Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma: Sensitivity analysis of survival from the NAPOLI 3 trial

Liposomal irinotecan and 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) after progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumour activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m 2 , 5-FU 2400 mg/m2, LV 400 mg/m2 and oxaliplatin 60 mg/m 2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized open-label phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m 2 + gemcitabine 1000 mg/m 2 (Gem+NabP) as first-line therapy in patients with mPDAC.

Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both according to Response Evaluation Criteria in Solid Tumours version 1.1 as per investigator assessment. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. A sensitivity analysis of OS censored at initiation of subsequent anticancer therapy was performed using a stratified log-rank test.

Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) comprised the intention-to-treat population. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group and 9.2 months in the Gem+NabP group (hazard ratio [HR] 0.83 [95% confidence interval [CI] 0.70–0.99], p = 0.04); survival at 18 months was 26.2% and 19.3%, respectively. Median PFS was 7.4 months for NALIRIFOX versus 5.6 months for Gem+NabP (HR 0.69 [95% CI 0.58–0.83]; p < 0.0001); at 18 months, 11.4% and 3.6% of patients receiving NALIRIFOX and Gem+NabP, respectively, were progression-free. When censored at initiation of subsequent anticancer therapy, median OS was 15.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group (HR 0.71 [95% CI 0.56–0.90], p < 0.005). ORR (95% CI) was 41.8% (36.8–46.9) for NALIRIFOX and 36.2% (31.4–41.2) for Gem+NabP (p = 0.11); median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months, respectively. In the safety population, grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX (n = 370) versus Gem+NabP (n = 379) included diarrhoea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalaemia (15.1% vs 4.0%), anaemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%).

First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. These results support the NALIRIFOX regimen as a new reference regimen for the first-line treatment of patients with mPDAC.

NCT04083235.

The authors thank Emma Bolton, D.Phil., of Oxford PharmaGenesis, Oxford, UK for providing medical writing support, which was sponsored by Ipsen in accordance with Good Publication Practice guidelines.

Ipsen.

Ipsen.

Z. Wainberg: Advisory / Consultancy: Daiichi, Ipsen, BMS, Bayer, Amgen, Astra Zeneca, Arcus, Seagen, Pfizer, Astellas, Novartis, Merck; Research grant / Funding (self): Arcus, BMS; Research grant / Funding (institution): Plexxikon, Merck; Travel / Accommodation / Expenses: Amgen. T. Macarulla: Advisory / Consultancy: Ability Pharmaceuticals SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Incyte, Ipsen Bioscience Inc, ; Speaker Bureau / Expert testimony: Janssen, Lilly, ; Research grant / Funding (self): MSD, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Zymeworks; Travel / Accommodation / Expenses: Servier, AstraZeneca, Sanofi, Incyte and MSD. S. Chandana: Advisory / Consultancy: Daiichi Sankyo; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Janssen Biotech, Natera; Research grant / Funding (institution): AbbVie, AstraZeneca, Exact Sciences, Biosplice, Ipsen, Johnson & Johnson, Merck, Mirati Therapeutics, TerSera Therapeutics, QED Therapeutics, Zymeworks. E. Van Cutsem: Advisory / Consultancy: Array BioPharma, Astellas Pharma, Astrazeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, GSK, Halozyme, Incyte, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, SERVIER, Sirtex Medical, Taiho Pharmaceutical; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. S. Paulson: Advisory / Consultancy: Ipsen; Research grant / Funding (institution): Ipsen; Travel / Accommodation / Expenses: Ipsen. T. Bekaii-Saab: Honoraria (self): Royalties: Uptodate; Advisory / Consultancy: CConsulting (to institution): Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGA and Merck. , CConsulting (to self): Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine and Sanofi. IDMC/DSMB: The Valley Hospital, Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan and 1Globe. Scientific Advisory Board: Imugene, Immuneering, Xilis, Replimune, Artiva and Sun Biopharma.; Research grant / Funding (institution): Research Funding (to institution): Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS. ; Licensing / Royalties: WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF – Licensed to Imugene, WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA – Licensed to Recursion. Z. Xiao: Shareholder / Stockholder / Stock options: IPSEN; Full / Part-time employment: IPSEN. H. Chen: Shareholder / Stockholder / Stock options: Ipsen, Ipsen, Ipsen; Full / Part-time employment: Ipsen, Ipsen, Ipsen. F. Benzaghou: Shareholder / Stockholder / Stock options: IPSEN ; Full / Part-time employment: IPSEN. E. O'Reilly: Advisory / Consultancy: Boehringer Ingelheim, BioNTech, Ipsen, Merck, Novartis, AstraZeneca, BioSapien, Astellas, Thetis, Autem, Novocure, Neogene, BMS, Tempus, Fibrogen, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse); Research grant / Funding (institution): Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Pertzye; Spouse / Financial dependant: Agios, Genentech-Roche, Eisai; Non-remunerated activity/iesA: BioSapien, Thetis. All other authors have declared no conflicts of interest.