晚期大腸癌的個體化治療課件

1、Individualized Treatments for Advanced Colorectal Cancer:The KRAS StoryDavid Z. Chang, MD, PhDUT MD Anderson Cancer Center張 宗 圣CSCO Annual Meeting 2008SUMMARYTargeted therapies have improved clinical outcome of mCRCNeed judicious use of these agents: when, howMany questions remainingHow to overcome

2、the high cost Treatments need to be individualized: biomarkers and genetic signaturesStory for GI at ASCO 20081st biomarker for individualized therapy for colorectal cancer: KRAS status predicts responsiveness (or lack of responsiveness) to EGFR targeted therapiesAdvances in the Treatment of Colorec

3、tal Cancer198019851990199520002005CapecitabineOxaliplatinCetuximabBevacizumabIrinotecan5-FUPanitumumabMedian SurvivalBSC: 4-6 months5FU: 10-14 months5FU/OX/Iri: 20 months+ targeted therapy: 30 months?Some Historical DataEGFR Targeted Therapies in CRCCetuximab & PanitumumabBOND 1: Randomized Pivotal

4、Trial in Metastatic Colorectal CancerRANDOMIZECetuximab + irinotecanCetuximab (initial dose, 400 mg/m2 then weekly infusion 250 mg/m2) + irinotecan (same as prestudy therapy)(n=218)N=329Patients with mCRC who progressed during or within 3 mo after irinotecanEGFR+ CRC Histamine receptor antagonist pr

5、emedication given before at least the first cetuximab infusion.Cetuximab (initial dose, 400 mg/m2 then weekly infusion 250 mg/m2)(n=111)Cunningham D, et al. N Engl J Med. 2004;351:337-345.0510152025012345622.9%5.7 mo4.2 mo10.8%Objective Response RateMedian Duration of Response Cetuximab with irinote

6、can (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.CRYSTAL: Phase III Trial of FOLFIRI +/- Cetuximab in First-line mCRCRANDOMIZEFOLFIRI + cetuximab(608)First-line mCRCFOLFIRI(609)Cutsem et aI, et

7、 al. ASCO 2007. 4000.CRYSTAL 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 FOLFIRIPhase III Study: Panitumumab vs Best Supportive CarePeeters M, et al. AACR 2006. Abstract CP-1.

8、RANDOMIZEPanitumumab (6 mg/kg q2 wk) + BSC (n=231)N=463Patients third-line mCRCEGFR expression requiredOptional panitumumab crossover study(n=174)Best supportive care(n=232)PDPDStratification based on ECOG score, geographic regionPhase III Study: Panitumumab vs Best Supportive CareKRAS Mutation Pred

9、icts No Benefit from PanitumumabCRYSTAL: Phase III Trial of FOLFIRI +/- Cetuximab in First-line mCRCRANDOMIZEFOLFIRI + cetuximab(608)First-line mCRCFOLFIRI(609)Cutsem et aI, et al. ASCO 2007. 4000.CRYSTAL: PFS in Patients With WT KRAS00.20.40.60.81.004812Mos18Cetuximab + FOLFIRIFOLFIRIWT KRAS (n = 3

10、48): 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 Estimate CRYSTAL: Initial and Retrospective ResultsITT PopulationK-ras Wild

11、 TypeK-ras MutationFOLFIRIFOLFIRIFOLFIRIWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX# of Patients 599 599 172 176 105 87Overall Response Rate 47% 39% p=0.004 59% 43% p=0.003 36% 40% p=0.46Median PFS 8.9 mos 8.0 mos Hazard Ratio: 0.85 p=0.05 9.9 mos 8.7 mos Hazard Ratio: 0.68

12、 p=0.02 7.6 mos 8.1 mos Hazard Ratio: 1.07 p=0.75KRAS 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

13、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. Abstract 4000.OPUS: Initial and Retrospective ResultsITT PopulationK-ras Wild Type

14、K-ras MutationFOLFOXFOLFOXFOLFOXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX# of Patients 169 168 61 73 52 47Overall Response Rate 46% 36% p=0.006 61% 37% p=0.01 33% 49% p=0.11Median PFS 7.2 mos 7.2 mos Hazard Ratio: 0.93 p=NSS 7.7 mos 7.2 mos Hazard Ratio: 0.57 p=0.02 5.5 m

15、os 8.6 mos Hazard Ratio: 1.83 p=0.02CAIRO2 SummaryCetuximab + bevacizumab/capecitabine/oxaliplatin decreased PFS without affecting OSAlthough manageable, cetuximab + bevacizumab/ chemotherapy increases skin toxicity and diarrhea adverse eventsTreatment discontinuation due to toxicity did not differ

16、between armsNegative interaction between anti-VEGF and anti-EGFR cannot be discountedPunt CJ, et al. J Clin Oncol. 2008;26(May 20 suppl):abstr LBA4011.Is KRAS independent from skin rash as a predictor for response?Can dose escalation overcome KRAS mutant-type?KRAS and Efficacy of Irinotecan and Cetu

17、ximab in mCRC: EVERESTPatients with irinotecan-refractory metastatic cancerCetuximab 400 mg/m2 initial dose then 250 mg/m2/wk + Irinotecan 180 mg/m2 Q2WControl Standard Cetuximab regimen (250 mg/m2/wk)(n = 23)Dose Escalation Cetuximab dose increasesof 50 mg/m2 Q2W up to maximum 500 mg/m2/wk(n = 31)N

18、onrandomized Standard Cetuximab regimen (250 mg/m2/wk)SCREENINGDay 22Randomized:skin toxicity grade 0/1Not eligible for randomization:skin toxicity grade 2/3All patients continued to receive irinotecan Treatment until progression, unacceptable toxicity or withdrawal of consentSkin and tumor biopsy a

19、t baseline, Week 3, and at maximum cetuximab dose in dose-escalation armTejpar S, et al. ASCO 2008. Abstract 4001.EVEREST: PFS (ITT Population)00.20.40.60.81.00200400600DaysPFS Estimate800P .0001KRAS mutantWT KRASKRAS mutation present83 days (95% CI: 75.9-90.2)173 days (95% CI: 141.3-204.7)Tejpar S,

20、 et al. ASCO 2008. Abstract 4001. Reproduced with permission.EVEREST: PFS by Treatment Group and KRAS Status0.00.20.40.60.81.002004006008000.00.20.40.60.81.002004006008000.00.20.40.60.81.00200400600800DaysDaysDaysKRAS mutantWT KRASControlKRAS mutation presentP = .014KRAS mutantWT KRASDose Escalation

21、KRAS mutation presentKRAS mutantWT KRASNonrandomizedKRAS mutation presentP .001P = .020Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.PFS EstimatePFS EstimatePFS EstimateEVEREST SUMMARYDose escalation of cetuximab did increase response rateAmong patients without rash receiving

22、, KRAS status still predicted response to cetuximabAmong patients receiving escalated dose of cetuximab (to rash), KRAS MT still did not respond Higher dose did not overcome KRAS statusSkin rash and KRAS are independent predictorsSUMMARY of Kras DataKras status is a predictive marker for EGFR target

23、ed therapyPatients with wild-type Kras may benefit from EGFR targeted therapyPatients with mutant Kras may NOT benefit from EGFR targeted therapyCetuximab may have detrimental effects in patients with mutant KrasWhenever considering to use EGFR targeted therapy, Kras status should be tested.Question

24、s Raised by KRAS DataWhat to do with current trials involving EGFR targeted-agents?What to do for patients with mutated KRAS?Any other predictive markers?Develop more reliable, affordable assays to test KRAS statusOngoing Studies: CALGB/SWOG 80405Cetuximab, Bevacizumab, and FOLFOX/FOLFIRIInvestigator/PatientChemotherapy ChoiceFOLFIRIorFOLFOX+ Bevacizumab+ Cetuximab+ Bevacizumab+ Cetuximab+ Bevacizumab+ Cetuximab