Impact of dose reduction or dose delay on the efficacy of liposomal irinotecan (nal-IRI)+5-fluorouracil/leucovorin (5-FU/LV): Survival analysis from NAPOLI-1 (2018)

Background: Chemotherapy dose modifications to manage adverse events (AEs) is common in clinical practice. In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.49–0.92; P = 0.012). The study protocol permitted dose modifications (reduction or delay) to address toxicity. In this exploratory post-hoc analysis, we evaluated the impact of nalIRI dose modifications on overall survival (OS) and progression-free survival (PFS). Methods: All pts enrolled under protocol v2 who received nal-IRI+5-FU/LV during the first 6 wks were included in the analysis. Pts were grouped according to those with dose modification or those without dose modification. Dose reduction was defined as any decrease from initial dose, delay as any dosing delay >3 days from target date. Pts without dose modification received the first 3 scheduled doses of nal-IRI+5-FU/LV without qualifying delay/reduction. OS and PFS (KaplanMeier estimates) were compared within the nal-IRI+5-FU/LV arm. Unstratified hazard ratios (HRs) were calculated using Cox regression. Results: Among pts in the nal-IRI+5-FU/LV arm (n = 93), 40 pts had no dose modification and 53 had a dose modification (delay, n = 49; reduction, n = 34). Within the nal-IRI+5-FU/LV arm, there was no significant difference in median OS or PFS between pts with vs without dose modification (Table). Conclusions: Dose modification of nal-IRI+5-FU/LV in the first 6 wks does not significantly impact OS or PFS compared to patients without dose modifications. This suggests that tolerability-guided dose modification of nal-IRI does not adversely affect efficacy outcomes.Table: 734PMedian OSMedian PFSPts (n)MonthsHR (95% CI)Pts (n)MonthsHR (95% CI)nal-IRI+5-FU/LV Delay498.41.10 (0.71, 1.70)494.21.03 (0.66, 1.61)nal-IRI+5-FU/LV No delay438.3434.0nal-IRI+5-FU/LV Reduction349.40.87 (0.54, 1.39)344.20.91 (0.56, 1.48)nal-IRI+5-FU/LV No reduction488.4484.1 Open table in a new tab Clinical trial identification: NCT01494506. Editorial acknowledgement: Editorial assistance for the abstract was provided by The Medicine Group (New Hope, PA); Philip Sjostedt, BPharm; Susan Martin, PhD. Legal entity responsible for the study: Ipsen Biopharmaceuticals, Inc. Funding: Ipsen Biopharmaceuticals, Inc. Disclosure: L-T. Chen: Consulting, Advisory role: Bristol-Myers Squibb, Five Prime Therapeutics, Lilly, Merrimack, MSD, Novartis, Ono Pharmaceutical, PharmaEngine, Syncope, Taiwan, TTY Biopharm Research funding (Inst): GlaxoSmithKline, Merck Serono, Novartis, Polaris, TTY Biopharm, Patents, Royalties, Other intellectual property: Anti-alpha-enolase (ENO-1) monoclonal antibody to HuniLife Technology, Taiwan. J. Blanc: Honoraria: Baxalta/Shire, Bayer Schering Pharma, Gilead Sciences; Consulting, Advisory role: Baxalta/Shire, Bristol-Myers Squibb, Novartis, Onxeo; Travel, accommodations, expenses: Bayer Schering Pharma. B. Mirakhur, B. Belanger: Employee, Stock and other ownership interests: Ipsen Biopharmaceuticals, Inc. F.A. de Jong: Employee: Shire; Stock and other ownership interests: Amgen, Shire. T. Bekaii-Saab: Consulting, Advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Genentech/Roche, Glenmark, Lilly, Merrimack, NCCN, Pfizer, Research to practice, Sirtex Medical, Taiho Pharmaceutical; Other relationship: Exelixis, Merck, Polaris. J. Siveke: Consulting, advisory role: Baxalta, Celgene, Lilly, Merrimack Research funding: 4SC, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Novartis; Travel, accommodations, expenses: Celgene, Roche. All other authors have declared no conflicts of interest.