LBA63 - A randomized phase I/II study of second line treatment with liposomal irinotecan and S-1 versus liposomal irinotecan and 5-fluorouracil in patients with metastatic pancreatic cancer following gemcitabine-based chemotherapy

Background

The 5-year overall survival (OS) of metastatic pancreatic cancer patients is less than 5%. Second-line treatment options are limited, necessitating new therapeutic strategies. This study aimed to compare second-line treatment with S-1 and liposomal irinotecan (nal-IRI) to 5-fluorouracil/ leucovorin (5-FU/LV) and nal-IRI in metastatic pancreatic cancer patients.

Methods

An international, multi-center, open-label, randomized phase I/II trial. Patients ≥18 years with pancreatic adenocarcinoma, previously treated with gemcitabine-based treatment and an ECOG performance score (PS) of 0 or 1 were included in five international centers. In phase I (20 patients), the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for the combination of nal-IRI with S-1 were determined. In phase II, patients received 25 mg/m² S-1 orally twice daily for 14 days, followed by 2 weeks rest, and nal-IRI 70 mg/m2 IV on day 1 and 15 every 4 weeks (S-1 arm) versus nal-IRI 70 mg/m2 followed by LV 400 mg/m2 and 5-FU 2400 mg/m2 IV over 46-hours every 2 weeks (5-FU arm), until disease progression. Randomization was stratified for PS. The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS and serious adverse event (SAE) rate. To detect a hazard ratio (HR) of 0.415 with two-sided α=0.05 and 80% power, 120 patients were needed. HR and 95%CI were estimated using a stratified Cox model.

Results

Between November 2021 and May 2023, 120 patients were randomized to the S-1 arm (n=61) or the 5-FU arm (n=59). Three patients were excluded because of ineligibility (2 in the S-1 arm, 1 in the 5-FU arm). Median PFS was 3.5 months for S-1 and 3.7 months for 5-FU (HR 1.265; 95% CI 0.838-1.910, p=0.26). Median OS was 6.0 months for S-1 and 9.1 months for 5-FU (HR 1.468; 95% CI 0.993-2.171, p=0.054). SAE rates were 39% for S-1 and 19% for 5-FU (p=0.029).

Conclusions

Second-line treatment with nal-IRI plus S-1 did not improve PFS compared with nal-IRI plus 5-FU/LV in patients with metastatic pancreatic cancer following first-line gemcitabine-based chemotherapy. However, OS tended to improve in patients treated with nal-IRI plus 5-FU/LV.

Clinical trial identification

EudraCT: 2017-004675-31.

Editorial acknowledgement

Legal entity responsible for the study

Amsterdam UMC.

Funding

Servier, Nordic Pharma.

Disclosure

G. Prager: Financial Interests, Personal, Advisory Board: Merck, Amgen, Servier, Bayer, Pierre Fabre, CECOG, Daiichi Sankyo Austria, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche, Sanofi, Lilly, BMS, MSD, Incyte; Financial Interests, Personal, Advisory Board, Advisory: Takeda; Financial Interests, Institutional, Local PI: Incyte, Servier, BMS, Novartis. J. de vos-Geelen: Financial Interests, Institutional, Research Grant: Servier. T. Macarulla Mercade: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd, Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dhome, Novocure, QED Therapeutics Inc, Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZecena, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, Fibrogen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, Medimmune, Merimarck, Millenim, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO; Other, Editorial Board: GI Annals og¡f Oncology. D. Melisi: Financial Interests, Personal, Advisory Board: Incyte co., Servier, iOnctura, Tahio; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Research Grant: iOnctura. H. Wilmink: Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Board: MSD, Servier, Nordic Pharma. All other authors have declared no conflicts of interest.