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Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naïve, HER2-positive advanced gastric cancer

  • Daisuke TakahariEmail author
  • Keisho Chin
  • Naoki Ishizuka
  • Atsuo Takashima
  • Keiko Minashi
  • Shigenori Kadowaki
  • Tomohiro Nishina
  • Takako Eguchi Nakajima
  • Kenji Amagai
  • Nozomu Machida
  • Masahiro Goto
  • Keisei Taku
  • Takeru Wakatsuki
  • Hirokazu Shoji
  • Shuichi Hironaka
  • Narikazu Boku
  • Kensei Yamaguchi
Original Article
  • 294 Downloads

Abstract

Background

Trastuzumab with cisplatin and fluoropyrimidines improves overall survival (OS) in patients with HER2-positive advanced gastric cancer (AGC). S-1 plus oxaliplatin (SOX) is one of the standard regimens for HER2-negative AGC in Japan. However, few studies have evaluated trastuzumab combined with SOX in patients with HER2-positive AGC.

Methods

This was a multicenter, phase II study conducted at 10 institutions in Japan. Patients with HER2-positive AGC received S-1 twice a day on days 1–14 and oxaliplatin and trastuzumab on day 1 of a 21-day cycle. The primary endpoint was the confirmed overall response rate (ORR), and the secondary endpoints were OS, progression-free survival (PFS), and safety. The sample size was 75 to have 90% power with an alpha error of 0.1 (one-sided), expecting an ORR of 65% and threshold of 50%.

Results

From June 2015 to January 2018, 75 patients were enrolled. The ORR was 70.7% [95% confidence interval (CI) 59.0–80.6]. The median OS and PFS were estimated as 18.1 months (95% CI 15.6–26.5) and 8.8 months (95% CI 7.4–12.2), respectively. The major grade 3 or 4 adverse events were sensory neuropathy (16.0%) and neutropenia (10.7%).

Conclusions

Trastuzumab with SOX had promising activity with well-tolerated toxicities for patients with HER2-positive AGC.

Clinical trial registration

UMIN000017602.

Keywords

Advanced gastric cancer HER2-positive Trastuzumab S-1 Oxaliplatin 

Notes

Acknowledgements

The authors thank all the participating patients, their families, and site staff; Kohei Shitara (National Cancer Center Hospital East), Yozo Sato (Aichi Cancer Center Hospital) and Takayuki Kobayashi (The Cancer Institute Hospital of JFCR) for their work in the Data and Safety Monitoring Committee; and Akemi Egami and Yuko Yamahara (The Cancer Institute Hospital of JFCR) for their dedicated support for data management. This study was previously presented in part at the ESMO 2018 Congress, which took place between 19 and 23 October in Munich, Germany. The authors acknowledge the writing assistance from JAM Post, Inc.

Funding

This study was partially sponsored by the Japanese Foundation for Multidisciplinary Treatment of Cancer (JMFC2015; no Grant Number).

Compliance with ethical standards

Conflict of interest

Dr. Takahari reports grants and personal fees from Taiho Pharmaceutical Co. and Ono Pharmaceutical Co., and personal fees from Eli Lilly Japan, Bristol-Myers Squibb, Yakult Honsha Co., Ltd., and Chugai Pharmaceutical Co., Ltd. Naoki Ishizuka reports personal fees from Bristol-Myers Squibb, Novartis, and Merck Sharp and Dohme. Dr. Takashima reports grants and personal fees from Taiho Pharmaceutical Co. and Takeda Pharmaceutical Company Ltd, personal fees from Eli Lilly Japan, Ono Pharmaceutical Co., Yakult Honsha Co., Ltd., and Chugai Pharmaceutical Co., Ltd., and grants from Sumitomo Dainippon Pharma and LSK BioPartners. Dr. Minashi reports grants from Merck Sharp and Dohme and Ono Pharmaceutical Co. Dr. Kadowaki reports grants and personal fees from Taiho Pharmaceutical Co. and Eli Lilly, grants from Ono Pharmaceutical Co. and Bristol-Myers Squibb, and personal fees from Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bayer, and Merck. Dr. Nishina reports grants and personal fees from Taiho Pharmaceutical Co., grants and personal fees from Eli Lilly Japan, Ono Pharmaceutical Co., Bristol-Myers Squibb, Yakult Honsha Co., Ltd., and Chugai Pharmaceutical Co., Ltd., and grants from Daiichi Sankyo, Dainippon Sumitomo Pharma, Boehringer Ingelheim, and Merck Sharp and Dohme. Dr. Nakajima reports grants and personal fees from Taiho Pharmaceutical Co., Ono Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Merck, Merck Sharp and Dohme, and Takeda Pharmaceutical Company Ltd, and personal fees from Eli Lilly Japan, Bristol-Myers Squibb, Yakult Honsha Co., Ltd., Bayer, Sanofi, Sawai Pharmaceutical Company, Limited, Mochida Pharmaceutical Company, Ltd, Kyowa Hakko-Kirin, Dainippon Sumitomo Pharma, Maruho Co. Ltd., Daiichi Sankyo, Eisai Co., Ltd, and AstraZeneca. Dr. Amagai reports grants and personal fees from Taiho Pharmaceutical Co., grants from Merck Sharp and Dohme, and personal fees from Eli Lilly Japan, Bristol-Myers Squibb, Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, and Hisamitsu Pharmaceutical Co., Inc. Dr. Machida reports grants and personal fees from Taiho Pharmaceutical Co., personal fees from Eli Lilly Japan, Ono Pharmaceutical Co., Bristol-Myers Squibb, Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Nippon Kayaku, Daiichi Sankyo, Merck Sharp and Dohme. Dr. Goto reports grants, personal fees and non-financial support from Taiho Pharmaceutical Co., Yakult, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Takeda Pharmaceutical Company Ltd, Kyowa Hakko Kirin, Novartis, Bayer, and Mochida Pharmaceutical Company, Ltd. Dr. Wakatsuki reports personal fees from Taiho Pharmaceutical Co., Eli Lilly Japan, Bayer, and Chugai Pharmaceutical Co., Ltd. Dr. Hironaka reports personal fees from Taiho Pharmaceutical Co., Eli Lilly Japan, Ono Pharmaceutical Co., Bristol-Myers Squibb, Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Daiichi-Sankyo. Dr. Boku reports grants from Taiho Pharmaceutical Co., Ono Pharmaceutical Co. and Bristol-Myers Squibb, and personal fees from Taiho, Ono Pharmaceutical Co., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., and Eli Lilly. Dr. Yamaguchi reports grants and personal fees from Taiho Pharmaceutical Co., Eli Lilly Japan, Ono Pharmaceutical Co., Bristol-Myers Squibb, Yakult Honsha Co., Ltd., and Chugai Pharmaceutical Co., Ltd., and personal fees from Takeda Pharmaceutical Company Ltd, Bayer, Daiichi-Sankyo, Sanofi, Dainippon-Sumitomo Pharma, Merck Sharp and Dohme, and Gilead Sciences, Inc. All remaining authors have declared no conflicts of interest.

Human rights statement and informed consent

All procedures followed were in accordance with the ethical standards of the institutional and national committees governing human experimentation and in compliance with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent or an appropriate substitute was obtained from all patients prior to their inclusion in the study.

Supplementary material

10120_2019_973_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 25 kb)
10120_2019_973_MOESM2_ESM.docx (17 kb)
Supplementary material 2 (DOCX 17 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:E359–86.CrossRefGoogle Scholar
  2. 2.
    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;376:687–97.CrossRefGoogle Scholar
  3. 3.
    Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20:1–19.CrossRefGoogle Scholar
  4. 4.
    Muro K, Van Cutsem E, Narita Y, Pentheroudakis G, Baba E, Li J, et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with metastatic gastric cancer; a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann Oncol. 2019;30:34–43.CrossRefGoogle Scholar
  5. 5.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.CrossRefGoogle Scholar
  6. 6.
    Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015;26:141–8.CrossRefGoogle Scholar
  7. 7.
    Kurokawa Y, Sugimoto N, Miwa H, Tsuda M, Nishina S, Okuda H, et al. Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1). Br J Cancer. 2014;110:1163–8.CrossRefGoogle Scholar
  8. 8.
    Miura Y, Sukawa Y, Hironaka S, Mori M, Nishikawa K, Tokunaga S, et al. Five-weekly S-1 plus cisplatin therapy combined with trastuzumab therapy in HER2-positive gastric cancer: a phase II trial and biomarker study (WJOG7212G). Gastric Cancer. 2018;21:84–95.CrossRefGoogle Scholar
  9. 9.
    Ryu MH, Yoo C, Kim JG, Ryoo BY, Park YS, Park SR, et al. Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer. 2015;51:482–8.CrossRefGoogle Scholar
  10. 10.
    Kim GM, Jeung HC, Rha SY, Kim HS, Jung I, Nam BH, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine–oxaliplatin in advanced gastric cancer. Eur J Cancer. 2012;48:518–26.CrossRefGoogle Scholar
  11. 11.
    Kito Y, Machida N, Kawai S, Hamauchi S, Tsushima T, Todaka A, et al. Phase II study of S-1 plus oxaliplatin 130 mg/m2 in Japanese patients with advanced gastric cancer. Int J Clin Oncol. 2018;23:1084–9.CrossRefGoogle Scholar
  12. 12.
    Sawaki A, Ohashi Y, Omuro Y, Satoh T, Hamamoto Y, Boku N. Efficacy of trastuzumab in Japanese patients with HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study. Gastric Cancer. 2012;15:313–22.CrossRefGoogle Scholar
  13. 13.
    Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013;14:1278–86.CrossRefGoogle Scholar
  14. 14.
    Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 With oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a Gercor Study. J Clin Oncol. 2006;24:394–400.CrossRefGoogle Scholar
  15. 15.
    Park SR, Kim MJ, Nam BH, Kim CG, Lee JY, Cho SJ, et al. A randomised phase II study of continuous versus stop-and-go S-1 plus oxaliplatin following disease stabilisation in first-line chemotherapy in patients with metastatic gastric cancer. Eur J Cancer. 2017;83:32–42.CrossRefGoogle Scholar
  16. 16.
    Kimura Y, Fujii M, Masuishi T, Nishikawa K, Kunisaki C, Matsusaka S, et al. Multicenter phase II study of trastuzumab plus S-1 alone in elderly patients with HER2-positive advanced gastric cancer (JACCRO GC-06). Gastric Cancer. 2018;21:421–7.CrossRefGoogle Scholar
  17. 17.
    Zhou J, Peng Z, Liu Y, Gong J, Zhang X, Lu M, et al. Predictive value of serum HER2 ECD in patients with HER2-positive advanced gastric cancer treated with trastuzumab plus chemotherapy. J Gastroenterol. 2015;50:955–61.CrossRefGoogle Scholar
  18. 18.
    Wakatsuki T, Yamamoto N, Sano T, Chin K, Kawachi H, Takahari D, et al. Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy in patients with HER2-positive gastric cancer. J Gastroenterol. 2018;53:1186–95.CrossRefGoogle Scholar
  19. 19.
    Yagi S, Wakatsuki T, Yamamoto N, Chin K, Takahari D, Ogura M, et al. Clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens in patients with advanced HER2 positive gastric cancer. Gastric Cancer. 2019;22:518–25.CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Daisuke Takahari
    • 1
    Email author
  • Keisho Chin
    • 1
  • Naoki Ishizuka
    • 2
  • Atsuo Takashima
    • 3
  • Keiko Minashi
    • 4
  • Shigenori Kadowaki
    • 5
  • Tomohiro Nishina
    • 6
  • Takako Eguchi Nakajima
    • 7
  • Kenji Amagai
    • 8
  • Nozomu Machida
    • 9
  • Masahiro Goto
    • 10
  • Keisei Taku
    • 11
  • Takeru Wakatsuki
    • 1
  • Hirokazu Shoji
    • 3
  • Shuichi Hironaka
    • 4
    • 12
  • Narikazu Boku
    • 3
  • Kensei Yamaguchi
    • 1
  1. 1.Department of GastroenterologyThe Cancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  2. 2.Department of Clinical Trial Planning and ManagementThe Cancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  3. 3.Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
  4. 4.Clinical Trial Promotion DepartmentChiba Cancer CenterChibaJapan
  5. 5.Department of Clinical OncologyAichi Cancer Center HospitalNagoyaJapan
  6. 6.Department of Gastrointestinal Medical OncologyShikoku Cancer CenterMatsuyamaJapan
  7. 7.Department of Clinical OncologySt Marianna University School of MedicineKawasakiJapan
  8. 8.Department of GastroenterologyIbaraki Prefectural Central HospitalKasamaJapan
  9. 9.Department of Gastrointestinal OncologyShizuoka Cancer CenterShizuokaJapan
  10. 10.Department of Cancer Chemotherapy CenterOsaka Medical CollegeTakatsukiJapan
  11. 11.Department of Medical OncologyShizuoka General HospitalShizuokaJapan
  12. 12.Department of Medical Oncology and Hematology, Faculty of MedicineOita UniversityOitaJapan

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