CM 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

CM 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

CM 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

CM 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

CM 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

CM Trials Included *Defined Control

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

CM Question 1 Is PS 2 prognostic for poor outcomes? Is PS 2 prognostic for poor outcomes?

CM PFS in PS 0-1 vs. PS 2 p-value < HR: 1.52 ( )

CM OS in PS 0-1 vs. PS 2 p-value < HR: 2.18 ( )

CM 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

CM RR – Treatment by PS p-value < OR: 1.89 ( )

CM RR – Treatment by PS p-value = OR: 1.99 ( ) Interaction p-value = 0.89 p-value < OR: 1.89 ( )

CM PFS – Treatment by PS p-value < HR: 0.82 ( )

CM PFS – Treatment by PS p-value < HR: 0.82 ( ) p-value = 0.02 HR: 0.79 ( ) Interaction p-value = 0.68

CM Forest Plot of PFS for PS 0-1 vs PS 2 Patients

CM OS – Treatment by PS p-value < HR: 0.87 ( )

CM OS – Treatment by PS p-value = 0.21 HR: 0.88 ( ) Interaction p-value = 0.41 p-value < HR: 0.87 ( )

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

CM 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

CM LVFU2 Trials

CM PFS –Treatment by PS p-value < HR: 0.72 ( )

CM PFS –Treatment by PS p-value < HR: 0.72 ( ) p-value < HR: 0.78 ( ) Interaction p-value = 0.75

CM OS –Treatment by PS p-value = HR: 0.88 ( )

CM OS –Treatment by PS p-value = HR: 0.88 ( ) p-value = 0.27 HR: 0.88 ( ) Interaction p-value = 0.10

CM 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

CM Infusional-Based Combination Regimens

CM RR – Infusional Combo by PS p-value < OR: 2.49 ( )

CM RR – Infusional Combo by PS Interaction p-value = 0.02 p-value < OR: 3.00 ( ) p-value < OR: 2.49 ( )

CM PFS – Infusional Combo by PS p-value < HR: 0.72 ( )

CM PFS – Infusional Combo by PS Interaction p-value = 0.03 p-value = HR: 0.64 ( ) p-value < HR: 0.72 ( )

CM OS – Infusional Combo by PS p-value < HR: 0.84 ( )

CM OS – Infusional Combo by PS p-value < HR: 0.84 ( ) p-value < HR: 0.69 ( ) Interaction p-value = 0.004

CM 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.

CM 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

CM 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