1. CM923700-1 A pooled safety & efficacy analysis examining the effect of performance status on outcomes in 9 first line treatment trials of 6,286 patients with metastatic colorectal cancer RM Goldberg, C-H Köhne, MT Seymour, A de Gramont, R Porschen, L Saltz, P Rougier, C Tournigand, A Grothey, DJ Sargent

2. CM923700-2 BackgroundBackground PS is a known prognostic factor PS is a known prognostic factor Many trials exclude ECOG PS > 2 pts Many trials exclude ECOG PS > 2 pts Phase III studies: usually < 10% PS 2 pts Phase III studies: usually < 10% PS 2 pts Lacking data, oncologists may suggest Lacking data, oncologists may suggest Single agents; avoiding toxicity Single agents; avoiding toxicity Aggressive therapy; maximizing likelihood for response Aggressive therapy; maximizing likelihood for response PS is a known prognostic factor PS is a known prognostic factor Many trials exclude ECOG PS > 2 pts Many trials exclude ECOG PS > 2 pts Phase III studies: usually < 10% PS 2 pts Phase III studies: usually < 10% PS 2 pts Lacking data, oncologists may suggest Lacking data, oncologists may suggest Single agents; avoiding toxicity Single agents; avoiding toxicity Aggressive therapy; maximizing likelihood for response Aggressive therapy; maximizing likelihood for response

3. CM923700-3 In 9 First Line Phase III ChemoRx Trials Compare PS 0-1 to PS 2 patients Compare PS 0-1 to PS 2 patients Subset analyses Subset analyses Pool 5 trials comparing single agent to combination Rx Pool 5 trials comparing single agent to combination Rx Compare infusion FU/LV or bolus based 5-FU combination (IFL) to infusion 5-FU combinations Compare infusion FU/LV or bolus based 5-FU combination (IFL) to infusion 5-FU combinations Compare PS 0-1 to PS 2 patients Compare PS 0-1 to PS 2 patients Subset analyses Subset analyses Pool 5 trials comparing single agent to combination Rx Pool 5 trials comparing single agent to combination Rx Compare infusion FU/LV or bolus based 5-FU combination (IFL) to infusion 5-FU combinations Compare infusion FU/LV or bolus based 5-FU combination (IFL) to infusion 5-FU combinations

4. CM923700-4 EndpointsEndpoints Primary = Progression free survival (PFS) Primary = Progression free survival (PFS) Secondary Secondary Response rate (RR) Response rate (RR) Overall survival (OS) Overall survival (OS) Grade > 3 toxicity Grade > 3 toxicity 60-day all cause mortality 60-day all cause mortality Primary = Progression free survival (PFS) Primary = Progression free survival (PFS) Secondary Secondary Response rate (RR) Response rate (RR) Overall survival (OS) Overall survival (OS) Grade > 3 toxicity Grade > 3 toxicity 60-day all cause mortality 60-day all cause mortality

5. CM923700-5 MethodsMethods Defined a control vs experimental arm(s) in each trial Defined a control vs experimental arm(s) in each trial Efficacy modeled using Cox regression Efficacy modeled using Cox regression Stratified by study Stratified by study Adjusted for age & gender Adjusted for age & gender Primary outcome of interest: Primary outcome of interest: PS by Rx interaction PS by Rx interaction FOCUS: pooled 3 initial 5-FU/LV arms for PFS and RR analyses FOCUS: pooled 3 initial 5-FU/LV arms for PFS and RR analyses Defined a control vs experimental arm(s) in each trial Defined a control vs experimental arm(s) in each trial Efficacy modeled using Cox regression Efficacy modeled using Cox regression Stratified by study Stratified by study Adjusted for age & gender Adjusted for age & gender Primary outcome of interest: Primary outcome of interest: PS by Rx interaction PS by Rx interaction FOCUS: pooled 3 initial 5-FU/LV arms for PFS and RR analyses FOCUS: pooled 3 initial 5-FU/LV arms for PFS and RR analyses

6. CM923700-6 Trials Included *Defined Control

7. CM923700-7 Characteristics of 6,286 Patients PS 0-1 PS 2 No. Patients 5777509 Age, Median Years (Range) 63 (19-88) 63 (24-84) Sex, % Male 6458 Study Arm, % Control 4140

8. CM923700-8 Question 1 Is PS 2 prognostic for poor outcomes? Is PS 2 prognostic for poor outcomes?

9. CM923700-9 PFS in PS 0-1 vs. PS 2 p-value < 0.0001 HR: 1.52 (1.38-1.66)

10. CM923700-10 OS in PS 0-1 vs. PS 2 p-value < 0.0001 HR: 2.18 (1.98-2.40)

11. CM923700-11 Conclusion 1 PS 2 is prognostic for poor outcomes PS 2 is prognostic for poor outcomes Given the poorer prognosis, do PS 2 patients benefit from superior therapy? Given the poorer prognosis, do PS 2 patients benefit from superior therapy? PS 2 is prognostic for poor outcomes PS 2 is prognostic for poor outcomes Given the poorer prognosis, do PS 2 patients benefit from superior therapy? Given the poorer prognosis, do PS 2 patients benefit from superior therapy? Question 2

12. CM923700-12 RR – Treatment by PS p-value < 0.0001 OR: 1.89 (1.69-2.12)

13. CM923700-13 RR – Treatment by PS p-value = 0.002 OR: 1.99 (1.29-3.05) Interaction p-value = 0.89 p-value < 0.0001 OR: 1.89 (1.69-2.12)

14. CM923700-14 PFS – Treatment by PS p-value < 0.0001 HR: 0.82 (0.77-0.86)

15. CM923700-15 PFS – Treatment by PS p-value < 0.0001 HR: 0.82 (0.77-0.86) p-value = 0.02 HR: 0.79 (0.66-0.96) Interaction p-value = 0.68

16. CM923700-16 Forest Plot of PFS for PS 0-1 vs PS 2 Patients

17. CM923700-17 OS – Treatment by PS p-value < 0.0001 HR: 0.87 (0.82-0.93)

18. CM923700-18 OS – Treatment by PS p-value = 0.21 HR: 0.88 (0.73-1.07) Interaction p-value = 0.41 p-value < 0.0001 HR: 0.87 (0.82-0.93)

19. CM923700-19 Grade > 3 Toxicity by PS PS 0-1 PS 2 P-value Nausea*8%16% < 0.0001 Vomiting*8%12%0.006 Stomatitis*2%5%0.11 Diarrhea*17%15%0.32 N-penia*34%35%0.51 60 day mortality 3%12% < 0.0001 *Note: FOCUS Trial Excluded

20. CM923700-20 Conclusion 2 PS 2 pts benefit similarly to PS 0-1 pts from superior therapy PS 2 pts benefit similarly to PS 0-1 pts from superior therapy PS 2 pts experience elevated 60- day mortality, ↑ GI toxicity PS 2 pts experience elevated 60- day mortality, ↑ GI toxicity Do these findings hold true when restricted to the 5 trials testing mono vs combo therapy? Do these findings hold true when restricted to the 5 trials testing mono vs combo therapy? PS 2 pts benefit similarly to PS 0-1 pts from superior therapy PS 2 pts benefit similarly to PS 0-1 pts from superior therapy PS 2 pts experience elevated 60- day mortality, ↑ GI toxicity PS 2 pts experience elevated 60- day mortality, ↑ GI toxicity Do these findings hold true when restricted to the 5 trials testing mono vs combo therapy? Do these findings hold true when restricted to the 5 trials testing mono vs combo therapy? Question 3

21. CM923700-21 LVFU2 Trials

22. CM923700-22 PFS –Treatment by PS p-value < 0.0001 HR: 0.72 (0.67-0.78)

23. CM923700-23 PFS –Treatment by PS p-value < 0.0001 HR: 0.72 (0.67-0.78) p-value < 0.0001 HR: 0.78 (0.62-0.98) Interaction p-value = 0.75

24. CM923700-24 OS –Treatment by PS p-value = 0.002 HR: 0.88 (0.82-0.95)

25. CM923700-25 OS –Treatment by PS p-value = 0.002 HR: 0.88 (0.82-0.95) p-value = 0.27 HR: 0.88 (0.69-1.11) Interaction p-value = 0.10

26. CM923700-26 Conclusion 3 When restricted to the 5 trials testing mono vs combo therapy, combo is better for both PS 0,1 and PS 2 When restricted to the 5 trials testing mono vs combo therapy, combo is better for both PS 0,1 and PS 2 Do these findings hold true when comparing infusion based regimens with oxaliplatin or irinotecan versus other regimens (5-FU monotherapy or 5-FU bolus combination)? Do these findings hold true when comparing infusion based regimens with oxaliplatin or irinotecan versus other regimens (5-FU monotherapy or 5-FU bolus combination)? When restricted to the 5 trials testing mono vs combo therapy, combo is better for both PS 0,1 and PS 2 When restricted to the 5 trials testing mono vs combo therapy, combo is better for both PS 0,1 and PS 2 Do these findings hold true when comparing infusion based regimens with oxaliplatin or irinotecan versus other regimens (5-FU monotherapy or 5-FU bolus combination)? Do these findings hold true when comparing infusion based regimens with oxaliplatin or irinotecan versus other regimens (5-FU monotherapy or 5-FU bolus combination)? Question 4

27. CM923700-27 Infusional-Based Combination Regimens

28. CM923700-28 RR – Infusional Combo by PS p-value < 0.0001 OR: 2.49 (2.17-2.86)

29. CM923700-29 RR – Infusional Combo by PS Interaction p-value = 0.02 p-value < 0.0001 OR: 3.00 (1.73-5.22) p-value < 0.0001 OR: 2.49 (2.17-2.86)

30. CM923700-30 PFS – Infusional Combo by PS p-value < 0.0001 HR: 0.72 (0.67-0.77)

31. CM923700-31 PFS – Infusional Combo by PS Interaction p-value = 0.03 p-value = 0.0003 HR: 0.64 (0.50-0.81) p-value < 0.0001 HR: 0.72 (0.67-0.77)

32. CM923700-32 OS – Infusional Combo by PS p-value < 0.0001 HR: 0.84 (0.78-0.91)

33. CM923700-33 OS – Infusional Combo by PS p-value < 0.0001 HR: 0.84 (0.78-0.91) p-value < 0.0001 HR: 0.69 (0.54-0.88) Interaction p-value = 0.004

34. CM923700-34 Conclusion 4 Infusion 5-FU based combination regimens are beneficial for all patient groups, with a greater benefit in the PS 2 group. Infusion 5-FU based combination regimens are beneficial for all patient groups, with a greater benefit in the PS 2 group.

35. CM923700-35 Limitations of Study Despite pooling, still only ~500 PS 2 patients Despite pooling, still only ~500 PS 2 patients Very select group of PS 2 patients enrolled on trials Very select group of PS 2 patients enrolled on trials Varied treatment regimens Varied treatment regimens Trials all in the pre-biologic rx era Trials all in the pre-biologic rx era Despite pooling, still only ~500 PS 2 patients Despite pooling, still only ~500 PS 2 patients Very select group of PS 2 patients enrolled on trials Very select group of PS 2 patients enrolled on trials Varied treatment regimens Varied treatment regimens Trials all in the pre-biologic rx era Trials all in the pre-biologic rx era

36. CM923700-36 ConclusionsConclusions Among patients entered onto clinical trials, PS 2 patients: Have a poorer prognosis Accrue similar benefit to PS 0-1 pts from superior Rx Benefit more from 5-FU infusion with oxaliplatin or irinotecan Have higher rates of nausea, vomiting, & 60-day mortality Among patients entered onto clinical trials, PS 2 patients: Have a poorer prognosis Accrue similar benefit to PS 0-1 pts from superior Rx Benefit more from 5-FU infusion with oxaliplatin or irinotecan Have higher rates of nausea, vomiting, & 60-day mortality