27O Lurbinectedin plus irinotecan in pre-treated gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs)

Lurbinectedin received FDA approval for the treatment of small cell lung cancer and has shown activity in neuroendocrine tumours from other primary sites (Eur J Cancer 2022; 172: 340-348). Previous data has shown synergy between lurbinectedin and irinotecan (Cancer Res2013;73 (8 Supl 1) Abs 5499). We show here the results from a phase I/II study expansion cohort evaluating lurbinectedin 2.0 mg/m2 plus irinotecan 75 mg/m2 with primary G-CSF prophylaxis in pre-treated G3 GEP-NECs. Phase II expansion stage included a cohort of 20 pts with G3 (Ki67>20%) poorly differentiated NECs of GEP or unknown primary site after progression to platinum-based therapy. Primary endpoint was overall response rate (ORR) per RECIST v.1.1. Other endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetics (PK). Primary tumour sites included oesophagus (2), stomach (4), pancreas (5), small bowel (2), colorectal (2), biliary tract (1) and unknown (4). Median Ki67 was 80% (60% of pts had Ki67 >55%). Thirteen pts (65%) were treated in second line, 5 pts (25%) in third line, and 2 pts (10%) in further lines. Confirmed partial response (PR) was reported in 3 pts (ORR=15%) and disease stabilization (SD) in 9 pts (DCR=60%). Median duration of the 3 PRs was 8.1 months. ORR was greater in NECs with lower Ki67 (28.6% in Ki67 20-55% vs. 8.3% in Ki67 >55%). Median PFS was 3.8 mo (95%CI, 1.4-9.0 mo) and 6-mo PFS rate was 30.1% (95%CI, 8.9-51.3%). Six of 20 pts (30%) showed PFS longer than that observed with prior therapy. Median OS was 6.9 mo (95%CI, 2.9-18.9 mo) and 6-mo and 1-year OS rates were 53.3% and 35.6%, respectively. Most common G3/4 toxicities were haematological: neutropenia (45%; G4 15%), anaemia (30%, all G3), and thrombocytopenia (15%; G4, 5%). There was one treatment-related death (bacteraemia). Total plasma clearance of lurbinectedin, irinotecan and SN38 were 9.5, 25.6 and 448.3 L/h, respectively, in line with reference values. The combination of irinotecan and lurbinectedin is active in pts with pre-treated G3 GEP-NECs with manageable toxicity. The PK analysis showed no evidence of drug-drug interaction.