Nivolumab Plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402)

Abstract

PURPOSE This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection. METHODS This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naïve patients of age > 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy. RESULTS A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values. CONCLUSIONS Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile.

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis

“…The ORR is in line with another previously published retrospective study reporting 11.6% to dual ICB [9] as well as to our previous report of 15.6% [10]. Two recently published prospective trials of the combination of ipilimumab with nivolumab in patients with metastatic UM showed results that slightly deviate [4,5]. Piulats et al enrolled only treatment-naïve patients and reported a lower OS (12.7 vs. 19.1 months), PFS (3 vs. 5.5 months), and ORR (11.5% vs. 18%) compared to Pelster et al, who enrolled patients with any number of prior treatments.…”

“…Furthermore, Piulats et al reported a median number of two liver metastases (range 1-25) and a median size of the biggest liver metastases of 25 mm (range 10-90 mm); 78.8% of the patients had liver metastases and 57.7% presented with extrahepatic disease. The number of patients with exclusive liver metastases was not presented [4]. In comparison, Pelster et al reported that 49% of patients presented with hepatic and extrahepatic metastases, 31% with liver metastases only, and 20% with extrahepatic metastasis only [5].…”

“…Two recent phase II trials investigated the value of dual ICB in metastatic UM. Piulats et al reported that the OS in patients with exclusive liver metastases was shorter than that in patients with metastases in locations other than the liver and those with both liver and other metastases [4]. Pelster et al achieved a response in 6 patients of whom 5 had both liver and extrahepatic metastasis [5].…”

How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma

“…Results from combination therapy with PV-10 and ICBs are awaited with interest. Complete results of the Spanish GEM-1402 study (ClinicalTrials.gov Identifier: NCT02626962) were recently published [ 75 ] ( Table 1 and Table 3 ). This phase II trial tested the efficacy of the combination of Nivolumab and Ipilimumab as first-line therapy in 52 patients with M-UM.…”

Immune Profile Of Uveal Melanoma Patients: Impact On Clinical Outcome

“…Pembrolizumab showed a limited e cacy also in a prospective observational study, with a PFS of 3.8 months [16]. The association of Nivolumab and Ipilimumab allowed an overall survival (OS) of 12.7 months and a PFS of 3 months [17].…”