Abstract
BACKGROUND: Dual checkpoint inhibitor therapy with anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein 4 therapy has shown promising results in patients with high-grade neuroendocrine neoplasms (NENs), demonstrating varying response rates of 9%-44%. More data are needed to evaluate the true response in a real-world cohort of patients. PATIENTS AND METHODS: We conducted a retrospective study of all patients with high-grade NENs treated at the Moffitt Cancer Center and Mayo Clinic between September 2017 and July 2020 who received combination therapy with ipilimumab and nivolumab. RESULTS: Thirty-four patients met the eligibility criteria. Patients had received an average of two prior lines of therapy, including at least one cytotoxic chemotherapy regimen. Twenty-seven (79.4%) patients had poorly differentiated neuroendocrine carcinomas, and seven (20.6%) had well-differentiated high-grade neuroendocrine tumors. The most common primary site (10, 29.4%) was pancreas; other primary sites of disease included colon (n = 5), endometrium (n = 3), anorectum (n = 2), esophagus (n = 2), cervix (n = 1), stomach (n = 1), small intestine (n = 1), and unknown primary (n = 9). Five patients (14.7%) exhibited a best response of partial response as per RECIST 1.1 criteria, 9 (26.5%) stable disease, and 17 (50%) progressive disease: 3 patients did not have a follow-up scan as they discontinued treatment shortly after initiation due to clinical progression. The objective response rate was 14.7%, and disease control rate was 41.2%. Median progression-free survival was 1 month [95% confidence interval (CI), 0.54-1.46 months]; median overall survival (OS) from time of treatment initiation was 5.0 months (95% CI, 4.07-5.93 months), and median OS from diagnosis was 14.0 months (95% CI, 11.79-16.21 months). The median duration of treatment was 1 month (range 0-10 months). Twenty-eight patients discontinued treatment for progression, four patients for toxicity, and two remain on treatment at the time of data cut-off. Twelve patients (35%) experienced grade 3 and 4 treatment-emergent toxicities. CONCLUSIONS: The ipilimumab and nivolumab regimen has modest activity in aggressive and heavily pretreated high-grade NENs who have progressed on prior cytotoxic chemotherapy.