Lurbinectedin plus irinotecan in pretreated gastroenteropancreatic neuroendocrine neoplasms: results of a phase II expansion cohort

BACKGROUND: D1 and D8 every three weeks combination in multiple solid tumors. Data from the phase II cohort of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are reported in this manuscript. PATIENTS AND METHODS: Thirty-four patients with NENs (second line or greater) were included, 20 with poorly differentiated neuroendocrine carcinomas (NECs), and 14 with grade 2/3 well-differentiated neuroendocrine tumors (NETs) of digestive origin. The primary efficacy endpoint was objective response rate (ORR) according to RECIST v.1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. RESULTS: In patients with NECs, the ORR with lurbinectedin plus irinotecan was 15.0% [95% confidence interval (CI) 3.2%-37.9%], the median PFS was 3.1 months (95% CI 1.4-5.6 months), and the median OS was 7.2 months (95% CI 2.9-17.8 months). In patients with NETs, the ORR with lurbinectedin plus irinotecan was 7.1% (95% CI 0.2%-33.9%), the median PFS was 3.4 months (95% CI 1.4-8.9 months), and the median OS was 16.6 months (95% CI 3.9 months-not reached). The most common treatment-related adverse events were gastrointestinal disorders (nausea, 61.8% of patients; diarrhea, 44.1%; and vomiting, 35.3%), fatigue (58.8%), and decreased appetite (20.6%); these events were mostly grades 1 and 2. Grade ≥3 neutropenia was observed in 47.1% of patients and febrile neutropenia in 5.9%. Grade ≥3 transaminase increases were the most common severe laboratory biochemical abnormalities reported during treatment regardless of relationship to study drugs. CONCLUSIONS: The combination of lurbinectedin plus irinotecan with primary granulocyte colony-stimulating factor prophylaxis showed antitumor activity in GEP-NECs but limited activity in GEP-NETs. This combination had a predictable and manageable safety profile, with myelosuppression, gastrointestinal disorders, and fatigue as main toxicities. The lurbinectedin plus irinotecan combination deserves to be further explored in GEP-NECs after failure of platinum therapy.