Background: Dual checkpoint inhibitor therapy with anti-PD-1 and ant-CTLA-4 therapy has shown promising results in patients with high-grade NENs, demonstrating varying response rates of 9 – 44%. More data are needed to evaluate the true response in a real-world cohort of patients. Methods: Retrospective study of all patients with high-grade neuroendocrine neoplasms treated at the Moffitt Cancer Center and Mayo Clinic between 9/2017 and 7/2020 who received combination therapy with ipilimumab and nivolumab. Primary endpoint was objective response rate. Results: 34 patients met eligibility criteria for evaluation. Patients had received an average of 2 lines of therapy prior to treatment with ipilimumab/nivolumab, including at least one cytotoxic chemotherapy regimen. 27 (79.4%) of patients had poorly differentiated NECs and 7 (20.6%) had well-differentiated high grade NETs. The most common primary site (10, 29.4%) was pancreas; other primary sites of disease included unknown primary (n = 9), colon (n = 5), uterus (n = 3), anorectum (n = 2), esophagus (n = 2), cervix (n = 1), stomach (n = 1), and small intestine (n = 1). 5 patients (14.7%) exhibited a best response of PR per RECIST 1.1 criteria, 9 (26.5%) SD, and 17 (50%) PD: 3 patients did not have a follow-up scan and discontinued treatment shortly after initiation due to clinical progression. ORR was 14.7% and DCR was 41.2%. Median PFS was 1 month (95% CI, 0.45 – 1.55); median OS from time of treatment initiation was 5.0 months (95% CI, 3.42 – 6.59) and median OS from diagnosis was 14.0 months (95% CI, 1.49 – 26.51). Median duration on treatment was 1 month (range 0 – 10 months). 26 patients discontinued treatment for progression, 4 patients for toxicity, and 4 remain on treatment at the time of data cut off. 12 patients (35%) experienced grade 3 and 4 treatment-emergent toxicities: liver transaminitis, elevated blood bilirubin, arthralgia, myalgia, peripheral sensory neuropathy, lower extremity edema, confusion, diarrhea, encephalopathy, acute kidney injury, rhabdomyolysis, myocarditis, and colitis. Conclusions: The ipilimumab and nivolumab regimen has modest activity in aggressive and heavily pretreated high-grade NENs who have progressed on prior cytotoxic chemotherapy. Use of this regimen may be considered in patients with particularly aggressive, refractory high-grade NENs.

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