1Individualized Treatments for Advanced Colorectal Cancer: The KRAS StoryDavid Z. Chang, MD, PhD UT MD Anderson Cancer Center 张 宗 圣CSCO Annual Meeting 20082SUMMARYTargeted therapies have improved clinical outcome of mCRCNeed judicious use of these agents: when, howMany questions remainingHow to overcome the high cost Treatments need to be individualized: biomarkers and genetic signatures3Story for GI at ASCO 20081st biomarker for individualized therapy for colorectal cancer: KRAS status predicts responsiveness (or lack of responsiveness) to EGFR targeted therapies4Advances in the Treatment of Colorectal Cancer198019851990199520002005CapecitabineOxaliplatinCetuximabBevacizumabIrinotecan5-FUPanitumumabMedian Survival BSC: 4-6 months 5FU: 10-14 months 5FU/OX/Iri: 20 months + targeted therapy: 30 months?5Some Historical DataEGFR Targeted Therapies in CRCCetuximab 351:337-345.70510152025012345622.9%5.7 mo4.2 mo10.8%Objective Response RateMedian Duration of ResponseCetuximab with irinotecan (n=218)Cetuximab as a single agent (n=111)Cetuximab Randomized Pivotal Trial: Response Rates P=0.007Cunningham D, et al. N Engl J Med. 2004;351:337-345.8R A N D O M I Z EN=1298 Patients with CRC who progressed on 5FU, Oxaliplatin, GFR + IrinotecanCetuximab + IrinotecanJonker et al. AACR 2007. Abstract 3556.EPIC: Cetuximab + Irinotecan vs Irinotecan as 2nd-line Therapy9EPIC Study Efficacy Data Cetuximab is active in 2nd line, irinotecan nave pts Lack of overall survival: cross-over effect?10CRYSTAL: Phase III Trial of FOLFIRI +/- Cetuximab in First-line mCRCR A N D O M I Z EFOLFIRI + cetuximab (608) First-line mCRCFOLFIRI (609)Cutsem et aI, et al. ASCO 2007. 4000.11CRYSTAL Efficacy DataCetuximab +FOLFIRI (N=608)Irinotecan (N=609)P ValuePFS8.98 0.036Response Rate (%) 46.9%38.7% 0.005 Cetuximab improves RR, PFS in 1st line, in combination with FOLFIRI12Phase III Study: Panitumumab vs Best Supportive CarePeeters M, et al. AACR 2006. Abstract CP-1.R A N D O M I Z EPanitumumab (6 mg/kg q2 wk) + BSC (n=231) N=463 Patients third -line mCRC EGFR expression requiredOptional panitumumab crossover study (n=174)Best supportive care (n=232)PDPDStratification based on ECOG score, geographic region13Panitumumab Improves PFS over Best Supportive CarePFS longer with panitumumab vs BSC -HR, 0.54 (95% CI, 0.44-0.66; P0.000000001)*P0.0001. Peeters M, et al. AACR 2006. Abstract CP-1.Panitumumab (n=231)BSC (n=232)PR, n (%)19 (8)*0 (0)SD, n (%)64 (28)24 (10)Median duration response, wk (range)17 (4+-40+)n/a14Only a small portion of patients responded to EGFR targeted therapiesMajority of patients suffered the side effects and high cost without benefitsDilemmaWhat may help select these patients?15EGF/EGFR PathwayProliferationApoptosis ResistanceTranscriptionShcPI3KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1EGFR1617Phase III Study: Panitumumab vs Best Supportive Care18KRAS Mutation Predicts No Benefit from Panitumumab19CRYSTAL: Phase III Trial of FOLFIRI +/- Cetuximab in First-line mCRCR A N D O M I Z EFOLFIRI + cetuximab (608) First-line mCRCFOLFIRI (609)Cutsem et aI, et al. ASCO 2007. 4000.20CRYSTAL: PFS in Patients With the KRAS Mutation00.20.40.60.81.004812MosPFS Estimate16Cetuximab + FOLFIRIFOLFIRIKRAS mutation (n = 192) HR: 1.07; P = .47261014Median PFS cetuximab + FOLIFIRI: 7.6 mosMedian PFS FOLIFIRI: 8.1 mos0.10.30.50.70.9Van Cutsem E, et al. ASCO 2008. Abstract 2. Reproduced with permission.21CRYSTAL: PFS in Patients With WT KRAS00.20.40.60.81.004812Mos18Cetuximab + FOLFIRIFOLFIRIWT KRAS (n = 348): HR: 0.68; P = .017261014Median PFS cetuximab + FOLIFIRI: 9.9 mosMedian PFS FOLIFIRI: 8.7 mos0.10.30.50.70.9161-yr PFS rate: 43%Van Cutsem E, et al. ASCO 2008. Abstract 2. Reproduced with permission.1-yr PFS rate: 25%PFS Estimate22CRYSTAL: Initial and Retrospective ResultsITT PopulationK-ras Wild TypeK-ras MutationFOLFIRIFOLFIRIFOLFIRIWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX# of Patients 599 599 172 176 105 87Overall Response Rate47% 39%p=0.00459% 43% p=0.00336% 40%p=0.46Median PFS 8.9 mos 8.0 mosHazard Ratio: 0.85 p=0.059.9 mos 8.7 mosHazard Ratio: 0.68 p=0.027.6 mos 8.1 mosHazard Ratio: 1.07 p=0.75232425KRAS Status and Efficacy of First-Line FOLFOX Cetuximab: OPUSGenomic DNA was isolated from archived tumor materialKRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay Population with tissue available for KRAS analysis (n = 233) was representative of overall ITT population (n = 337) in terms of demographics and efficacy parametersKRAS mutations detected in 42% (99/233) of evaluable samplesBokemeyer C, et al. ASCO 2008. Abstr