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Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. *C. Bokemeyer, C.-H. Köhne, P. Rougier, C. Stroh, M. Schlichting, E. Van Cutsem
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Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status *C. Bokemeyer, C.-H. Köhne, P. Rougier, C. Stroh, M. Schlichting, E. Van Cutsem *Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Disclosures • Dr Bokemeyer would like to disclose: • Involvement in advisory boards and receipt of honoraria for presentations on behalf of Merck Serono
Background • The addition of cetuximab to standard 1st-line irinotecan- or oxaliplatin-based therapy in the CRYSTAL1 and OPUS2 trials improved efficacy in mCRC patients with KRAS wild-type (wt) tumors • The serine-threonine kinase BRAF is a direct downstream effector of KRAS • BRAF gene mutations have been detected in 8% of CRC tumors3 • BRAF mutation status has been suggested to be predictive of cetuximab efficacy in pretreated patients with mCRC4 1Van Cutsem E, et al. N Engl J Med 2009;360:1408-17 2Bokemeyer C, et al. J Clin Oncol 2009;27:663-71 3Roth A, et al. J Clin Oncol 2009 E pub doi/10.1200/JCO.2009.23.3452 4Di Nicolantonio F, et al. J ClinOncol 2008;26:5705-12
BRAF – pre-treated patients *Significant; †All patients; ‡KRAS wt patients only (Ruzzo n=66 out of 117; Di Nicolantonio, n=79 out of 113); §Data not available CT, chemotherapy; mt, mutant; pts, patients; PFS, progression-free survival; RR, response rate; wt, wild-type 1Lambrechts D, et al. J ClinOncol 2009;27:15s: Abstract 4020 2Ruzzo A, et al. J ClinOncol 2009;27:15s: Abstract 4058 3Di Nicolantonio F, et al. J ClinOncol 2008;26:5705-12 ITT = intent to treat (Abbreviations defined at first use)
Study objectives: Pooled analysis • To investigate the efficacy of cetuximab in expanded KRAS evaluable patient populations from the CRYSTAL and OPUS trials: • In patients with KRAS wt tumors • According to tumor BRAF mutation status in patients with KRAS wt tumors
Efficacy endpoints: Pooled analysis • The key efficacy endpoints from the two trials: • Progression-free survival (CRYSTAL) • Overall response rate (OPUS) • The secondary endpoint of overall survival from both trials
Patients and samples • Patients were randomized to receive cetuximab in combination with FOLFIRI (CRYSTAL)1 or FOLFOX4 (OPUS)2 or the standard 1st-line treatment alone • The number of samples evaluable for KRAS mutations were: • 1063 (89%) from the CRYSTAL study – increased from 45% previously1 • 315 (93%) from the OPUS study – increased from 69% previously2 • In the CRYSTAL and OPUS studies 625 and 175 KRAS wt tumors respectively, were evaluable for BRAF mutation status 1Van Cutsem E, et al. N Engl J Med 2009;360:1408-17 2Bokemeyer C, et al. J Clin Oncol 2009;27:663-71
Assessments: CRYSTAL and OPUS • PFS and OR rates were based on CT or MRI scans as assessed by an independent radiology review committee according to modified WHO criteria • Additional tumor KRAS and BRAF mutation analyses were performed on DNA extracted from material from stained slides previously collected to evaluate tumor EGFR expression status • KRAS (codons 12/13) and BRAF (V600E)mutations were detected using a polymerase chain reaction clamping and melting curve technique
Statistical considerations • The pooled analysis was performed on individual patient data from the two trials • CRYSTAL study data cuts-offs were: PFS, OR (27th July 2006), OS 31st May 2009 • OPUS study data cut-offs were: PFS, OR (1st March 2007), OS (30th November 2008) • Treatment groups were compared using: • A Cox proportional hazards model for OS and PFS • A logistic regression model for OR • Inter-study heterogeneity was assessed by testing for individual treatment effect estimates across the studies
Baseline characteristics of patients by KRAS and BRAF mutation status CT, chemotherapy; ECOG PS, Eastern Cooperative Group performance status; mt, mutant; wt, wild-type; yrs, years
Clinical efficacy in patients with KRAS wt tumors aHazard ratios <1 for OS and PFS and odds ratios >1 for OR indicate a benefit for the addition of cetuximab to chemotherapy compared with chemotherapy alone;bLikelihood ratio test on treatment effect in stratified Cox’s proportional hazards model; cPooled (stratified) likelihood ratio test on study treatment interaction in stratified Cox’s proportional hazards model CI, confidence interval; CT, chemotherapy; OR, best overall response; OS, overall survival; PFS, progression-free survival; mt, mutant; wt, wild-type
0.5 0.7 1.0 1.3 2.0 Pooled analysis of OS in patients with KRAS wt tumors Study KRAS wt Hazard Ratio [95% CI] Pooled analysis n=845 0.81[0.69–0.94] 0.80 [0.67–0.95] CRYSTAL n=666 0.85 [0.60–1.22] n=179 OPUS Benefit under chemotherapy+ cetuximab Benefit under chemotherapy
Pooled analysis of OS by treatment group for patients with KRAS wt tumors KRAS wt HR [95% CI]: 0.81 [0.69–0.94] p=0.0062 FOLFIRI / FOLFOX4 + cetuximab: (n=398) median 23.5 months FOLFIRI / FOLFOX4: (n=447) median 19.5 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Probability of overall survival Time (months) Number of patients CT+cetuximab 398 356 296 246 177 128 83 65 21 4 0 CT 447 395 313 227 159 112 67 48 18 2 0 CI, confidence interval; CT, chemotherapy; PFS, progression-free survival
0.5 0.7 1.0 1.3 2.0 Pooled analysis of PFS in patients with KRAS wt tumors Study KRAS wt Hazard Ratio [95% CI] 0.66[0.55–0.80] Pooled analysis n=845 0.70 [0.56–0.87] CRYSTAL n=666 0.57 [0.38–0.86] OPUS n=179 Benefit under chemotherapy + cetuximab Benefit under chemotherapy
Pooled analysis of PFS by treatment group for patients with KRAS wt tumors KRAS wt HR [95% CI]: 0.66 [0.55–0.80] p<0.0001 FOLFIRI / FOLFOX4 + cetuximab: (n=398) median 9.6 months FOLFIRI / FOLFOX4: (n=447) median 7.6 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12 16 20 Probability of progression-free survival Time (months) Number of patients CT+cetuximab 398 286 154 46 9 1 CT 447 298 128 24 4 0 CI, confidence interval; CT, chemotherapy; PFS, progression-free survival
0.5 0.7 1.0 1.3 2.0 Pooled analysis of OR in patients with KRAS wt tumors Study KRAS wt population Odds Ratio [95% CI] Pooled analysis n=845 2.16 [1.64–2.86] 2.07 [1.52–2.83] CRYSTAL n=666 2.55 [1.38–4.72] OPUS n=179 Benefit under chemotherapy Benefit under chemotherapy+cetuximab
Clinical efficacy by KRAS/BRAF tumor mutation status aHazard ratios <1 for OS and PFS and odds ratios >1 for OR indicate a benefit for the addition of cetuximab to chemotherapy compared with chemotherapy alone;bLikelihood ratio test on treatment effect in stratified Cox’s proportional hazards model; cPooled (stratified) likelihood ratio test on study treatment interaction in stratified Cox’s proportional hazards model CI, confidence interval; CT, chemotherapy; OR, best overall response; OS, overall survival; PFS, progression-free survival; mt, mutant; wt, wild-type
Pooled analysis of OS in patients withKRAS wt/BRAF wt tumors KRAS wt/BRAF wt HR [95% CI]: 0.840 [0.710–0.993] p=0.041 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months FOLFIRI / FOLFOX4: (n=381) median 21.1 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Probability of overall survival Time (months) Number of patients CT +cetuximab 349 317 268 225 163 120 80 63 19 4 0 CT 381 350 283 212 149 107 63 46 17 2 0 CI, confidence interval; CT, chemotherapy; HR, hazard ratio;mt, mutant;OS, overall survival; wt, wild-type
KRAS wt/BRAF mt HR [95% CI]: 0.633 [0.378–1.060] p=0.079 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 14.1 months FOLFIRI / FOLFOX4: (n=38) median 9.9 months KRAS wt/BRAF wt HR [95% CI]: 0.840 [0.710–0.993] p=0.041 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months FOLFIRI / FOLFOX4: (n=381) median 21.1 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Pooled analysis of OS in patients withKRAS wt/BRAF mt tumors Probability of overall survival Time (months) Number of patients CT+cetuximab 349 317 268 225 163 120 80 63 19 4 0 CT 381 350 283 212 149 107 63 46 17 2 0 CT +cetuximab 32 25 16 12 8 5 2 2 2 0 0 CT 38 24 14 6 6 3 3 1 0 0 0 CI, confidence interval; CT, chemotherapy;HR, hazard ratio;mt, mutant;OS, overall survival; wt, wild-type
KRAS wt/BRAF wt HR [95% CI]: 0.635 [0.514–0.783] p<0.001 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 10.9 months FOLFIRI / FOLFOX4: (n=381) median 7.7 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12 16 20 Pooled analysis of PFS in patients with KRAS wt/BRAF wt tumors Probability of progression-free survival Time (months) Number of patients CT +cetuximab 349 260 141 45 9 1 CT 381 264 115 21 4 0 CI, confidence interval; CT, chemotherapy; HR, hazard ratio;mt, mutant;PFS, progression-free survival; wt, wild-type
Pooled analysis of PFS in patients with KRAS wt tumors according to BRAF mutation status KRAS wt/BRAF wt HR [95% CI]: 0.635 [0.514–0.783] p=0.001 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 10.9 months FOLFIRI / FOLFOX4: (n=381) median 7.7 months 1.0 0.9 KRAS wt/BRAF mt HR [95% CI]: 0.693 [0.362–1.329] p=0.267 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 7.1 months FOLFIRI / FOLFOX4: (n=38) median 3.7 months 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12 16 20 Probability of progression-free survival Time (months) Number of patients CT +cetuximab 349 260 141 45 9 1 CT 381 264 115 21 4 0 CT +cetuximab 32 16 8 1 0 0 CT 38 14 4 0 0 0 CI, confidence intervals; CT, chemotherapy;HR, hazard ratio;mt, mutant;PFS, progression-free survival; wt, wild-type
Conclusions • In this pooled analysis, a significant improvement in OS time was demonstrated for patients with KRAS wt tumors receiving cetuximab plus chemotherapy compared with chemotherapy alone • Patients with BRAF mutations also appear to benefit from cetuximab, although a mutation in BRAF would appear to be an indicator of poor prognosis • This pooled analysis confirms the consistency of the benefit obtained, across all efficacy endpoints, by the addition of cetuximab to 1st-line chemotherapy in mCRC patients with KRAS wt tumors