A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer

Zishuo Ian Hu, Johanna C Bendell, Andrea Bullock, Noelle K LoConte, Hassan Hatoum, Paul Ritch, Hugo Hool, Joseph W Leach, James Sanchez, Davendra P S Sohal, John Strickler, Ravindranath Patel, Andrea Wang-Gillam, Irfan Firdaus, Kenneth H Yu, Ann M Kapoun, Eric Holmgren, Lei Zhou, Jakob Dupont, Vincent Picozzi, Vaibhav Sahai, Eileen M O'Reilly, Zishuo Ian Hu, Johanna C Bendell, Andrea Bullock, Noelle K LoConte, Hassan Hatoum, Paul Ritch, Hugo Hool, Joseph W Leach, James Sanchez, Davendra P S Sohal, John Strickler, Ravindranath Patel, Andrea Wang-Gillam, Irfan Firdaus, Kenneth H Yu, Ann M Kapoun, Eric Holmgren, Lei Zhou, Jakob Dupont, Vincent Picozzi, Vaibhav Sahai, Eileen M O'Reilly

Abstract

Purpose: Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors.

Patients and methods: Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation.

Results: Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group.

Conclusions: The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients.

Clinical trial registry no: NCT01647828.

Keywords: Notch 2/3 receptor inhibitor; Pancreatic cancer; cancer stem cell; gemcitabine; nab-paclitaxel; tarextumab.

Conflict of interest statement

J. Bendell: Research grant from OncoMed for performance of the study covered by the submitted work; payment to her institution for consulting/advisory services and/or clinical trial activities from the following for activities outside of the study covered by the submitted work: Bristol Myers Squibb, Roche, Merck, Taiho Oncology, Amgen, Genentech, Merrimack, Celgene, MedImmune, Seattle Genetics, Daiichi Sankyo, Janssen, Translational Drug Development, Five Prime Therapeutics, Moderna Therapeutics, Tolero, Evelo Biosciences, Array Therapeutics, Forma Therapeutics, Tanabe Research Laboratories, BeiGene, Continuum Clinical, Cerulean, AbbVie, AstraZeneca, EMD Serono, Ipsen Biopharma, Incyte, Novartis, Eisai, Pfizer, Millennium, Imclone, Boston Biomedical, CALGB, Acerta Pharma, Lilly, Gilead Sciences, Leap Therapeutics, Macrogenics, OncoMed Pharmaceuticals, Takeda Pharmaceuticals, Rgenix, Novocure, Merus, NV, Blueprint Medicine, Array Biopharma, ARMO Biosciences, Agios. From time to time, the companies listed have reimbursed Dr Bendell for travel expenses and/or provided meals at meetings held in connection with her services. A. Bullock: Consulting/Advisory Boards: Eisai, Exilexis, Taiho. N. LoConte: Advisory Boards: Celgene, Bayer. Consultant: Abbvie, AstraZenica. D. Sohal: Consulting: Perthera. Honoraria: Foundation Medicine. Travel/Accomodation/Expense reimbursement: Foundation Medicine. Research funding: Agios, Bayer, Bristol‐Myers Squibb, Celgene, Genentech, Incyte, Loxo, Novartis, OncoMed. J. Strickler: Consulting/Advisory: Amgen, Genentech‐Roche, Bayer, Celgene, Chugai, AstraZenica, Seattle Genetics, OncoMed. Research Funding: Amgen, Abbvie, Gilead Sciences, Roche/Genentech, Exelixis, OncoMed, Sanofi, Regeneron, MedImmune, Cascadian Therapeutics, Seattle Genetics, Macrogenics, Leap Therapeutics, Nektar. A. Wang‐Gillam: Advisory Boards: Ipsen, Merrimack, BMS, Tyme, Repugene, Jacobio, Vicus. Research funding: BMS. Biomed Valley, Pfizer, Halozyme, AstraZeneca, Bayer, Xcovery, Novartis, Lily, Aduro, Verastem. Tyme, Boston Biomedical, Newlink Genetics, Precision Biologicis. K. Yu. Consulting/Advisory: Halozyme, Ipsen. Research Funding: Halozyme, BMS. A. Kapoun: Employee OncoMed. L. Zhou: Pain consultant to OncoMed. Stock ownership: OncoMed. J. Dupont: Employee OncoMed. Stock ownership: OncoMed. E. Holmgren: Employee OncoMed. Stock ownership: OncoMed. E. O'Reilly: Research funding to MSK: Genentech, Roche, BMS, Halozyme, Celgene, MabVax Therapeutics, ActaBiologica, OncoMed, Momenta Pharmaceuticals, Parker Institute, AstraZenica, Silenseed, Incyte, Pfizer, Polaris, Lustgarten Foundation, NCI‐CTEP. Consulting/Advisory: Cytomx, BioLineRx, Targovax, Halozyme, Celgene, Bayer, Loxo, Polaris. All remaining authors have declared no conflicts of interest.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
CONSORT diagram. ITT, intent to treat; nab‐p, nab‐paclitaxel; gem, gemcitabine
Figure 2
Figure 2
(A) Overall survival and (B) Progression‐free survival in the intent‐to‐treat population. Red, tarextumab with gemcitabine and nab‐paclitaxel; black, placebo with gemcitabine and nab‐paclitaxel
Figure 3
Figure 3
Kaplan‐Meier analysis of overall survival in the intent‐to‐treat population divided by percentile. (A) OS for patients with ≥25th percentile Notch3 expression, (B) OS for patients with ≥50th percentile Notch3 expression, (C) OS for patients with ≥75th percentile Notch3 expression. Red, tarextumab with gemcitabine and nab‐paclitaxel; black, placebo with gemcitabine and nab‐paclitaxel

References

    1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA: Cancer J Clin. 2017;67:7‐30.
    1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab‐paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691‐1703.
    1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817‐1825.
    1. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355:1253‐1261.
    1. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756‐760.
    1. Dylla SJ, Beviglia L, Park I‐K, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE. 2008;3:e2428.
    1. Doucas H, Mann CD, Sutton CD, et al. Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. J Surg Oncol. 2008;97:63‐68.
    1. Hong SP, Wen J, Bang S, Park S, Song SY. CD44‐positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int J Cancer. 2009;125:2323‐2331.
    1. Koch U, Lehal R, Radtke F. Stem cells living with a Notch. Development. 2013;140:689‐704.
    1. Mann CD, Bastianpillai C, Neal CP, et al. Notch3 and HEY‐1 as prognostic biomarkers in pancreatic adenocarcinoma. PLoS ONE. 2012;7:e51119.
    1. Yao J, Qian C. Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt‐dependent pathway. Med Oncol. 2010;27:1017‐1022.
    1. Yen W‐C, Fischer MM, Axelrod F, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor‐initiating cell frequency. Clin Cancer Res. 2015;21:2084‐2095.
    1. Hamzah J, Jugold M, Kiessling F, et al. Vascular normalization in Rgs5‐deficient tumours promotes immune destruction. Nature. 2008;453:410‐414.
    1. O'Reilly EM, Smith LS, Bendell JC, et al. Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP‐59R5, TRXT, anti‐Notch 2/3) in combination with nab‐paclitaxel and gemcitabine (Nab‐P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC). J Clin Oncol. 2015;33:278‐278.
    1. National Institutes of Health, National Cancer Institute . Common Terminology Criteria for Adverse Events (CTCAE) version 4.02, in Services UDoHaH (ed), 2009.
    1. Pietanza MC, Spira AI, Jotte RM, et al. Final results of phase Ib of tarextumab (TRXT, OMP‐59R5, anti‐Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive‐stage small‐cell lung cancer (ED‐SCLC). J Clin Oncol. 2015;33:7508‐7508.
    1. Tentler JJ, Tan AC, Weekes CD, et al. Patient‐derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol. 2012;9:338‐350.
    1. Fu X, Guadagni F, Hoffman RM. A metastatic nude‐mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci U S A. 1992;89:5645‐5649.
    1. Banerjee D, Hernandez SL, Garcia A, et al. Notch suppresses angiogenesis and progression of hepatic metastases. Cancer Res. 2015;75:1592‐1602.
    1. Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha‐induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003;3:565‐576.
    1. Mazur PK, Einwachter H, Lee M, et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 2010;107:13438‐13443.
    1. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437‐450.
    1. De La OJ, Murtaugh LC. Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling. Cell Cycle. 2009;8:1860‐1864.
    1. Plentz R, Park JS, Rhim AD, et al. Inhibition of gamma‐secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology. 2009;136:1741–1749:e6.
    1. Hanlon L, Avila JL, Demarest RM, et al. Notch1 functions as a tumor suppressor in a model of K‐ras‐induced pancreatic ductal adenocarcinoma. Cancer Res. 2010;70:4280‐4286.
    1. Cubillo Gracian A, Dean A, Muñoz A, et al. 620PDYOSEMITE: A 3 arm double‐blind randomized phase 2 study of gemcitabine, paclitaxel protein‐bound particles for injectable suspension, and placebo (GAP) versus gemcitabine, paclitaxel protein‐bound particles for injectable suspension and either 1 or 2 truncated courses of demcizumab (GAD). Ann Oncol. 2017;28:v209-v268.

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