Background
Phase III, randomized, open-label, international trial of 417 patients with metastatic pancreatic ductal adenocarcinoma who progressed after gemcitabine-based chemotherapy. Stratified by baseline albumin, KPS, and ethnicity.
Interventions and follow up
Arm A: Nanoliposomal irinotecan 80 mg/m2 (= 70 mg/m2 irinotecan base) + folinic acid 400 mg/m2 over 30 min, then 5-FU 2400 mg/m2 over 46 h, Q2W
Arm B: Nanoliposomal irinotecan monotherapy 120 mg/m2 (= 100 mg/m2 irinotecan base) Q3W
Arm C: Folinic acid 200 mg/m2 over 30 min then 5-FU 2000 mg/m2 over 24 h, weekly for first 4 weeks of each 6-week cycle
Primary endpoint: Overall survival (OS)
Key secondary endpoints: PFS, ORR
Arm B: Nanoliposomal irinotecan monotherapy 120 mg/m2 (= 100 mg/m2 irinotecan base) Q3W
Arm C: Folinic acid 200 mg/m2 over 30 min then 5-FU 2000 mg/m2 over 24 h, weekly for first 4 weeks of each 6-week cycle
Primary endpoint: Overall survival (OS)
Key secondary endpoints: PFS, ORR
Results
mOS (per-protocol): 6.1 mo (Arm A) vs 4.2 mo (Arm C); HR 0.67, 95% CI 0.49–0.92; P=.012
mOS, Arm B vs C: 4.9 mo vs 4.2 mo; HR 0.99, 95% CI 0.77–1.28; P=.94
mOS (ITT, updated): 6.2 mo (Arm A) vs 4.2 mo (Arm C); HR 0.75, 95% CI 0.57–0.99; P=.039
mPFS, Arm A vs C: 3.1 mo vs 1.5 mo; HR 0.57; P=.0001
mPFS, Arm B vs C: 2.7 mo vs 1.5 mo; HR 0.81; P=.105
ORR, Arm A vs C: 17% vs 1%; P<.0001
ORR, Arm B vs C: 6% vs 1%; P=.02
mOS, Arm B vs C: 4.9 mo vs 4.2 mo; HR 0.99, 95% CI 0.77–1.28; P=.94
mOS (ITT, updated): 6.2 mo (Arm A) vs 4.2 mo (Arm C); HR 0.75, 95% CI 0.57–0.99; P=.039
mPFS, Arm A vs C: 3.1 mo vs 1.5 mo; HR 0.57; P=.0001
mPFS, Arm B vs C: 2.7 mo vs 1.5 mo; HR 0.81; P=.105
ORR, Arm A vs C: 17% vs 1%; P<.0001
ORR, Arm B vs C: 6% vs 1%; P=.02
Adverse events
Hematologic (grade 3-4, A vs B vs C): Neutropenia 15.4% vs 4.1% vs 2.2%
GI (grade 3-4, A vs B vs C): Diarrhea 9.4% vs 6.1% vs 3.0%; vomiting 6.0% vs 2.7% vs 2.2%
Constitutional (grade 3-4, A vs B vs C): Fatigue 6.8% vs 2.0% vs 0.7%
Dose modification (A vs B vs C): Dose reduction 34.2% vs 31.3% vs 4.5%; discontinuation 12.8% vs 13.6% vs 8.2%
GI (grade 3-4, A vs B vs C): Diarrhea 9.4% vs 6.1% vs 3.0%; vomiting 6.0% vs 2.7% vs 2.2%
Constitutional (grade 3-4, A vs B vs C): Fatigue 6.8% vs 2.0% vs 0.7%
Dose modification (A vs B vs C): Dose reduction 34.2% vs 31.3% vs 4.5%; discontinuation 12.8% vs 13.6% vs 8.2%
Conclusions
Nanoliposomal irinotecan plus 5-FU/folinic acid improved survival versus 5-FU/folinic acid alone in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Nanoliposomal irinotecan monotherapy did not improve survival.
Key Limitations
Open-label design; the combination arm was added by protocol amendment, limiting direct three-arm comparison; absolute survival gains modest in a heavily pretreated population.
Clinical Context
NAPOLI-1 established nanoliposomal irinotecan + 5-FU/LV as a standard second-line option after gemcitabine, leading to FDA (2015) and EMA approval in this setting. Subsequently, first-line NALIRIFOX (NAPOLI-3) supplanted some sequencing decisions. ESMO guidelines incorporate nal-IRI/5-FU as preferred post-gemcitabine therapy.
References
Wang-Gillam et al, Lancet, 2016, PMID: 26615328
Wang-Gillam A et al, Eur J Cancer, 2019 (long-term update), PMID: 30654298
Wang-Gillam A et al, Eur J Cancer, 2019 (long-term update), PMID: 30654298