Phase II basket trial of Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: pancreatic neuroendocrine neoplasm (PNEN) cohort

PURPOSE: umors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort. EXPERIMENTAL DESIGN: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites. RESULTS: 19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited. CONCLUSIONS: Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients. TRIAL REGISTRATION NUMBER: NCT02834013.