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Time course of selected treatment emergent adverse events (TEAEs) in NAPOLI-1: A phase 3 study of nal-IRI (MM-398) ± 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy

Date

08 Oct 2016

Session

Poster Display

Presenters

Richard Hubner

Citation

Annals of Oncology (2016) 27 (6): 207-242. 10.1093/annonc/mdw371

Authors

R.A. Hubner1, L. Chen2, J.T. Siveke3, C. Li4, G. Bodoky5, A. Dean6, Y. Shan7, G.S. Jameson8, T. Macarulla9, K. Lee10, D. Cunningham11, J. Blanc12, C. Chiu13, G. Schwartsmann14, F. Braiteh15, K. Mamlouk16, B. Belanger16, F. de Jong17, D.D. von Hoff8, A. Wang-Gillam18

Author affiliations

  • 1 Department Of Medical Oncology, Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 2 National Institute Of Cancer Research, National Health Research Institutes, 704 - Tainan/TW
  • 3 University Hospital Essen, West German Cancer Center, Essen/DE
  • 4 Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei/TW
  • 5 Medical Oncology, St. László Teaching Hospital, 1097 - Budapest/HU
  • 6 Cancer Services, St John of God Hospital, 6008 - Subiaco/AU
  • 7 National Cheng Kung University, National Cheng Kung University Hospital, Tainan/TW
  • 8 Medical Oncology, TGen, Phoenix/US
  • 9 Oncology Service, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, 08035 - Barcelona/ES
  • 10 Internal Medicine, Seoul National University Hospital, Seoul/KR
  • 11 Gi & Lymphoma Unit, Royal Marsden Hospital, SM2 5PT - Sutton/GB
  • 12 Hepato-gastroenterology And Digestive Oncology, Hôpital Saint-André, Bordeaux/FR
  • 13 Cancer Center, China Medical University Hospital, Taichung/TW
  • 14 Ufrgs, Hospital de Clínicas de Porto Alegre, Porto Alegre/BR
  • 15 Medicine, Comprehensive Cancer Centers of Nevada, 89169 - Las Vegas/US
  • 16 Medicine, Merrimack Pharmaceuticals, Inc., Cambridge/US
  • 17 Medicine, Baxalta GmbH, Zürich/CH
  • 18 Medicine, Washington University School of Medicine, St. Louis/US
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Background

Liposomal irinotecan (nal-IRI) plus 5-FU/LV is approved in the US for patients (pts) with mPAC previously treated with gemcitabine-based therapy. Primary analysis from NAPOLI-1 (NCT01494506) showed a significant median survival advantage for nal-IRI + 5-FU/LV vs 5-FU/LV (6.1 vs 4.2 mo; HR 0.67; 95% CI 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). The most common TEAEs included diarrhea, vomiting, nausea, decreased appetite, fatigue, neutropenia, and anemia. Here we report incidence and prevalence of selected TEAEs over time in NAPOLI-1.

Methods

Pts were randomly assigned to nal-IRI + 5-FU/LV, nal-IRI, or 5-FU/LV. In this post hoc analysis (data cutoff, Feb 14, 2014), incidence (ie, first occurrence) and prevalence (ie, first occurrence, ongoing event, or recurrence) of selected TEAEs were analyzed by treatment period (first 6 wk [period 1], second 6 wk [period 2], and beyond second 6 wk [period 3]). Denominators for percentages were the number of pts in the risk set during each period (for incidence: pts still on treatment without a previous event; for prevalence: all safety-evaluable pts).

Results

398 pts were treated with nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 147), or 5-FU/LV (n = 134). In the nal-IRI + 5-FU/LV arm, most first occurrences of neutropenia, diarrhea, nausea, and vomiting were during the first 6 wk of treatment, with incidence and severity generally decreasing thereafter (Table). Similarly, prevalence and severity were highest in the first 6 wk and tended to decrease over time. Similar trends were observed in the nal-IRI and 5-FU/LV arms.

Incidence, % nal-IRI + 5-FU/LV nal-IRI 5-FU/LV
Period Period Period
1 2 3 1 2 3 1 2 3
Neutropenia grade n = 117 n = 73 n = 34 n = 147 n = 95 n = 43 n = 134 n = 111 n = 43
1 1 3 3 1 2 0 1 0 0
2 8 3 3 8 3 0 1 2 2
3 14 4 9 5 1 0 2 0 0
4 7 0 0 6 2 0 0 0 0
5 0 0 0 0 0 0 0 0 0
Diarrhea grade n = 117 n = 51 n = 24 n = 147 n = 46 n = 11 n = 134 n = 89 n = 32
1 21 4 0 25 11 18 15 5 6
2 17 12 4 20 7 9 2 1 0
3 12 0 4 16 4 0 2 1 3
4 0 0 0 1 0 0 0 0 0
5 0 0 0 1 0 0 0 0 0
Nausea grade n = 117 n = 56 n = 28 n = 147 n = 53 n = 25 n = 134 n = 87 n = 26
1 21 5 7 23 4 8 19 4 12
2 16 0 7 27 4 8 5 4 4
3 7 2 0 5 2 0 2 2 0
4 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0
Vomiting grade n = 117 n = 61 n = 35 n = 147 n = 61 n = 28 n = 134 n = 89 n = 29
1 19 5 11 27 2 7 16 2 4
2 14 0 9 10 3 4 5 1 4
3 10 0 3 12 2 0 1 1 4
4 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0

Conclusions

Neutropenia, diarrhea, nausea, and vomiting typically first occur early during the course of treatment with nal-IRI + 5-FU/LV and tend to decrease in incidence and severity thereafter.

Clinical trial identification

NCT01494506

Legal entity responsible for the study

Merrimack Pharmaceuticals, Inc.

Funding

Merrimack Pharmaceuticals, Inc.

Disclosure

L-T. Chen: 1. Merrimack/ NAPOLI-1 study Steering Committee Member, uncompensated 2. Baxalta/ Advisory Meeting, honorarium 3. PharmaEngine/ Consultant, honorarium. J.T. Siveke: 1. Baxalta/ Ad Board, honoraria. A. Dean: Merrimack/ Investigator meeting, travel grant. D. Cunningham: Amgen, AstraZeneca, Bayer, Celgene, Medimmune, Merck Serono, Merrimack, Sanofi: research funding to my institution. J-F. Blanc: Baxalta, honoraria. F. Braiteh: Merrimack, institutional research funding.

K. Mamlouk: Merrimack, employee and stock. B. Belanger: Merrimack, employee. F. de Jong: Baxalta, employee and stock. D.D. von Hoff: Merrimack/ Clinical trial. A. Wang-Gillam: 1. Merrimack/ Ad Board 2. Newlink/ Ad Board 3. Pfizer/ Ad Board. All other authors have declared no conflicts of interest.

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