GNA11, SF3B1, or chromosomal alterations with ORR, OS, or PFS.1

TRAEs were observed in 49 of 52 patients (94%), including skin-related events (61.5%), fatigue (57.7%), liver-related events (36.5%), and diarrhea (28.8%). Grade 3 TRAEs occurred in 30 (57.7%) patients. There were 56 serious adverse events; the most frequent serious TRAEs were fever (4), liver-related events (3), and diarrhea (3). There was 1 death with thyroiditis and 1 with Guillain-Barré syndrome that were thought to be treatment-related. Other thyroid-associated serious TRAEs included 1 patient with thyroiditis who recovered, 1 with hypothyroidism, and 1 with hyperthyroidism.1

The investigators concluded that NIVO plus IPI holds promise as a treatment for uveal melanoma, with good OS and a reasonable toxicity profile. The adverse events were similar to those observed in patients with cutaneous melanoma treated with NIVO plus IPI. This study also found that patients with extrahepatic disease, regardless of liver involvement, benefited from this treatment.1


  1. Piulats JM, Espinosa E, de la Cruz Merino L, et al. Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: an open-label, multicenter, phase II trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021;39:586-598.

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