1. www.OncologyEducation.ca Reviewer: Dr Scott Berry Date posted: June 21, 2007 CAPEOX vs. FOLFOX4 +/- Bevacizumab: survival results from NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC) Authors: Cassidy, Saltz et al.

2. www.OncologyEducation.ca Background This randomized trial was designed to answer the following questions: –CapeOx vs FOLFOX Is capecitabine non-inferior to infusional 5FU when combined with oxaliplatin for the first line treatment of colorectal cancer (ie does CapeOx = FOLFOX) Recruited 634 patients before being converted to randomized 2x2 design after emergence of bevacizumab data –FOLFOX/CapeOx vs FOLFOX/CapeOx + Bevacizumab Does bevacizumab add to the first line treatment of colorectal cancer with oxaliplatin based combinations (PRIMARY OUTCOME PFS) 1400 further patients recruited PFS data has been presented previously - this is first presentation of OS data

3. www.OncologyEducation.ca CAPEOX + placebo n=350 Initial 2-arm open-label study (n=634) Protocol amended to 2x2 placebo- controlled design after bevacizumab phase III data 8 became available (n=1400) Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 FOLFOX-4 + placebo n=351 CAPEOX + bevacizumab n=350 FOLFOX-4 + bevacizumab n=349 CAPEOX n=317 FOLFOX-4 n=317

4. www.OncologyEducation.ca CAPEOX + bevacizumab (or placebo) –Bev (or placebo) 7.5 mg/kg i.v. over 30–90 min, day 1 –Oxaliplatin 130 mg/m 2 i.v. over 2 hours, day 1 –Capecitabine1000 mg/m 2 orally, twice daily, days 1–14 –Schedule repeated every 21 days FOLFOX 4 + bevacizumab (or placebo) –Bev (or placebo) 5 mg/kg i.v. over 30–90 min, day 1 –Oxaliplatin 85 mg/m 2 i.v. over 2 hours, day 1 –Folinic acid 200 mg/m 2 i.v. over 2 hours, days 1, 2 –Fluorouracil 400 mg/m 2 i.v. bolus, days 1, 2 –Fluorouracil 600 mg/m 2 i.v. inf over 22 hours, days 1, 2 –Schedule repeated every 14 days Treatment Schedules

5. www.OncologyEducation.ca RESULTS : CAPECITABINE VS INFUSIONAL 5FU CAPEOXFOLFOX HR (97.5% CI) PFS (median, mos) 88.5 HR 1.01 (0.91-1.12) OS (median, mos) 19.619.8 HR 0.99 (0.88-1.12)

6. www.OncologyEducation.ca SELECTED TOXICITY (%) CAPECITABINE VS INFUSIONAL 5FU CAPEOX Gr 3/4 FOLFOX Gr 3/4 DIARRHEA2012 FEBRILE NEUTROPENIA <25 HAND FOOT SYNDROME 61

7. www.OncologyEducation.ca RESULTS : Bevacizumab vs Placebo CAPEOX/FOLFOX + BEV CAPEOX/FOLFOX + PLACEBO HR (97.5% CI) P value PFS (median, mos) 9.48 0.83 (0.72-0.95) P=0.0023 OS (median, mos) 21.319.9 0.89 (0.76-1.03) P=0.0769

8. www.OncologyEducation.ca STUDY COMMENTARY Capecitabine + Oxaliplatin (CapeOx) is non inferior to FOLFOX4 in terms of PFS and OS There is a differential toxicity pattern: Grade 3/4 Diarrhea (20 vs 6 %) and Hand Foot Syndrome (6 vs 1%) higehr for CapeOx Febrile neutropenia higher for FOLFOX4 (5 vs <2%)

9. www.OncologyEducation.ca STUDY COMMENTARY Bevacizumab added to Oxaliplatin combination chemotherapy for the first line treatment of metastatic colon cancer does not improve overall survival ? Why - when bevacizumab has demonstrated survival benefit with 1st line IFL and 5FULV and 2nd line FOLFOX One hypothesis relates to the duration of exposure to bevacizumab. Most patients in this trial had their bevacizumab discontinued when their chemotherapy was discontinued (on average at about the 6 month time point - presumably because of oxaliplatin neurotoxicity) Even though patients with neurotoxicity were permitted to stop oxaliplatin and continued with bevacizumab and a fluoropyrimidine, this rarely happened. In other bevacizumab trials like the pivotal IFL +/- bevacizumab trial patients were able to have longer exposure to bevacizumab because of the absence of a dose-limiting toxicity like neurotoxicity. pivotal IFL +/- bevacizumab trial This hypothesis is interesting to consider but does not explain why the response rates - presented at ASCO GI 2007 showed that chemotherapy + bevacizumab had very similar response rates to chemotherapy + placebo (47% vs 49% investigator reported responses, 38% vs 38% for independent review committee confirmed responses)

10. www.OncologyEducation.ca BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS This is an important trial for Canadian oncologists. It confirms that capecitabine can be substituted for the infusional 5FU component of combination chemotherapy with oxaliplatin without sacrificing any efficacy allowing patients to forego pump therapy It also provides information about the differential toxicity profile of the 2 regimens that will allow oncologists to have more informed discussions with their patients as they make decisions about therapy for metastatic colorectal cancer. However, this trial will not resolve issues around the differential funding and access available for capecitabine and oxaliplatin across the country. Other abstracts demonstrated that capecitabine could replace the infusional 5FU component of 1st line FOLFOX6 (Ducreux et al) and 2nd line FOLFOX (Rothenberg)

11. www.OncologyEducation.ca BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS This was a major study whose results have anxiously been awaited because it was the first randomized trial to assess the value of adding bevacizumab to a commonly used first line combination chemotherapy regimen. However, bevacizumab does not improve survival when added to first line FOLFOX4

12. www.OncologyEducation.ca BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS This is an important trial for Canadian oncologists. It confirms that capecitabine can be substituted for the infusional 5FU component of combination chemotherapy with oxaliplatin without sacrificing any efficacy allowing patients to forego pump therapy It also provides information about the differential toxicity profile of the 2 regimens that will allow oncologists to have more informed discussions with their patients as they make decisions about therapy for metastatic colorectal cancer.