1. Patterns of Care in Medical Oncology Treatment of Metastatic Colon Cancer

2. Which systemic therapy is your typical first-line choice for a chemotherapy-naïve patient with metastatic colon cancer in otherwise average health at the following ages? 65-year-old patient FOLFOX + bevacizumab 76%77% FOLFIRI + bevacizumab 16%5% XELOX/CAPOX + bevacizumab 8%3% FOLFOX 0%7% Other 0%8% Clinical investigators Practicing oncologists

3. Which systemic therapy is your typical first-line choice for a chemotherapy-naïve patient with metastatic colon cancer in otherwise average health at the following ages? (continued) 85-year-old patient FOLFOX + bevacizumab 40%22% FOLFOX ± cetuximab 20%8% Capecitabine ± bevacizumab * 24%33% 5-FU/LV ± bevacizumab † 12%26% XELOX/CAPOX ± bevacizumab 4% FOLFIRI + bevacizumab 0%5% No systemic therapy 0%2% Clinical investigators Practicing oncologists * CI = capecitabine alone 12%; capecitabine + bevacizumab 12%; PO = capecitabine alone 22%; capecitabine + bevacizumab 11% † CI = 5-FU/LV + bevacizumab 8%; 5-FU/LV alone 4%; PO = 5-FU/LV + bevacizumab 20%; 5-FU/LV alone 6%

4. Do you generally check the K-ras mutation status of a tumor in patients with metastatic colon cancer? Yes 96%38% No 0%17% No, but I plan to 4%45% If yes, approximately when did you begin checking this? Prior to Dec 2007 0%6% Jan-Feb 2008 25%0% March-April 2008 17%5% May-June 2008 37%39% July-August 2008 21%45% Sept 2008-present 0%5% Clinical investigators Practicing oncologists

5. CRYSTAL trial: A Phase III randomized study of FOLFIRI with or without cetuximab as first-line therapy for EGFR-expressing metastatic colorectal cancer Efficacy FOLFIRI + cetuximab (n = 599) FOLFIRI (n = 599)p-value Median PFS8.9 months8.0 months0.048 One-year PFS rate34%23%— Overall response rate * 46.9%38.7%0.0038 PFS = progression-free survival * Complete response + partial response Source: Van Cutsem E et al. Proc ASCO 2007;Abstract 4000.

6. CRYSTAL trial: A Phase III randomized study of FOLFIRI with or without cetuximab as first-line therapy for EGFR-expressing metastatic colorectal cancer (continued) † No Grade IV skin reactions Source: Van Cutsem E et al. Proc ASCO 2007;Abstract 4000. Safety: Grade III/IV adverse events FOLFIRI + cetuximab (n = 600) FOLFIRI (n = 602) Neutropenia26.7%23.3% Diarrhea15.2%10.5% Skin reactions † 18.7%0.2% Infusion related2.3%0%

7. Which systemic therapy would be your typical first- line choice for a chemotherapy-naïve patient with metastatic colon cancer that is K-ras wild type? 65-year-old patient FOLFOX + bevacizumab 76%62% FOLFIRI + bevacizumab 16%5% XELOX/CAPOX + bevacizumab 8%5% FOLFOX + cetuximab 0%12% FOLFOX 0%5% FOLFIRI + cetuximab 0%5% Other systemic therapy 0%6% Clinical investigators Practicing oncologists

8. Which systemic therapy would be your typical first- line choice for a chemotherapy-naïve patient with metastatic colon cancer (continued) Which systemic therapy would be your typical first- line choice for a chemotherapy-naïve patient with metastatic colon cancer that is K-ras wild type? (continued) 85-year-old patient FOLFOX + bevacizumab 40%13% Capecitabine ± bevacizumab 24%30% FOLFOX 16%5% 5-FU/LV ± bevacizumab 12%26% FOLFOX + cetuximab 4%7% FOLFIRI + biologic * 0%10% Other systemic therapy 4%7% No systemic therapy 0%2% Clinical investigators Practicing oncologists * PO: FOLFIRI + bevacizumab 6%; FOLFIRI + cetuximab 4%

9. Which systemic therapy would be your typical first- line choice for a chemotherapy-naïve patient with metastatic colon cancer that is mutant K-ras? 65-year-old patient FOLFOX + bevacizumab 76%68% FOLFOX ± cetuximab 0%14% FOLFIRI ± biologic * 16%8% XELOX/CAPOX ± bevacizumab 8%5% Capecitabine 0%2% 5-FU/LV + bevacizumab 0%2% FOLFOXIRI 0%1% Clinical investigators Practicing oncologists * CI: FOLFIRI + bevacizumab 16%; PO: FOLFIRI + bevacizumab 5%; FOLFIRI 2%; FOLFIRI + cetuximab 1%

10. Which systemic therapy would be your typical first- line choice for a chemotherapy-naïve patient with metastatic colon cancer that is mutant K-ras? (continued) 85-year-old patient FOLFOX + bevacizumab 40%16% Capecitabine ± bevacizumab 24%36% FOLFOX 20%7% 5-FU/LV ± bevacizumab 12%25% XELOX/CAPOX ± bevacizumab 4%3% FOLFIRI + biologic † 0%7% Other systemic therapy 0%4% No systemic therapy 0%2% Clinical investigators Practicing oncologists † PO: FOLFIRI + bevacizumab 4%; FOLFIRI + cetuximab 3%

11. Which of the following treatment strategies, if any, are you most likely to recommend for this patient with colon cancer? Resection of liver mets  systemic therapy60%50% Preop systemic therapy  resection  systemic therapy 24%35% Periop systemic therapy with 1/2 of cycles prior to resection and 1/2 after 16%12% Immediate resection of liver mets alone, no postop systemic therapy 0%3% Clinical investigators Practicing oncologists Case 2: Metastatic Colon Cancer, No Prior Systemic Therapy A 65-year-old patient in otherwise average health Three years ago, treated for Stage II sigmoid cancer (no adjuvant chemotherapy) Now with 2 metastases in right lobe of liver that are considered to be surgically resectable (maximum diameter 3 centimeters) No evidence of extrahepatic metastases

12. Trial evaluating the benefit of perioperative FOLFOX4 for patients with potentially resectable colorectal cancer hepatic metastases Surgery FOLFOX4 x 6  surgery  FOLFOX4 x 6 Protocol ID: EORTC-40983; Accrual: 364 (Closed) R Source: Nordlinger B et al. Lancet 2008;371(9617):1007-16. Abstract

13. Trial evaluating the benefit of perioperative FOLFOX4 for patients with potentially resectable colorectal cancer hepatic metastases (continued) HR = hazard ratio; CI = confidence interval Source: Nordlinger B et al. Lancet 2008;371(9617):1007-16. Abstract Three-year progression-free survival Perioperative FOLFOX4 + surgery Surgery aloneHR (95.66% CI)p-value All patients randomly assigned (n = 182, 182)35.4%28.1% 0.79 (0.62-1.02)0.058 All patients who underwent resection (n = 152, 151)42.4%33.2% 0.73 (0.55-0.97)0.025 Reversible postoperative complications (n = 159, 170)25%16%—0.04

14. For patients with colon cancer and liver metastases that are surgically removed, which postoperative treatment option would you most likely recommend for the patients who have received no prior chemotherapy? FOLFOX + bevacizumab 60%67% FOLFOX 32%17% XELOX/CAPOX + bevacizumab 8%1% FOLFOX + cetuximab 0%4% XELOX/CAPOX 0%3% No systemic therapy 0%2% Other 0%6% Clinical investigators Practicing oncologists

15. Approximately how many patients per year do you evaluate who have colorectal cancer with potentially resectable hepatic metastases? Median 216 Clinical investigators Practicing oncologists

16. 2008 Preop systemic therapy  resection  systemic therapy 76%71% Periop systemic therapy, 1/2 cycles prior to resection and 1/2 after 12%13% Systemic therapy alone4%6% Resection of liver mets  systemic therapy4%6% Clinical investigators Practicing oncologists Case 3: Metastatic Colon Cancer, No Prior Systemic Therapy A 65-year-old patient in otherwise average health Three years ago, treated for Stage II sigmoid cancer (no adjuvant chemotherapy) CT scan reveals 6 metastases in both lobes of liver (5/8 liver segments affected) No evidence of extrahepatic metastases Which treatment strategies, if any, are you most likely to recommend for this patient?

17. 2008 Resection of liver mets0%3% Preop systemic therapy  resection0% Other4%1% Clinical investigators Practicing oncologists Case 3: Metastatic Colon Cancer, No Prior Systemic Therapy (continued) A 65-year-old patient in otherwise average health Three years ago, treated for Stage II sigmoid cancer (no adjuvant chemotherapy) CT scan reveals 6 metastases in both lobes of liver (5/8 liver segments affected) No evidence of extrahepatic metastases Which treatment strategies, if any, are you most likely to recommend for this patient?

18. 2005 Preop systemic therapy  resection  systemic therapy0% Periop systemic therapy, 1/2 cycles prior to resection and 1/2 after 0% Systemic therapy alone79% Resection of liver mets  systemic therapy2% Practicing oncologists Case 3: Metastatic Colon Cancer, No Prior Systemic Therapy (continued) A 65-year-old patient in otherwise average health Three years ago, treated for Stage II sigmoid cancer (no adjuvant chemotherapy) CT scan reveals 6 metastases in both lobes of liver (5/8 liver segments affected) No evidence of extrahepatic metastases Which treatment strategies, if any, are you most likely to recommend for this patient?

19. 2005 Resection of liver mets0% Preop systemic therapy  resection9% Other10% Case 3: Metastatic Colon Cancer, No Prior Systemic Therapy (continued) A 65-year-old patient in otherwise average health Three years ago, treated for Stage II sigmoid cancer (no adjuvant chemotherapy) CT scan reveals 6 metastases in both lobes of liver (5/8 liver segments affected) No evidence of extrahepatic metastases Which treatment strategies, if any, are you most likely to recommend for this patient? Practicing oncologists

20. Which systemic therapy, if any, are you most likely to recommend for this patient? FOLFIRI + bevacizumab68%50% FOLFIRI12%6% FOLFOX + bevacizumab4%28% XELOX/CAPOX + bevacizumab 4%3% Irinotecan + cetuximab 4%1% Other 8%12% Clinical investigators Practicing oncologists Case 4: Metastatic Colon Cancer, Previous Adjuvant Treatment A 65-year-old patient in otherwise average health One year ago, completed treatment for a Stage III lesion with resection and adjuvant FOLFOX (5-FU + leucovorin + oxaliplatin) chemotherapy for 6 months Now presents with 12 liver metastases

21. Chemotherapy + bevacizumab Chemotherapy + cetuximab Protocol IDs: CALGB-C80405, C80405, SWOG-C80405, NCT00265850 Target Accrual: 2,300 (Temporarily Closed) Eligibility Previously untreated metastatic adenocarcinoma of the colon or rectum Phase III randomized study of cetuximab and/or bevacizumab in combination with either FOLFOX or FOLFIRI Source: NCI Physician Data Query, December 2008. Chemotherapy + cetuximab/bevacizumab R

22. Chemotherapy-free intervals are a reasonable option when treating a patient with FOLFOX for metastatic colon cancer. Strongly agree 24%17% Agree 32%53% In between 20%18% Disagree 20%12% Strongly disagree 4%0% Clinical investigators Practicing oncologists

23. With informed patient consent, it is reasonable to use bevacizumab for patients with advanced disease who have stable, treated brain metastases. Agree 80%57% In between 0%26% Disagree 20%17% Clinical investigators Practicing oncologists

24. Assume your patient is being treated with FOLFOX or FOLFIRI, with bevacizumab. When utilizing “planned drug holidays” to minimize toxicity in the management of metastatic disease, do you routinely: Discontinue the oxali/irinotecan component only (maintaining fluoropyrimidine and bev) 64%45% Completely discontinue all medical treatment (chemo-free interval) 28%26% Discontinue all chemo (maintaining bev only) 0%24% Discontinue the oxali/irinotecan and bev components (maintaining fluoropyrimidine only) 0%5% Other 8%0% Clinical investigators Practicing oncologists

25. Patients who demonstrate significant responses to FOLFOX/bevacizumab or FOLFIRI/bevacizumab should have planned discontinuation of oxaliplatin or irinotecan prior to the development of significant toxicity. Agree 64%55% In between 16%35% Disagree 20%10% Clinical investigators Practicing oncologists

26. For a patient who demonstrates stable disease on FOLFOX/bevacizumab and who is then continued on bevacizumab alone, how long do you generally continue bevacizumab if the patient is tolerating it well? I don’t use maintenance bev 60%17% Until disease progression 32%68% A specified number of cycles 4%13% Other 4%2% Clinical investigators Practicing oncologists

27. A 60-year-old patient has an excellent response to FOLFOX + bevacizumab as first-line therapy for metastatic disease and is continued on bevacizumab. At 14 months, the patient develops slow but definite disease progression. Outside of a protocol setting, the bevacizumab should generally be continued with the addition of another agent/regimen. Agree 60%52% In between 12%27% Disagree 28%21% Clinical investigators Practicing oncologists

28. Which systemic therapy, if any, are you most likely to recommend as second-line therapy for this patient? Irinotecan ± cetuximab52%19% FOLFIRI + biologic * 32%52% FOLFIRI alone8%17% Chemotherapy + panitumumab 4%1% Clinical investigators Practicing oncologists Case 5: Second-Line Treatment for Metastatic Colon Cancer A 65-year-old patient in otherwise average health Received FOLFOX (5-FU + leucovorin + oxaliplatin) + bevacizumab as first-line therapy for 6 months for hepatic metastases Demonstrates a partial response, then develops subsequent pulmonary metastases and progression of hepatic metastases * CI: FOLFIRI + bevacizumab 28%; FOLFIRI + cetuximab 4% PO: FOLFIRI + bevacizumab 31%; FOLFIRI + cetuximab 21%

29. Which systemic therapy, if any, are you most likely to recommend as second-line therapy for this patient? Capecitabine ± bevacizumab0%5% XELOX/CAPOX ± bevacizumab0%5% Other4%1% Clinical investigators Practicing oncologists Case 5: Second-Line Treatment for Metastatic Colon Cancer (continued) A 65-year-old patient in otherwise average health Received FOLFOX (5-FU + leucovorin + oxaliplatin) + bevacizumab as first-line therapy for 6 months for hepatic metastases Demonstrates a partial response, then develops subsequent pulmonary metastases and progression of hepatic metastases

30. Approximately how many patients with metastatic colon cancer have you treated with panitumumab? Median 123 Approximately how many patients with metastatic colon cancer have you treated with cetuximab? Median 11113 Of the patients with metastatic colon cancer you have treated with cetuximab, approximately how many have developed significant infusion reactions? Median 32 Clinical investigators Practicing oncologists

31. The severity of skin toxicity in patients undergoing treatment with EGFR inhibitors such as cetuximab and panitumumab correlates with response. Agree 88%61% In between 8%31% Disagree 4%8% Clinical investigators Practicing oncologists

32. How often do you use a regimen that contains cetuximab with bevacizumab or panitumumab with bevacizumab for patients with metastatic colon cancer? Very frequently 0%4% Frequently 0%13% Sometimes 24%12% Rarely 36%25% Never 40%46% Clinical investigators Practicing oncologists