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CED-CCO SPECIAL ADVICE REPORT #8 CED-CCO Special Advice Report #8 The Use of Epidermal Growth Factor Receptor Inhibitors in Advanced Colorectal Cancer D. Jonker, J. Biagi, and A.E. Haynes Report Date: July 9, 2008 The full CED-CCO Special Advice Report #8 consists of a Summary and a Full Report and is available on the CCO website (http://www.cancercare.on.ca) PEBC CED-CCO page at: http://www.cancercare.on.ca/toolbox/qualityguidelines/other-reports/evaldrug-rep/ SUMMARY QUESTIONS Primary Research Question: Is treatment with epidermal growth factor receptor (EGFR) inhibitors in patients with advanced colorectal cancer (CRC) recommended? Outcomes of interest: overall survival, progression-free survival, objective tumour response rates, quality of life, and adverse events. Can K-RAS testing be used to identify patients with advanced CRC who may benefit from treatment with EGFR inhibitors? Outcomes of interest: overall survival, progression-free survival, objective tumour response rates, quality of life, and adverse events. Secondary Research Question: Is one EGFR inhibitor superior or inferior to another when used to treat patients with advanced CRC? Outcomes of interest: overall survival, progression-free survival, objective tumour response rates, quality of life, and adverse events. TARGET POPULATION Adult patients with advanced CRC who are suitable candidates for therapy (ECOG performance status grade 0-2) RECOMMENDATIONS The two clinically available EGFR inhibitors, cetuximab and panitumumab, are recommended for patients with advanced CRC after failure of standard chemotherapy CED-CCO SPECIAL ADVICE REPORT #8 and whose tumours have tested negative for K-RAS gene mutations (i.e. patients with K-RAS wild-type). The recommended dose of cetuximab is a loading dose of 400 mg/m2 of body surface area (BSA) intravenously (iv) followed by a weekly 250 mg/m 2 infusion; pre-medication with an antihistamine is required. The dose of panitumumab is 6 mg/kg iv every two weeks; no pre-medication is required. Key Evidence o A randomized phase III study that compared cetuximab plus best supportive care (BSC) versus (vs.) BSC alone (1) demonstrated response rates of 8.0% in the cetuximab group vs. 0% in the BSC group (p<0.001) and stable disease in 31.4% vs. 10.9% (p<0.001), respectively. Progression-free survival was superior for the cetuximab arm (hazard ratio [HR] 0.68, p<0.001), as was overall survival (HR 0.77, p=0.005). Quality of life was superior for physical function and global health status scores (both p<0.05). Sixty-nine percent of the intent-to-treat population was retrospectively analyzed according to K-RAS status. In the K-RAS wild-type population, cetuximab treatment resulted in an increase of median progression-free survival 3.8 vs. 1.9 months (HR 0.40, p<0.001), median overall survival 9.5 vs. 4.8 months (HR 0.55, p<0.0001) (2). Within the K-RAS mutant population, no effect of cetuximab was apparent on progression-free survival (HR 0.99) or overall survival (HR 0.98). o A randomized phase III study compared panitumumab plus BSC versus BSC alone (3). The response rate was 10% for panitumumab vs. 0% for BSC (p<0.0001); stable disease 27% vs. 10%. Progression-free survival was superior for the panitumumab arm (HR 0.54, p<0.0001). There was no difference in overall survival (HR 1.0), which may have been affected by the high proportion of patients undertaking the protocol-sanctioned crossover to panitumumab after progression on the BSC arm. Quality of life was not reported. Toxicities of panitumumab treatment were manageable. Ninety-two percent of the intent-to-treat population was retrospectively analyzed according to K-RAS status (4). In the K-RAS wild-type population, panitumumab treatment resulted in an increase of median progression-free survival 2.8 vs. 1.7 months (HR 0.45, p<0.0001) and response rate (17% vs. 0%). Median overall survival was not significantly different (HR 1.02); however, it was likely affected by crossover. Within the K-RAS mutant population, no effect of panitumumab was apparent on progression-free survival (HR 0.99), response rate, or overall survival (HR 1.02). For patients who have not yet failed chemotherapy treatment, there is mounting evidence that EGFR inhibitors are safe and effective when combined with chemotherapy in advanced CRC patients who are confirmed to be K-RAS gene wildtype. However, at this time there is insufficient evidence to recommend it over the current standards of care. Key Evidence o There are two trials published in abstract form involving the addition of cetuximab to chemotherapy in previously untreated patients, for which exploratory K-RAS mutation analysis have been reported: one in combination with folinic acid plus fluorouracil plus irinotecan (FOLFIRI) and the other with folinic acid plus fluorouracil plus oxaliplatin (FOLFOX). In these trials, there was a statistically significant reduction of the risk of progression of 32% and 43% with the addition of cetuximab to FOLFIRI and FOLFOX, respectively (5,6). ii CED-CCO SPECIAL ADVICE REPORT #8 o In patients with one prior line of chemotherapy, there are two trials examining the addition of cetuximab to second-line chemotherapy. In the Erbitux® (ImClone Systems Incorporated and Bristol-Myers Squibb Company; cetuximab) Plus Irinotecan for Metastatic Colorectal Cancer (EPIC) study, 1,298 patients who received first-line oxaliplatin-based chemotherapy were randomized to cetuximab plus irinotecan versus irinotecan alone (7). Superior response rate (16.4% vs. 4.2%, p<0.0001) and progression-free survival (median 4.0 vs. 2.6 months, HR 0.692; p<0.0001) were demonstrated. Median overall survival was not statistically different (HR 0.98), a possible effect of the crossover by 47% of the monotherapy arm to receive subsequent cetuximab. The quality of life scores were superior for global health status (p=0.047). An analysis by K-RAS status has not been reported. In the Cetuximab Plus FOLFOX For Colorectal Cancer (EXPLORE) study, 102 patients who had first-line irinotecan-based chemotherapy were randomized to cetuximab plus FOLFOX versus FOLFOX alone (8). This study was terminated early for poor accrual. No differences in outcomes were noted between arms for progression-free survival. For patients who have not yet failed chemotherapy treatment, the combination of EGFR inhibitors with both chemotherapy and the vascular endothelial growth factor (VEGF) antibody bevacizumab is not recommended outside of a clinical trial. Key Evidence o There are two trials published in abstract form that suggest a detrimental effect of the dual EGFR-VEGF inhibition plus oxaliplatin-based chemotherapy (9-11). In these K-RAS unselected populations, the risk of progression with the addition of EGFR antibody therapy was increased by between 17 to 22%. The two agents that are clinically available, panitumumab and cetuximab, have not been directly compared for efficacy or toxicity in a randomized clinical trial. Therefore, neither agent can be recommended over the other after failure of standard chemotherapy. Qualifying Statements o There are no clinical trials of EGFR inhibitor efficacy where patients were prospectively tested for K-RAS status and selected, based on these results. Observations of benefit for EGFR inhibitors in K-RAS wild-type patients are based on retrospective tumour assessment from prospective trials; nonetheless, the consistency of the demonstrated effect across multiple trials is sufficient to strongly recommend restricting the use of EGFR inhibitors to K-RAS wild-type patients. o Although not the topic of this systematic review, the addition of irinotecan to cetuximab resulted in superior progression-free survival and response rate in the randomized phase II Bowel Oncology and Cetuximab Antibody (BOND) study with a primary endpoint of response rate (12). This study assigned 329 patients who progressed on irinotecan to cetuximab plus irinotecan vs. cetuximab alone. The response rate was 22.9% vs. 10.8% (p=0.007); median time to progression was 4.1 vs. 1.5 months (p<0.001); median overall survival was 8.6 vs. 6.9 months (p=0.48). Patients on the cetuximab monotherapy arm were permitted to cross over at the time of progression to receive the combination. The opinion of the authors is that irinotecan should be added to cetuximab for suitable patients. The authors are not aware of any clinical trials of irinotecan combined with panitumumab. Therefore, this combination is not currently recommended. iii CED-CCO SPECIAL ADVICE REPORT #8 o Standard first-line therapy for advanced CRC is either FOLFOX or 5fluorouracil/irinotecan regimen in combination with bevacizumab, where the addition of bevacizumab results in an improved progression-free survival (HR=0.83 and 0.54, respectively) (13,14). The improvement in progression-free-survival in K-RAS wildtype patients with the addition of cetuximab to FOLFOX or FOLFIRI is of a similar magnitude (HR 0.57 or HR 0.68, respectively). Determining whether cetuximab is superior to bevacizumab as an adjunct to first-line chemotherapy in the wild-type population will require the results of ongoing trials (i.e. CALGB 80405: A Phase III Trial of Irinotecan / 5-FU / Leucovorin or Oxaliplatin / 5-FU/ Leucovorin With Bevacizumab, or Cetuximab (C225), or With the Combination or Bevacizumab and Cetuximab for Patients With Untreated Metastatic Adenocarcinoma of the Colon or Rectum). RELATED GUIDELINES Practice Guideline #2-16: Use of Irinotecan in the Second-line Treatment of Metastatic Colorectal Carcinoma. Practice Guideline #2-16b: Use of Irinotecan (Camptosar , CPT-11) Combined with 5Fluorouracil and Leucovorin (5FU/LV) as First-line Therapy for Metastatic Colorectal Cancer. Practice Guideline #2-22: The Role of Oxaliplatin Combined with 5-Fluorouracil and Folinic Acid in the First and Second-line Treatment of Advanced Colorectal Cancer. Practice Guideline #2-25: The Role of Bevacizumab (Avastin ) Combined with Chemotherapy in the Treatment of Patients with Advanced Colorectal Cancer. Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way. Contact Information For further information about this advice report, please contact Dr. J. Biagi, Co-Chair, Gastrointestinal Cancer Disease Site Group, Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King St W, Kingston, ON, K7L-5P9, Phone: 613-544-2630 ext. 4502; Fax: 613-546-8209. For information about the PEBC and the most current version of all reports, please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 iv CED-CCO SPECIAL ADVICE REPORT #8 REFERENCES—SUMMARY 1. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au H-J, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040-8. 2. Karapetis C, Khambata-Ford S, Jonker D, O’Callaghan C, Tu D, Tebbutt N, et al. KRAS mutation status is a predictive biomarker for cetuximab benefit in the treatment of advanced colorectal cancer – results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care [abstract]. ESMO International Symposium 10 th World Congress on Gastrointestinal Cancer. 2008 [cited 2008 Jun 30]. Available from: http://www.worldgicancer.com/WCGI/WGIC08/WGIC08_pressinfo_combined.pdf. 3. 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