转移性结肠癌的一种新的治疗模式

A new treatment paradigm for mCRC Heinz-Josef Lenz Professor of Medicine Associate Director, Clinical Research USC Norris Comprehensive Cancer Center Los Angeles, CA Anti-EGFR antibodies in mCRC 3rd line BOND: cetuximab irinotecan NCIC C0.17: cetuximab vs BSC Panitumumab vs BSC (KRAS wild-type) 2nd line BOND: cetuximab irinotecan EPIC: irinotecan cetuximab 1st line (Randomized) Phase II studies (chemo + cetuximab) CRYSTAL: FOLFIRI cetuximab PACCE: chemo/bevacizumab panitumumab CAIRO2: capecitabine/oxaliplatin/bevacizumab cetuximab Other phase III studies in progress Comparison of cetuximab and bevacizumab Bleeding possible, wound-healing complications No complicationsPerioperative Hypertension, thromboembolic events Acne-like skin rash Specific side effect +?+RR with FOLFOX +RR with FOLFIRI First lineSecond/third lineRegistered ?YesSingle-agent activity VEGF proteinEGF receptorAntibody BevacizumabCetuximabCharacteristic Phase III CRYSTAL study: Study design Stratification factors: Region ECOG performance status Populations: Randomized patients (n=1217) Safety population (n=1202) ITT population (n=1198) FOLFIRI Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-h continuous infusion) + LV (every 2 weeks) ERBITUX + FOLFIRI ERBITUX (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) + LV (every 2 weeks) REGFR-expressing mCRC Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000) Study endpoints Primary endpoint PFS time (as assessed by blinded independent review) Secondary endpoints ORR (independently reviewed) DCR (CR+PR+SD) OS Quality of life (EORTC QLQ-C30) Safety Van Cutsem E, et al. ECCO 2007 (Abstract No. 3001) 1.0 0.8 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0 2 4 6 8 10 12 14 16 18 20 Primary endpoint: PFS (ITT population) PFS estimate Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000) PFS time (months) 1-year PFS rate: 23% vs 34% FOLFIRI (n=599)ERBITUX + FOLFIRI (n=599) PFS ITT: HR=0.85; p=0.048 mPFS ERBITUX + FOLFIRI: 8.9 months mPFS FOLFIRI: 8.0 months Independent assessment of response Outcome FOLFIRI (n=599) (%) ERBITUX + FOLFIRI (n=599) (%) CR PR SD PD 0.3 38.4 46.7 9.0 0.5 46.4 37.4 8.8 ORR 95% CI 38.7 34.842.8 46.9 42.951.0 DCR 85.4 84.3 Van Cutsem E, et al. ECCO 2007 (Abstract No. 3001) 39% 47% Response rate (%) p=0.0038a aCochranMantelHaenszel test KRAS analysis: Objective and methodology To retrospectively investigate the impact of the KRAS mutation status of tumors on PFS and RR in the first-line treatment of mCRC with FOLFIRI ERBITUX Efficacy analyses repeated on KRAS evaluable population Genomic DNA isolated from archived tumor material Paraffin-embedded, formalin-fixed tissue KRAS mutation status of codons 12/13 determined using quantitative PCR-based assay Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2) KRAS evaluable population 587 subjects analysed for KRAS mutation status 540 (45%) subjects: KRAS evaluable population 348 (64.4%) KRAS wild-type 192 (35.6%) KRAS mutant 171 subjects with events (49.1%) Group A: 105 (54.7%) Group B: 87 (45.3%) 101 subjects with events (52.6%) 1198 subjects (ITT) Group A: 172 (49.4%) Group B: 176 (50.6%) FOLFIRIERBITUX + FOLFIRI Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2) Patient demographics at baseline according to KRAS status KRAS evaluable population, % KRAS wild-type(n=348) KRAS mutant(n=192) Age 10m Resection rate of metastases and tumor response Studies including all patients with mCRC (solid line) (r=0.74; p0.001) Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) Phase III studies including all patients with mCRC (dashed line) (r=0.67; p=0.024) Folprecht, et al. Ann Oncol 2005;16:13111319 54% Survival after primary or secondary resection of liver metastases Proportion Surviving Survival Time (years) 9876543210 1 .9 .8 .7 .6 .5 .4 .3 .2 .1 0 29%34% 50% 34% 27% Resectable (n = 425) Initially non resectable (n = 95) Bismuth et al, 1996 CRYSTAL Trial: Surgery with Curative Intent *CMH test n=599 / group n=599 / group n=134 / n=122 p=0.0034* odds ratio 3.0 95% CI: 1.4 - 6.5 FOLFIRI alone ERBITUX + FOLFIRI No residual tumor in patients with liver metastases ITT population Liver-limited disease population Van Cutsem et al, ASCO 2007 OncoSurgical strategies in liver metastases from palliative to curative Palliative Curative Survival Time Conclusions KRAS is the first molecular marker used to select a targeted therapy in combination with a stand