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

BACKGROUND

A phase I/II trial (NCT02611024) evaluated the lurbinectedin 2.0 mg/m2 Day (D)1 plus irinotecan 75 mg/m2 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.