Skip to main content

Advertisement

SpringerLink
Log in

Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan, oxaliplatin, and fluoropyrimidines (KSCC 0901 study)

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines.

Methods

The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m2, followed by weekly infusion at 250 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2 orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status.

Results

Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3–4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia.

Conclusions

Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, Grothey A, Vauthey JN, Nagorney DM, McWilliams RR (2009) Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27:3677–3683

    Article  PubMed  PubMed Central  Google Scholar 

  2. Baselga J (2001) The EGFR as a target for anticancer therapy-focus on cetuximab. Eur J Cancer 37:S16–S22

    Article  CAS  PubMed  Google Scholar 

  3. Ciardiello F, Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7:2958–2970

    CAS  PubMed  Google Scholar 

  4. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048

    Article  CAS  PubMed  Google Scholar 

  5. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345

    Article  CAS  PubMed  Google Scholar 

  6. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417

    Article  Google Scholar 

  7. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671

    Article  CAS  PubMed  Google Scholar 

  8. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR (2008) K-ras Mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765

    Article  CAS  PubMed  Google Scholar 

  9. Nukatsuka M, Saito H, Nakagawa F, Tsujimoto H, Sakamoto K, Tsukioka S, Uchida J, Kiniwa M, Kobunai T, Takechi T (2012) Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice. Exp Ther Med 3:755–762

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Overholser JP, Prewett MC, Hooper AT, Waksal HW, Hicklin DJ (2000) Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer 89:74–82

    Article  CAS  Google Scholar 

  11. Kobunai T, Waranabe T, Fukusato T (2011) Antitumor activity of S-1 in combination with Cetuximab on human gastric cancer cell lines in vivo. Anticancer Res 31:3691–3696

    CAS  PubMed  Google Scholar 

  12. Fukuda K, Saikawa Y, Takahashi M, Takahashi T, Wada N, Kawakubo H, Takeuchi H, Kitagawa Y (2012) Antitumor effect of cetuximab in combination with S-1 in EGFR-amplified gastric cancer cells. Int J Oncol 40:975–982

    CAS  PubMed  Google Scholar 

  13. Shirasaka T (2009) Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol 39:2–15

    Article  PubMed  Google Scholar 

  14. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634

    Article  CAS  PubMed  Google Scholar 

  15. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. J Clin Oncol 25:1658–1664

    Article  PubMed  Google Scholar 

  16. André T, Blons H, Mabro M, Chibaudel B, Bachet JB, Tournigand C, Bennamoun M, Artru P, Nguyen S, Ebenezer C, Aissat N, Cayre A, Penault-Llorca F, Laurent-Puig P, de Gramont A, GERCOR (2013) Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol 24:412–419

    Article  PubMed  Google Scholar 

  17. Shitara K, Yokota T, Takahari D, Shibata T, Ura T, Utsunomiya S, Inaba Y, Yamaura H, Sato Y, Najima M, Kawai H, Tajika M, Sawaki A, Yatabe Y, Muro K (2011) Phase II study of combination chemotherapy with irinotecan and cetuximab for pretreated metastatic colorectal cancer harboring wild-type KRAS. Invest New Drugs 29:688–693

    Article  CAS  PubMed  Google Scholar 

  18. Shitara K, Yuki S, Yoshida M, Takahari D, Utsunomiya S, Yokota T, Sato Y, Inaba Y, Tajika M, Kawai H, Yamaura H, Kato M, Yamazaki K, Komatsu Y, Muro K (2012) Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Invest New Drugs 30:787–793

    Article  CAS  PubMed  Google Scholar 

  19. Tahara M, Shirao K, Boku N, Yamaguchi K, Komatsu Y, Inaba Y, Arai T, Mizunuma N, Satoh T, Takiuchi H, Nishina T, Sakata Y (2008) Multicenter phase II study of cetuximab plus irinotecan in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. Jpn J Clin Oncol 38:762–769

    Article  Google Scholar 

  20. Muro K, Yoshino T, Doi T, Shirao K, Takiuchi H, Hamamoto Y, Watanabe H, Yang BB, Asahi D (2009) A Phase 2 clinical trial of panitumumab monotherapy in Japanese patient as with metastatic Colorectal Cancer. Jpn J Clin Oncol 39:321–326

    Article  PubMed  Google Scholar 

  21. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319

    Article  CAS  PubMed  Google Scholar 

  22. Oki E, Emi Y, Miyamoto Y, Kabashima A, Higashi H, Ogata Y, Ikebe M, Saeki H, Tokunaga S, Shirabe K, Beppu T, Uchida S, Takatsuki M, Sakoda M, Eguchi S, Akagi Y, Kakeji Y, Baba H, Natsugoe S, Maehara Y, Kyushu Study Group of Clinical Cancer (KSCC) (2015) Phase II trial of S-1 and oxaliplatin plus cetuximab for colorectal cancer patients with initially unresectable or not optimally resectable liver metastases (KSCC1002). Ann Surg Oncol 22:S1067–S1074

    Article  PubMed  Google Scholar 

  23. Ogawa M, Anan T, Suzuki T, Okuma M, Ichihara K, Hasegawa T, Yoshida K, Yanaga K (2016) Initial report of phase II study on bi-weekly SOX plus cetuximab treatment for wild-type K-RAS advanced and recurrent colorectal cancer. Anticancer Res 36:2505–2511

    PubMed  Google Scholar 

  24. Chuah B, Goh BC, Lee SC, Soong R, Lau F, Mulay M, Dinolfo M, Lim SE, Soo R, Furuie T, Saito K, Zergebel C, Rosen LS (2011) Comparison of the pharmacokinetics and pharmacodynamics of S-1 between Caucasian and East Asian patients. Cancer Sci 102:478–483

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The KSCC0901 was conducted by the KSCC and Clinical Research Support Center (CReS) Kyushu. Merck Serono and Taiho Pharmaceutical Co. provided an unrestricted contribution to CReS Kyushu. We greatly thank the participated patients and their families. We are indebted to the physicians and all of the clinical study teams at the participating institutions. We thank all other co-medical staff, and the Independent Data Monitoring Committee (Kuniaki Shirao, Toshiro Kuroiwa, Yoichi Nakanishi, Shuji Nakano, and Eishi Baba) who contributed to this study. We also thank Ms. Taniguchi, Ms. Sakamoto, Ms. Shimamoto, Mr. Aratani, and the other staff at CReS Kyushu for their excellent collection and manage of data, secretarial assistance, and other support.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan

    Takao Takahashi & Kazuhiro Yoshida

  2. Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan

    Yasunori Emi

  3. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Eiji Oki & Yoshihiko Maehara

  4. Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kazuma Kobayashi

  5. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan

    Akihito Tsuji

  6. Department of Cancer Information Research, National Kyushu Cancer Center Clinical Research Institute, Fukuoka, Japan

    Mototsugu Shimokawa

  7. Department of Surgery, Social Insurance Tagawa Hospital, Tagawa, Japan

    Takaho Tanaka

  8. Department of Surgery, Kurume University School of Medicine, Kurume, Japan

    Yoshito Akagi

  9. Department of Surgery, Kurume University Medical Center, Kurume, Japan

    Yutaka Ogata

  10. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Hideo Baba

  11. Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Shoji Natsugoe

Authors
  1. Takao Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasunori Emi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eiji Oki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuma Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akihito Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mototsugu Shimokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takaho Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshito Akagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yutaka Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideo Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kazuhiro Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shoji Natsugoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yoshihiko Maehara
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Kyushu Study Group of Clinical Cancer (KSCC)

Corresponding author

Correspondence to Yoshihiko Maehara.

Ethics declarations

Conflict of interest

H. Baba and K. Yoshida have received research grants from Merck Serono and Taiho Pharmaceutical Co., Ltd. T. Takahashi, E. Oki, A. Tsuji, H. Baba, K. Yoshida and Yoshihiko Maehara have received speaker honorarium from Merck Serono and Taiho Pharmaceutical Co., Ltd.. Y. Emi, K. Kobayashi, M. Shimokawa, T. Tanaka, Y. Akagi, Y. Ogata, S. Natsugoe declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahashi, T., Emi, Y., Oki, E. et al. Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan, oxaliplatin, and fluoropyrimidines (KSCC 0901 study). Cancer Chemother Pharmacol 78, 585–593 (2016). https://doi.org/10.1007/s00280-016-3109-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-016-3109-4

Keywords

Search

Navigation