1. eastern cooperative oncology group Impact of Bevacizumab Dose Reduction on Clinical Outcomes for Patients Treated on the Eastern Cooperative Oncology Group’s Study E3200. Bruce J. Giantonio, Paul J. Catalano, Peter J. O’Dwyer, Neal J. Meropol, and Al B. Benson III. University of Pennsylvania, Philadelphia, PA, Dana-Farber Cancer Institute, Boston, MA Fox Chase Cancer Center, Philadelphia, PA, Northwestern University, Chicago, IL Bruce J. Giantonio, Paul J. Catalano, Peter J. O’Dwyer, Neal J. Meropol, and Al B. Benson III. University of Pennsylvania, Philadelphia, PA, Dana-Farber Cancer Institute, Boston, MA Fox Chase Cancer Center, Philadelphia, PA, Northwestern University, Chicago, IL

2. eastern cooperative oncology group Bevacizumab dose reduction/discontinuation criteria Dose reductions of bevacizumab to 5mg/kg were permitted for the following: 1. 1.Hypertension, bleeding, and thrombosis  Grade 2, 2. 2.Proteinuria of < 2 grams/24 hours that resolved to < 0.5 grams/24 hrs, 3. 3.Liver function test abnormalities  grade 3 that resolved to  Grade 1. Discontinuation of bevacizumab was required for: 1. 1.any of the above events that occurred at a grade in excess of that which didn’t meet criteria for reduction, or 2. 2.that did not resolve to the specified grade required for continuation. Note, the occurrence of Grade 3 thrombosis (defined as requiring anticoagulation) required discontinuation of bevacizumab Dose reductions of bevacizumab to 5mg/kg were permitted for the following: 1. 1.Hypertension, bleeding, and thrombosis  Grade 2, 2. 2.Proteinuria of < 2 grams/24 hours that resolved to < 0.5 grams/24 hrs, 3. 3.Liver function test abnormalities  grade 3 that resolved to  Grade 1. Discontinuation of bevacizumab was required for: 1. 1.any of the above events that occurred at a grade in excess of that which didn’t meet criteria for reduction, or 2. 2.that did not resolve to the specified grade required for continuation. Note, the occurrence of Grade 3 thrombosis (defined as requiring anticoagulation) required discontinuation of bevacizumab Giantonio ASCO 06

3. eastern cooperative oncology group Methods 1. Data on the application of dose reduction and discontinuation were obtained from a post study survey of institutions for all study participants who were treated with bevacizumab. 2. Median overall survival, median progression free survival, and hazard ratios were computed for patients who either had their bevacizumab discontinued (provided at least one cycle was administered), dose reduced, or dose reduced followed by discontinuation. 1. Data on the application of dose reduction and discontinuation were obtained from a post study survey of institutions for all study participants who were treated with bevacizumab. 2. Median overall survival, median progression free survival, and hazard ratios were computed for patients who either had their bevacizumab discontinued (provided at least one cycle was administered), dose reduced, or dose reduced followed by discontinuation. Giantonio ASCO 06

4. eastern cooperative oncology group E3200: Study Design FOLFOX4 + Bevacizumab (10 mg/kg, q 2 weeks) FOLFOX4 Bevacizumab (10mg/kg, q 2 wks) Previously treated metastatic CRC PD  Stratification factors:  ECOG PS: 0 vs 1, 2  Prior XRT Giantonio ASCO 06

5. eastern cooperative oncology group Dose Modification/Reduction Survey Giantonio ASCO 06

6. eastern cooperative oncology group Survey Response Demographics FOLFOX + bevacizumab Bevacizumab alone Returned Questionnaires246 (84%)205 (84%) Male59.1%58.5% Median Age6260 Median PS (%; 0/1/2)49.2/47.9/2.947.8/44.4/7.8 Median Cycles (range)11 (1,49)4 (1,48) Median Cycles with reduction42%52% Giantonio ASCO 06

7. eastern cooperative oncology group Survey Responses FOLFOX + bevacizumab Bevacizumab alone Reponses: No reduction or discontinuation 109124 Discontinuation w/o reduction6043 Reduction w/o discontinuation4831 Reduction then discontinuation297 Giantonio ASCO 06

8. eastern cooperative oncology group Dose Reductions by Toxicity Arm AArm C Reduction (any grade)n=246n=205 Hypertension2715 Thromboembolism10 Proteinuria6333 Bleeding64 SGOT/SGPT20 Giantonio ASCO 06

9. eastern cooperative oncology group Discontinuations by Toxicity Arm AArm C Discontinuation (any grade)n=246n=205 Hypertension1712 Thromboembolism81 Proteinuria76 Bleeding53 SGOT/SGPT20 Giantonio ASCO 06

10. eastern cooperative oncology group Outcomes by reduction/discontinuation of bevacizumab Giantonio ASCO 06

11. eastern cooperative oncology group Conclusions 1. 1.Study specified dose reduction and/or discontinuation of bevacizumab was performed for adverse events in 56% and 38% of patients treated in Arms A and C who responded to the questionnaire. 2. 2.Hypertension and proteinuria were the most common reasons for bevacizumab dose reduction or discontinuation. 3. 3.Overall survival and progression free survival were not compromised for patients who underwent dose reductions or discontinuation of bevacizumab. 4. 4.Randomized clinical trials will be required to determine the optimal dose of bevacizumab used in combination with chemotherapy for the treatment of colorectal cancer. 1. 1.Study specified dose reduction and/or discontinuation of bevacizumab was performed for adverse events in 56% and 38% of patients treated in Arms A and C who responded to the questionnaire. 2. 2.Hypertension and proteinuria were the most common reasons for bevacizumab dose reduction or discontinuation. 3. 3.Overall survival and progression free survival were not compromised for patients who underwent dose reductions or discontinuation of bevacizumab. 4. 4.Randomized clinical trials will be required to determine the optimal dose of bevacizumab used in combination with chemotherapy for the treatment of colorectal cancer. Giantonio ASCO 06