Biweekly cetuximab plus irinotecan as second-line chemotherapy for patients with irinotecan-refractory and KRAS wild-type metastatic colorectal cancer according to epidermal growth factor receptor expression status

Kang, Myoung Joo; Hong, Yong Sang; Kim, Kyu-Pyo; Kim, Sun Young; Baek, Ji Yeon; Ryu, Min‐Hee; Lee, Jae‐Lyun; Chang, Heung Moon; Kim, Mi‐Jung; Chang, Hee Jin; Kang, Yoon‐Koo; Kim, Tae Won

doi:10.1007/s10637-011-9703-8

Cited by 22 publications

(18 citation statements)

References 31 publications

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“…Patients were divided into three arms. Arm A, the experimental arm, consisted of 40 patients who participated in a previous prospective multicenter study (NCT00637091), (21) which was conducted between March 2008 and October 2009 and determined the feasibility of cetuximab plus irinotecan as second-line chemotherapy after failure of irinotecan plus fluoropyrimidines in oxaliplatinna€ ıve, wild-type KRAS tumors with or without epidermal growth factor receptor (EGFR) expression (measured by immunohistochemistry). For the control arms, 199 patients who received oxaliplatin plus fluoropyrimidines as second-line chemotherapy were screened during the same time period as the study described above, and 80 patients with the following 6…”

Section: Methodsmentioning

confidence: 99%

“…Patients in arm A, the experimental arm, were accrued prospectively and the results from our previous publication were updated. (21) For patients in arms B and C, the control arms, medical records were reviewed retrospectively. Descriptive statistics are presented as proportions and median values.…”

Section: Methodsmentioning

confidence: 99%

“…oxaliplatin-na€ ıve and harboring wild-type KRAS, were enrolled in arm A. (21) For the controls arms, 80 patients who were treated with second-line oxaliplatin plus fluoropyrimidines during the same time period were accrued retrospectively and their medical records were reviewed: 46 patients with wild-type KRAS tumors were included in arm B and 34 patients with mutant KRAS tumors were included in arm C (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…(19,20) We recently reported promising efficacy in a prospective phase II study of second-line cetuximab plus irinotecan in mCRC patients whose tumors were irinotecan-refractory, oxaliplatinna€ ıve and harboring wild-type KRAS. (21) Based on these results, the present study was designed to: (i) compare two different second-line treatment strategies, cetuximab plus irinotecan versus oxaliplatin plus fluoropyrimidines, in patients with irinotecan-refractory mCRC and oxaliplatin-na€ ıve mCRC patients; and (ii) to investigate whether the oxaliplatin plus fluoropyrimidines regimen could be delayed to third-line therapy in the treatment continuum of these patients.…”

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Second‐line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild‐type KRAS

et al. 2013

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The goal of the present study was to compare the efficacy of the combination of cetuximab and irinotecan to the combination of oxaliplatin and fluoropyrimidines as second-line chemotherapy in patients with irinotecan-refractory and oxaliplatin-na€ ıve metastatic colorectal cancer (mCRC) harboring wild-type KRAS. The study included 120 patients with mCRC who had progressed after irinotecan-containing first-line chemotherapy and were never treated with oxaliplatin; 40 patients with wild-type KRAS were accrued prospectively in the experimental arm (arm A), and 80 patients accrued retrospectively were divided into control arms B (n = 46) and C (n = 34) according to KRAS genotype. Second-line treatments consisted of cetuximab plus irinotecan for arm A, and oxaliplatin plus either 5-fluorouracil (FOLFOX) or capecitabine (CapeOX) for the control arms. The median progression-free survival (PFS) was 8.3, 5.8 and 3.9 months, for arms A, B and C, respectively, with statistical significance favoring arm A (P = 0.007). Differences in overall survival did not reach statistical significance (18.3 vs 12.6 vs 12.9, P = 0.138), although there was a trend toward longer overall survival in arm A. In terms of benefit from oxaliplatin-containing regimens either as second-line or third-line therapy, the median PFS was 5.0 months in arms B and C as second-line therapy, and 4.0 months in arm A as third-line therapy, with no statistical significance (P = 0.385). Second-line cetuximab plus irinotecan is a valid treatment strategy for mCRC patients with irinotecan-refractory and oxaliplatin-na€ ıve tumors harboring wild-type KRAS. Oxaliplatin-containing chemotherapy resulted in equivalent PFS both as a second-line and a third-line therapy, enabling delay of the administration of FOLFOX and CapeOX until subsequent treatment cycles. (Cancer Sci 2013; 104: 473-480) A t present, a limited number of active drugs are available for the treatment of metastatic colorectal cancer (mCRC), and the upfront doublet combination of fluoropyrimidines plus either oxaliplatin or irinotecan is regarded as the reference strategy for patients for whom intensive therapy is appropriate.(1-3) Before the era of targeted agents, treatment strategies in terms of the combination or sequence of cytotoxic agents were rather simple; survival outcomes did not differ according to either the administration sequence of oxaliplatin or irinotecan, and whether sequential or combination chemotherapy was applied in the treatment continuum was inconsequential.(4-7) Treatment strategies have become more complicated in the era of targeted agents.Bevacizumab plus chemotherapy as initial chemotherapy improved efficacy without significant adverse events and was proven effective as second-line continuation beyond progression; (8)(9)(10)(11)(12) however, limited overall survival (OS) benefit was observed when bevacizumab was combined with optimal doublet chemotherapy.As a first-line treatment, cetuximab has shown OS benefit when combined with irinotecan plus infusional 5-fluorouracil...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Second‐line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild‐type KRAS

et al. 2013

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“…Since 2004, the combination of a diagnostic test for EGFR (EGFR PharmDx™ Kit, Dako, Cambridgeshire, UK), and the subsequent application of cetuximab or panitumumab in EGFR-positive colon carcinomas has been approved by FDA, reviewed in [94]. However, subsequent studies have shown that EGFR-negative tumours may also benefit from cetuximab therapy [69,95,96]. These studies appear to indicate that analysis of EGFR expression via IHC may not be as reliable in predicting the efficacy of EGFR therapy.…”

Section: Reviewmentioning

confidence: 99%

Targeted therapies in colorectal cancer—an integrative view by PPPM

2013

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In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.

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Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status

Jensen

Schou

Yilmaz

et al. 2020

Intl Journal of Cancer

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Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third‐line setting. The intention‐to‐treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next‐generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS‐WT and RAS‐MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.

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Biweekly cetuximab plus irinotecan as second-line chemotherapy for patients with irinotecan-refractory and KRAS wild-type metastatic colorectal cancer according to epidermal growth factor receptor expression status

Abstract: Biweekly cetuximab plus irinotecan as second-line treatment showed significant anti-tumor activity in patients with irinotecan-refractory mCRC and WT-KRAS regardless of EGFR expression status.

Cited by 22 publications

References 31 publications

Second‐line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild‐type KRAS

Second‐line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild‐type KRAS

Targeted therapies in colorectal cancer—an integrative view by PPPM

Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status

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