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G. Folprecht,* M. Nowacki , I. Lang, S. Cascinu ,

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.

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G. Folprecht,* M. Nowacki , I. Lang, S. Cascinu ,

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  1. Cetuximab plus FOLFIRI 1st-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 1st-line treatment of metastatic colorectal cancer (mCRC) • Are suggested in single-arm phase II trials1,2 • Have been confirmed by the randomized CRYSTAL and OPUS trials3,4 1Raoul J-L, et al. BMC Cancer 2009;9:112 [E-pub ahead of print] 2Tabernero J, et al. J Clin Oncol 2007;25:5225-5232 3Bokemeyer 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 care1 • In combination with irinotecan compared with chemotherapy alone2 1Au H-J, et al. J Clin Oncol 2009;27:1822-1828 2Sobrero 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/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-h continuous infusion) + FA (every 2 weeks) EGFR- detectablemCRC R Cetuximab + FOLFIRI Cetuximab (iv 400 mg/m2 on day 1, then 250 mg/m2 weekly) + Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-h continuous infusion) + FA (every 2 weeks) Stratification by: Region ECOG PS Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent 5-FU, 5-fluorouracil; FA, folinic acid; ECOG, Eastern Cooperative Oncology Group

  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 questionnaire1 • 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 1Van 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 timea aScores not adjusted for between-group baseline differences bt-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 groupsa,b over timea,b 6.00 4.00 2.00 0.00 -2.00 -4.00 -6.00 -8.00 -10.00 Difference in LSmeans ** * Baseline 8 16 24 32 40 Time (weeks) Cetuximab + FOLFIRI, n 435 427 423 395 317 313 259 251 168 159 125 99 FOLFIRI, n aScores 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) bA higher score for role functioning/QoL indicates a better QoL

  19. EORTC QLQ-C30 fatigue scores: difference in LSmeans between treatment groups over timea,b 8.00 6.00 4.00 2.00 0.00 -2.00 -4.00 -6.00 -8.00 * Difference in LSmeans Baseline 8 16 24 32 40 Time (weeks) Cetuximab + FOLFIRI, n 438 427 424 395 318 314 259 252 168 159 125 99 FOLFIRI, n aScores 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) bA higher score for symptom/QoL represents increased symptoms and generally indicates a poorer QoL

  20. EORTC QLQ-C30 nausea/vomiting scores: difference in LS means between treatment groups over timea,b 4.00 2.00 0.00 -2.00 -4.00 -6.00 -8.00 -10.00 Difference in LSmeans * ** Baseline 8 16 24 32 40 Time (weeks) Cetuximab + FOLFIRI, n 437 426 423 394 318 314 259 252 168 158 125 99 FOLFIRI, n aScores 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) bA higher score for symptom/QoL represents increased symptoms and generally indicates a poorer QoL

  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 timea Cetuximab + FOLFIRI FOLFIRI 50 25 0 -25 -50 Change from baseline score Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Week 56 Week 64 Timepoint Cetuximab + FOLFIRI, n 310 298 239 231 192 188 130 112 94 77 59 41 31 18 13 8 FOLFIRI, n 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 aA positive change score represents an improvement in social functioning whereas a negative change score represents a worsening

  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 ap 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 populationthe 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 subgroupa,b Cetuximab + FOLFIRI FOLFIRI 80 60 40 20 0 -20 Lsmeans estimate 95% CI for difference in treatment groups Baseline Week 8 Week 16 Week 24 Week 32 Timepoint Cetuximab + FOLFIRI, n 118 123 123 125 96 104 84 87 64 61 FOLFIRI, n aScores not adjusted for between-group baseline differences bA higher score for global health status/QoL indicates a better QoL CI, confidence interval

  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 timea Cetuximab + FOLFIRI FOLFIRI 50 25 0 -25 -50 Change from baseline score Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Week 56 Week 64 Timepoint Cetuximab + FOLFIRI, n 92 98 77 78 66 64 51 42 36 32 24 14 14 8 8 5 FOLFIRI, n 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 aA positive change score represents improvement of social functioning whereas a negative change score represents worsening

  30. Conclusions (1) • Adding cetuximab to FOLFIRI in the 1st-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 mCRC1,2 • The data confirm that cetuximab increases the efficacy of standard 1st-line chemotherapy without any real impact on QoL 1Au H-J, et al. J Clin Oncol 2009;27:1822-1828 2Sobrero AF, et al. J Clin Oncol 2008;26:2311-2319

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