Skip to main content

Advertisement

SpringerLink
Log in

Phase II study of combination chemotherapy with irinotecan and cetuximab for pretreated metastatic colorectal cancer harboring wild-type KRAS

  • PHASE II STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

The aim of this study was to prospectively evaluate the efficacy of combination irinotecan and cetuximab chemotherapy in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. KRAS status was evaluated using the Cycleave PCR method; only patients without KRAS mutations were included. Cetuximab was administered initially at 400 mg/m2 followed by weekly 250 mg/m2 infusions. Irinotecan was administered biweekly. From October 2008 to April 2009, a total of 30 patients were enrolled. The objective response rate was 30.0% (95% confidence interval [CI], 14.7–49.4%) and the disease control rate (complete response, partial response, or stable disease) was 80.0% (95% CI, 61.4–92.3%). Among the 15 patients with stable disease, 11 patients experienced >10% tumor shrinkage. Median progression-free survival was 5.8 months (95% CI, 4.1–7.6). Median overall survival was not reached at a median follow-up of 10.1 months. Grade 2 skin toxicity was observed in 23 patients, while no grade 3 skin toxicity was observed. Combined irinotecan and cetuximab is effective for pretreated metastatic wild-type KRAS 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

Similar content being viewed by others

References

  1. 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  PubMed  CAS  Google Scholar 

  2. 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  PubMed  CAS  Google Scholar 

  3. 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  PubMed  CAS  Google Scholar 

  4. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboüé R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96:1166–1169

    Article  PubMed  Google Scholar 

  5. Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, André T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379

    Article  PubMed  Google Scholar 

  6. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508–515

    Article  PubMed  Google Scholar 

  7. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67(6):2643–2648

    Article  PubMed  CAS  Google Scholar 

  8. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. NCCN Practice Guidelines in Oncology, version 3. 2009

  9. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  10. Yatabe Y, Hida T, Horio Y, Kosaka T, Takahashi T, Mitsudomi T (2006) A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer. J Mol Diagn 8:335–341

    Article  PubMed  CAS  Google Scholar 

  11. Sakamoto H, Shimizu J, Horio Y, Ueda R, Takahashi T, Mitsudomi T, Yatabe Y (2007) Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol 212:287–294

    Article  PubMed  CAS  Google Scholar 

  12. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914–4921

    Article  PubMed  CAS  Google Scholar 

  13. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712

    Article  PubMed  Google Scholar 

  14. Kohne C, Stroiakovski D, Chang-chien C, Lim R, Pintér T, Bodoky G, Stroh C, Celik I, Rougier P, Van Cutsem E (2009) Predictive biomarker to improve treatment of metastatic colorectal cancer (mCRC): outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial. J Clin Oncol 27:15s (suppl; abstr 4068)

    Google Scholar 

  15. Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, Bertario L, Leo E, Pierotti MA, Pilotti S (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 20:84–90

    Article  PubMed  CAS  Google Scholar 

  16. Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961

    Article  PubMed  CAS  Google Scholar 

  17. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69:1851–1857

    Article  PubMed  CAS  Google Scholar 

  18. Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A (2009) PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 27:2622–2629

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

None declared.

Author information

Authors and Affiliations

  1. Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan

    Kohei Shitara, Tomoya Yokota, Daisuke Takahari, Takashi Shibata, Takashi Ura & Kei Muro

  2. Department of Gastroenterology, Nagoya Kyoritsu Hospital, Nagoya, Japan

    Setsuo Utsunomiya

  3. Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan

    Yoshitaka Inaba, Hidekazu Yamaura, Yozo Sato & Mina Najima

  4. Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan

    Hiroki Kawai, Masahiro Tajika & Akira Sawaki

  5. Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan

    Yasushi Yatabe

Authors
  1. Kohei Shitara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoya Yokota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daisuke Takahari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takashi Ura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Setsuo Utsunomiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshitaka Inaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hidekazu Yamaura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yozo Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mina Najima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroki Kawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Masahiro Tajika
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Akira Sawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yasushi Yatabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kei Muro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kohei Shitara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shitara, K., Yokota, T., Takahari, D. et al. 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 (2011). https://doi.org/10.1007/s10637-009-9382-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-009-9382-x

Keywords

Search

Navigation