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| Title: | Safety across subgroups in NAPOLI-1: A phase 3 study of nal-IRI (MM-398) +/- 5-fluorouracil and leucovorin (5-FU/LV) versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy |
| Authors: | Chen, LT;Siveke, J;Wang-Gillam, A;Hubner, R;Pant, S;Dragovich, T;Chung, V;Chang, D;Ross, P;Cooray, P;Tebbutt, N;Franke, F;Belanger, B;Dhindsa, N;de Jong, F;Mamlouk, K;Von Hoff, D |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Introduction: NAPOLI-1 was a randomized phase 3 study evaluating nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV versus 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. Nal-IRI + 5-FU/LV significantly improved overall survival compared with 5-FU/LV (6.1 vs 4.2 months; P = 0.012) and was generally well tolerated (Wang-Gillam et al, Lancet. 2016). The most common grade ≥3 treatment-emergent adverse events (TEAEs) in the nal-IRI + 5-FU/LV arm were neutropenia, fatigue, diarrhea, and vomiting. Based on NAPOLI-1, the nal-IRI + 5-FU/LV regimen received regulatory approval from the US. Food and Drug Administration for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Here, we present results of a prespecified safety analysis by patient subgroup from NAPOLI-1. Methods: TEAEs were graded by NCI CTCAE v4.0 and coded by MedDRA v14.1 for the following prespecified subgroups: sex, age (<65 vs ≥65 years), ethnicity (white vs Asian), UGT1A1*28 status, prior conventional irinotecan therapy (yes vs no), and prior 5-FU therapy (yes vs no). All TEAEs were followed until resolution or patient discontinuation. Analyses were performed on the safety population (ie, those who received ≥1 dose of study medication). Results herein are for the nal-IRI + 5-FU/LV arm unless otherwise noted. Results: Overall, the incidence and severity of TEAEs were similar between men (n = 67) and women (n = 50). Patients aged ≥65 years (n = 54) generally had a higher incidence of TEAEs than those <65 years (n = 63) (eg, stomatitis: 20.4% vs 7.9%; anemia: 46.3% vs 30.2%), although the most common types of TEAEs were similar regardless of age. Overall, Asian (n = 33) patients had a higher incidence of grade ≥3 TEAEs than white (n = 73) patients (87.9% vs 69.9%), primarily because of an increased incidence of neutropenia (24.2% vs 12.3%) and decreased neutrophil counts (33.3% vs 1.4%); febrile neutropenia was reported in 3.0% of Asian patients and 0 white patients. Gastrointestinal disorders also occurred slightly more frequently in Asian patients than white patients (any grade: 100% vs 87.7%), although diarrhea was less frequent and less severe among Asian patients (any grade: 48.5% vs 61.6%; grade ≥3: 3.0% vs 19.2%). The UGT1A1 gene encodes an enzyme responsible for glucuronidation of the active metabolite of irinotecan, SN-38. Patients homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) may be at increased risk for neutropenia during irinotecan treatment due to reduced glucuronidation of SN-38. However, in this analysis, there were no differences in incidence, type, and severity of TEAEs between patients homozygous (n = 7) for the UGT1A1*28 allele and those who were not (n = 110). There were also no notable differences in the incidence or severity of TEAEs between patients with (n = 12) and without (n = 105) prior conventional irinotecan therapy, or between patients with (n = 50) or without (n = 67) prior 5-FU therapy. Conclusion: Overall, the safety profile of nal-IRI + 5-FU/LV was generally similar across patient subgroups, apart from an increased risk of grade ≥3 neutropenia/reduced neutrophil counts in Asian patients. The results of this prespecified subgroup analysis further support the tolerability profile of nal-IRI + 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. |
| Date: | 2016-06 |
| Relation: | Annals of Oncology. 2016 Jun;27(Suppl. 2):110. |
| Link to: | http://dx.doi.org/10.1093/annonc/mdw200.23 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000379756200366 |
| Appears in Collections: | [陳立宗] 會議論文/會議摘要
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| ISI000379756200366.pdf | | 41Kb | Adobe PDF | 265 | View/Open |
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