Advertisement

A phase I/II study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer

  • Tae-Yong Kim
  • Hye Sook Han
  • Keun-Wook Lee
  • Dae Young Zang
  • Sun Young Rha
  • Young Iee Park
  • Jin-Soo Kim
  • Kyung-Hun Lee
  • Se Hoon Park
  • Eun-Kee Song
  • Soo-A Jung
  • NaMi Lee
  • Yeul Hong Kim
  • Jae Yong Cho
  • Yung-Jue BangEmail author
Original Article
  • 160 Downloads

Abstract

Background

Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC).

Methods

Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m2 infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks.

Results

In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8–21.9) and 29.5 weeks (95% CI 17.9–59.2), respectively.

Conclusions

The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.

Keywords

Chemotherapy Gastric cancer HER2 Poziotinib Trastuzumab 

Notes

Acknowledgements

Editorial assistance, under the guidance of the authors, was provided by David P. Figgitt PhD, ISMPP CMPP™, Content Ed Net, with funding from Hanmi Pharmaceutical Co., Ltd., Seoul, South Korea.

Funding

The study was sponsored by Hanmi.

Compliance with ethical standards

Conflict of interest

Yung-Jue Bang has served in consultant/advisory board roles for AstraZeneca, Novartis, Genentech/Roche, MSD, Bayer, BMS, Eli Lilly, Merck Serono, Taiho, Daiichi-Sankyo, Astellas, BeiGene, Green Cross, Samyang Biopharmaceuticals and Hanmi, and has received research grants from AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serono, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, CKD Pharma, Ono, Taiho, Takeda, BeiGene, Green Cross, Curis, Daiichi Sankyo and Astellas. Soo-A Jung and NaMi Lee are employees of Hanmi Pharmaceutical Co., Ltd., Seoul, South Korea. The other authors declare no conflicts of interest.

Ethical standards

All procedures followed were in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines and the study was approved by the Institutional Review Board of each participating center. All patients provided written informed consent before enrollment.

Supplementary material

10120_2019_958_MOESM1_ESM.docx (142 kb)
Supplementary material 1 (DOCX 142 kb)

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRefGoogle Scholar
  2. 2.
    Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8:CD004064.Google Scholar
  3. 3.
    Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39–51.CrossRefGoogle Scholar
  4. 4.
    Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523–9.CrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476–84.CrossRefGoogle Scholar
  6. 6.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.CrossRefGoogle Scholar
  7. 7.
    Henjes F, Bender C, von der Heyde S, Braun L, Mannsperger HA, Schmidt C, et al. Strong EGFR signaling in cell line models of ERBB2-amplified breast cancer attenuates response towards ERBB2-targeting drugs. Oncogenesis. 2012;1:e16.CrossRefGoogle Scholar
  8. 8.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New Engl J Med. 2006;355(26):2733–43.CrossRefGoogle Scholar
  9. 9.
    Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC–a randomized phase III trial. J Clin Oncol. 2016;34(5):443–51.CrossRefGoogle Scholar
  10. 10.
    Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN–a randomized, phase III study. J Clin Oncol. 2014;32(19):2039–49.CrossRefGoogle Scholar
  11. 11.
    Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 2004;44:195–217.CrossRefGoogle Scholar
  12. 12.
    Wang X, Batty KM, Crowe PJ, Goldstein D, Yang JL. The potential of panHER inhibition in cancer. Front Oncol. 2015;5:2.CrossRefGoogle Scholar
  13. 13.
    Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A, et al. Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J Biol Chem. 1996;271(7):3884–90.CrossRefGoogle Scholar
  14. 14.
    Nam HJ, Kim HP, Yoon YK, Hur HS, Song SH, Kim MS, et al. Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer. Cancer Lett. 2011;302(2):155–65.CrossRefGoogle Scholar
  15. 15.
    Kim TM, Lee KW, Oh DY, Lee JS, Im SA, Kim DW, et al. Phase 1 studies of poziotinib, an irreversible pan-HER tyrosine kinase inhibitor in patients with advanced solid tumors. Cancer Res Treat. 2018;50(3):835–42.CrossRefGoogle Scholar
  16. 16.
    O’Donovan N, Byrne AT, O’Connor AE, McGee S, Gallagher WM, Crown J. Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells. Invest New Drugs. 2011;29(5):752–9.CrossRefGoogle Scholar
  17. 17.
    Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel Plus trastuzumab with or without lapatinib. J Clin Oncol. 2016;34(6):542–9.CrossRefGoogle Scholar
  18. 18.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefGoogle Scholar
  19. 19.
    Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1–10.CrossRefGoogle Scholar
  20. 20.
    Oh DY, Lee KW, Cho JY, Kang WK, Im SA, Kim JW, et al. Phase II trial of dacomitinib in patients with HER2-positive gastric cancer. Gastric Cancer. 2016;19(4):1095–103.CrossRefGoogle Scholar
  21. 21.
    Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32.CrossRefGoogle Scholar
  22. 22.
    Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816):633–40.CrossRefGoogle Scholar
  23. 23.
    Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278–84.CrossRefGoogle Scholar
  24. 24.
    Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. New Engl J Med. 2015;372(8):724–34.CrossRefGoogle Scholar
  25. 25.
    Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018;19(10):1372–84.CrossRefGoogle Scholar
  26. 26.
    Wainberg ZA, Anghel A, Desai AJ, Ayala R, Luo T, Safran B, et al. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res. 2010;16(5):1509–19.CrossRefGoogle Scholar
  27. 27.
    Jackisch C, Welslau M, Schoenegg W, Selbach J, Harich HD, Schröder J, et al. Impact of trastuzumab treatment beyond disease progression for advanced/metastatic breast cancer on survival—results from a prospective, observational study in Germany. Breast. 2014;23(5):603–8.CrossRefGoogle Scholar
  28. 28.
    Palle J, Tougeron D, Pozet A, Soularue E, Artru P, Leroy F, et al. Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study. Oncotarget. 2017;8(60):101383–93.CrossRefGoogle Scholar
  29. 29.
    Makiyama A, Sagara K, Kawada J, Kashiwada T, Hosokawa A, Horie Y, et al. A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT). J Clin Oncol. 2018;36(15_Suppl):4011.CrossRefGoogle Scholar
  30. 30.
    Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640–53.CrossRefGoogle Scholar
  31. 31.
    Takegawa N, Nonagase Y, Yonesaka K, Sakai K, Maenishi O, Ogitani Y, et al. DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance. Int J Cancer. 2017;141(8):1682–9.CrossRefGoogle Scholar
  32. 32.
    Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017;18(11):1512–22.CrossRefGoogle Scholar
  33. 33.
    Iwasa S, Shitara K, Takahashi S, Park H, Kadowaki S, Modi S, et al. Updated results of phase 1 study of DS-8201a in subjects with HER2-expressing gastric cancer. J Clin Oncol. 2018;36(4_suppl):118.CrossRefGoogle Scholar
  34. 34.
    Watson S, Validire P, Cervera P, Zorkani N, Scriva A, Lemay F, et al. Combined HER2 analysis of biopsies and surgical specimens to optimize detection of trastuzumab-eligible patients in eso-gastric adenocarcinoma: a GERCOR study. Ann Oncol. 2013;24(12):3035–9.CrossRefGoogle Scholar
  35. 35.
    Pietrantonio F, Caporale M, Morano F, Scartozzi M, Gloghini A, De Vita F, et al. HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research. Int J Cancer. 2016;139(12):2859–64.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Tae-Yong Kim
    • 1
  • Hye Sook Han
    • 2
  • Keun-Wook Lee
    • 3
  • Dae Young Zang
    • 4
  • Sun Young Rha
    • 5
  • Young Iee Park
    • 6
  • Jin-Soo Kim
    • 7
  • Kyung-Hun Lee
    • 1
  • Se Hoon Park
    • 8
  • Eun-Kee Song
    • 9
  • Soo-A Jung
    • 10
  • NaMi Lee
    • 10
  • Yeul Hong Kim
    • 11
  • Jae Yong Cho
    • 12
  • Yung-Jue Bang
    • 1
    Email author
  1. 1.Department of Internal MedicineSeoul National University Hospital, Seoul National University College of MedicineSeoulSouth Korea
  2. 2.Chungbuk National University College of MedicineCheongjuSouth Korea
  3. 3.Seoul National University Bundang HospitalSeoul National University College of MedicineSeongnamSouth Korea
  4. 4.Hallym University Sacred Heart HospitalAnyang-siSouth Korea
  5. 5.Yonsei Cancer CenterYonsei University College of MedicineSeoulSouth Korea
  6. 6.National Cancer CenterSeoulSouth Korea
  7. 7.Seoul National University Boramae Medical CenterSeoulSouth Korea
  8. 8.Sungkyunkwan University Samsung Medical CenterSeoulSouth Korea
  9. 9.Chonbuk National University Medical SchoolJeonjuSouth Korea
  10. 10.Hanmi Pharmaceutical Co., Ltd.SeoulSouth Korea
  11. 11.Korea University Anam HospitalSeoulSouth Korea
  12. 12.Gangnam Severance HospitalSeoulSouth Korea

Personalised recommendations