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01-08-2011 | PHASE II STUDIES

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

Authors: Kohei Shitara, Tomoya Yokota, Daisuke Takahari, Takashi Shibata, Takashi Ura, Setsuo Utsunomiya, Yoshitaka Inaba, Hidekazu Yamaura, Yozo Sato, Mina Najima, Hiroki Kawai, Masahiro Tajika, Akira Sawaki, Yasushi Yatabe, Kei Muro

Published in: Investigational New Drugs | Issue 4/2011

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.

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 357:2040–2048PubMedCrossRef

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 351:337–345PubMedCrossRef

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 359:1757–1765PubMedCrossRef

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 96:1166–1169PubMedCrossRef

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 26:374–379PubMedCrossRef

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 19:508–515PubMedCrossRef

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):2643–2648PubMedCrossRef

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

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 92:205–216PubMedCrossRef

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 8:335–341PubMedCrossRef

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 212:287–294PubMedCrossRef

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 24:4914–4921PubMedCrossRef

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 26:5705–5712PubMedCrossRef

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)

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 20:84–90PubMedCrossRef

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 68:1953–1961PubMedCrossRef

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 69:1851–1857PubMedCrossRef

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 27:2622–2629PubMedCrossRef

Title: Phase II study of combination chemotherapy with irinotecan and cetuximab for pretreated metastatic colorectal cancer harboring wild-type KRAS
Authors: Kohei Shitara
Tomoya Yokota
Daisuke Takahari
Takashi Shibata
Takashi Ura
Setsuo Utsunomiya
Yoshitaka Inaba
Hidekazu Yamaura
Yozo Sato
Mina Najima
Hiroki Kawai
Masahiro Tajika
Akira Sawaki
Yasushi Yatabe
Kei Muro
Publication date: 01-08-2011
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2011
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-009-9382-x

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