Purpose:

Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (non-pancreatic) neuroendocrine neoplasm cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART). Experimental Design: We performed a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (non-pancreatic) neuroendocrine cohort reported here. Response assessment by grade was not pre-specified. The primary endpoint was overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial response (PR)); secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.

Results:

Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N= 15) and lung (19%; N= 6). The overall ORR was 25% (95% confidence interval (CI) 13-64%; CR, 3%, N= 1; PR, 22%, N= 7). Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients) (p=0.004). The 6-month PFS was 31% (95% CI 19-52%); median OS was 11 months (95% CI 6- ). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%); with alanine aminotransferase (ALT) elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.

Conclusions:

Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with non-pancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.