1. Cetuximab plus FOLFIRI 1 st -line in patients (pts) with metastatic colorectal cancer (mCRC): A quality of life (QoL) analysis of the CRYSTAL trial G. Folprecht,* M. Nowacki, I. Lang, S. Cascinu, I. Shchepotin, J. Maurel, P. Rougier, D. Cunningham, A. Zubel, E. Van Cutsem *University Hospital Carl Gustav Carus, Dresden, Germany (Presenting author)

2. Background (1) Cetuximab is an IgG1 monoclonal antibody Cetuximab specifically targets the epidermal growth factor receptor (EGFR) with high affinity Cetuximab competitively inhibits endogenous ligand binding

3. Background (2) The benefits of combining cetuximab with standard irinotecan- or oxaliplatin-based chemotherapy in the 1 st -line treatment of metastatic colorectal cancer (mCRC) –Are suggested in single-arm phase II trials 1,2 –Have been confirmed by the randomized CRYSTAL and OPUS trials 3,4 1 Raoul J-L, et al. BMC Cancer 2009;9:112 [E-pub ahead of print] 2 Tabernero J, et al. J Clin Oncol 2007;25:5225-5232 3 Bokemeyer C, et al. J Clin Oncol 2009;27:663-671 4 Van Cutsem E, et al. N Engl J Med 2009;360:1408-1417

4. Background (3) Cetuximab in combination with chemotherapy –Is generally well tolerated –Acne-like rash is the most common side effect The impact of treatment on quality of life (QoL) can be an important factor in treatment decision- making Cetuximab provided QoL benefits in previously treated mCRC patients –As monotherapy compared with best supportive care 1 –In combination with irinotecan compared with chemotherapy alone 2 1 Au H-J, et al. J Clin Oncol 2009;27:1822-1828 2 Sobrero AF, et al. J Clin Oncol 2008;26:2311-2319

5. Primary and secondary objectives of the CRYSTAL trial Primary objective –To examine differences in progression-free survival (PFS) between patients receiving cetuximab plus FOLFIRI and those receiving FOLFIRI Secondary objectives included –Determination of overall survival (OS) –Assessment of QoL changes

6. Primary objectives of the QoL analysis To assess differences between the treatment groups in QoL To pay particular attention to the effects of treatment on global health status and social functioning –The social functioning scale was expected to reflect any impact of cetuximab-associated acne-like rash on QoL

7. CRYSTAL trial design FOLFIRI Irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus + 2400 mg/m 2 as 46-h continuous infusion) + FA (every 2 weeks) Cetuximab + FOLFIRI Cetuximab (iv 400 mg/m 2 on day 1, then 250 mg/m 2 weekly) + Irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus + 2400 mg/m 2 as 46-h continuous infusion) + FA (every 2 weeks) R EGFR- detectable mCRC Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent 5-FU, 5-fluorouracil; FA, folinic acid; ECOG, Eastern Cooperative Oncology Group Stratification by: Region ECOG PS

8. Patients Main inclusion criteria –≥18 years of age –Histologically confirmed non resectable adenocarcinoma of the colon or rectum –Immunohistochemical evidence of EGFR expression –ECOG PS ≤2 Main exclusion criteria –Previous anti-EGFR therapy or irinotecan-based chemotherapy –Previous chemotherapy for mCRC –Adjuvant treatment that was terminated ≤6 months before start of treatment

9. EORTC QLQ-C30 questionnaire 1 Five functional scales –Physical, role, emotional, cognitive, and social functioning Three symptom scales –Fatigue, nausea and vomiting, and pain Six symptom single-item scales –Dyspnea, insomnia, appetite loss, constipation diarrhea and financial difficulties One global health status QoL scale 1 Fayers PM, et al. 1999. EORTC QLQ-C30 Scoring Manual. EORTC: Brussels EORTC, European Organisation for Research and Treatment of Cancer

10. QoL assessments and analysis QoL was assessed –At randomization –Every 8 weeks thereafter –At final tumor assessment QoL analysis was performed –On the primary analysis population –In a subgroup of patients with KRAS wild-type tumors

11. QoL statistics (1) Descriptive statistics –Were used for each treatment group at each of the assessment points For the multi-item scales and for single-item measures Primary QoL analysis –A pattern mixture analysis of global health status/QoL and social functioning scores Included the drop-out pattern –A post-hoc analysis on changes from baseline scores was also conducted

12. QoL statistics (2) An ANOVA model was used –To investigate QoL data changes over time –To generate least squares mean (LSmean) estimates for each timepoint –A post-hoc analysis of QoL over time as a function of changes from baseline scores was conducted Summary best and worst patient QoL scores were generated –For each scale –For the change to these scores from baseline –For the changes from baseline to final tumor assessment

13. Patient results Between July 2004 and November 2005, 2020 patients were screened at 189 centers –1217 patients underwent randomization 1198 patients were treated at 184 centers –Primary analysis population –Each treatment arm contained 599 patients Tumor KRAS mutation analysis was available for 540 patients –348 patients (64.4%) were KRAS wild-type –192 patients (35.6%) were KRAS mutant

14. Clinical efficacy Adding cetuximab to FOLFIRI significantly reduced the risk of disease progression –By 15% in the primary analysis population (HR=0.85; 95% CI 0.72–0.99; p=0.048) 1 –By 32% among patients with KRAS wild-type disease (HR=0.68; 95% CI 0.50–0.94, p=0.02) 1 1 Van Cutsem E, et al. N Engl J Med 2009;360:1408-1417

15. QoL analysis for the primary analysis population (1) Evaluability and compliance –1125 patients completed evaluable questionnaires 566 in the cetuximab plus FOLFIRI group 559 in the FOLFIRI group –Questionnaire evaluability rates 78.1% in the cetuximab plus FOLFIRI group 76.4% in the FOLFIRI group –Compliance rates Decreased from 70–80% at baseline and week 8 to around 30% at final tumor assessment Were similar between treatment groups

16. QoL analysis for the primary analysis population (2) Multi-item scales –Statistically significant differences in the LSmeans between treatment groups for the multi-item scales were found for Global health status/QoL Role functioning Fatigue Nausea/vomiting –Adjusting for between-group baseline differences None of the multi-item scales displayed significant results in favor of FOLFIRI

17. EORTC QLQ-C30 global health status/QoL scores: changes over time a Cetuximab + FOLFIRI n=556 FOLFIRI n=559 Difference in LSmeans 95% CIpbpb Baselinen LSmean 430 58.9 423 60.3-1.45(-4.06–1.16)0.2767 Week 8n LSmean 421 59.0 390 61.8-2.81(-5.44– -0.18)0.0360 Week 16n LSmean 312 60.8 309 63.3-2.52(-5.43– 0.39)0.0897 Week 24n LSmean 255 61.8 244 64.1-2.23(-5.48–1.02)0.1794 Week 32n LSmean 164 59.7 154 65.1-5.39(-9.37– -1.41)0.0080 Week 40n LSmean 122 63.4 96 64.0-0.60(-5.51– 4.32)0.8125 a Scores not adjusted for between-group baseline differences b t-test Higher scores for the global health/QoL scale indicate a better QoL CI, confidence interval; LSmean/s, least squares mean/s;QoL, quality of life

18. EORTC QLQ-C30 role functioning scores: difference in LSmeans between treatment groups a,b over time a,b a Scores not adjusted for between-group baseline differences; difference in LSmeans at each timepoint calculated as cetuximab/FOLFIRI LSmean minus FOLFIRI LSmean; *p=0.0221; **p=0.0482 (t-test) b A higher score for role functioning/QoL indicates a better QoL Difference in LSmeans 6.00 4.00 2.00 0.00 -2.00 -4.00 -6.00 -8.00 -10.00 Time (weeks) Baseline816243240 Cetuximab + FOLFIRI, n 435 427 423 395 317 313 259 251 168 159 125 99 FOLFIRI, n * **

19. EORTC QLQ-C30 fatigue scores: difference in LSmeans between treatment groups over time a,b a Scores not adjusted for between-group baseline differences; difference in LSmeans at each timepoint calculated as cetuximab/FOLFIRI LSmean minus FOLFIRI LSmean; *p=0.0281 (t-test) b A higher score for symptom/QoL represents increased symptoms and generally indicates a poorer QoL Difference in LSmeans 8.00 6.00 4.00 2.00 0.00 -2.00 -4.00 -6.00 -8.00 Time (weeks) Baseline816243240 438 427 424 395 318 314 259 252 168 159 125 99 * Cetuximab + FOLFIRI, n FOLFIRI, n

20. EORTC QLQ-C30 nausea/vomiting scores: difference in LS means between treatment groups over time a,b a Scores not adjusted for between-group baseline differences; difference in LSmeans at each timepoint calculated as cetuximab/FOLFIRI LSmean minus FOLFIRI LSmean; *p=0.0202; **p=0.0283 (t-test) b A higher score for symptom/QoL represents increased symptoms and generally indicates a poorer QoL Difference in LSmeans 4.00 2.00 0.00 -2.00 -4.00 -6.00 -8.00 -10.00 Time (weeks) Baseline816243240 437 426 423 394 318 314 259 252 168 158 125 99 * ** Cetuximab + FOLFIRI, n FOLFIRI, n

21. QoL analysis for the primary analysis population (3) Analysis of changes from baseline –The Wei-Lachin analysis of the global health status/QoL score over time revealed no significant differences between groups overall or at any visit –For best and worst post-baseline scores for the symptom, functioning and global health status QoL scales only physical functioning was significantly worse in the cetuximab plus FOLFIRI group (p=0.0432)

22. EORTC QLQ-C30 social functioning scores: changes from baseline scores over time a Boxes show the 25%-75% percentile, whiskers show the 10%-90% percentile and the lines connect the mean scores at each timepoint. Data for outliers (n≤7 at each time point) not shown a A positive change score represents an improvement in social functioning whereas a negative change score represents a worsening Change from baseline score 50 25 0 -25 -50 Timepoint Week 8 310 298 239 231 192 188 130 112 94 77 59 41 Week 16Week 24Week 32Week 40Week 48Week 56Week 64 31 18 13 8 Cetuximab + FOLFIRI FOLFIRI Cetuximab + FOLFIRI, n FOLFIRI, n

23. QoL analysis for the primary analysis population (4) Single-item scales –Only minor between-group differences in the mean changes from baseline to worst post-baseline values were found Consistent with the incidence of adverse events reported in each group Multivariate analysis among all QoL scales –Only fatigue was considered as a prognostic scale for survival Patients with lower fatigue score at baseline had significantly longer survival (p<0.0001)

24. Pattern-mixture analysis: change from baseline scores VariableTreatment effectpapa Global health status/QoL-1.4970.2917 Social functioning-1.3960.3914 a p value is an overall test of treatment effect; test used is the F statistic The treatment effect represents the adjusted difference in the LSmeans in the two treatment groups

25. QoL analysis in the KRAS wild-type population (1) 330 patients completed evaluable questionnaires –161 in the cetuximab plus FOLFIRI group –169 in the FOLFIRI group –Questionnaire evaluability rates were 79% in each group Compared with the QoL primary analysis population the QoL KRAS wild-type population had –Favorable age and ECOG PS values –Fewer disease sites involved –Fewer numbers of liver metastases

26. QoL analysis for the KRAS wild-type population (2) The results of the QoL analysis in the KRAS wild-type group confirmed the findings from the primary analysis population There were no statistically significant differences between the treatment groups for any multi-item scales at any time point –Including global health status/QoL

27. EORTC QLQ-C30 global health status/QoL LSmeans over time: KRAS wild-type subgroup a,b a Scores not adjusted for between-group baseline differences b A higher score for global health status/QoL indicates a better QoL CI, confidence interval Lsmeans estimate 80 60 40 20 0 -20 Timepoint Baseline 118 123 125 96 104 84 87 64 61 Cetuximab + FOLFIRI FOLFIRI Week 8Week 16Week 24Week 32 95% CI for difference in treatment groups Cetuximab + FOLFIRI, n FOLFIRI, n

28. QoL analysis for the KRAS wild-type population (3) According to changes from baseline –There were no significant differences found between the treatment groups in the global health status/QoL at any timepoint –There were similar best and worse post-baseline scores for symptom, functioning and global health status/QoL scales in the two treatment groups The only significant difference was in physical functioning, which was lower in the cetuximab plus FOLFIRI group (p=0.0172)

29. EORTC QLQ-C30 social functioning scores in the KRAS wild-type population: changes from baseline scores over time a Boxes show the 25%-75% percentile, whiskers show the 10%-90% percentile and the lines connect the mean scores at each timepoint; data for outliers (n≤4 at each timepoint) not shown a A positive change score represents improvement of social functioning whereas a negative change score represents worsening Change from baseline score Timepoint Week 8 92 98 77 78 66 64 51 42 36 32 24 14 Week 16Week 24Week 32Week 40Week 48Week 56Week 64 14 8 8585 Cetuximab + FOLFIRI FOLFIRI Cetuximab + FOLFIRI, n FOLFIRI, n 50 25 0 -25 -50

30. Conclusions (1) Adding cetuximab to FOLFIRI in the 1 st -line treatment of mCRC significantly reduced the risk of disease progression in patients with KRAS wild-type tumors compared with FOLFIRI alone In both the primary and KRAS wild-type subgroup QoL analyses –There was no significant difference between cetuximab plus FOLFIRI and FOLFIRI alone in the global health status/QoL and social functioning scores, when analyzed according to changes from baseline levels

31. Conclusions (2) These results support the QoL findings from trials in patients with previously treated mCRC 1,2 The data confirm that cetuximab increases the efficacy of standard 1 st -line chemotherapy without any real impact on QoL 1 Au H-J, et al. J Clin Oncol 2009;27:1822-1828 2 Sobrero AF, et al. J Clin Oncol 2008;26:2311-2319