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Established Biomarkers Guiding Treatment Decisions in Colorectal Cancer
Heinz-Josef Lenz Professor of Medicine and Preventive Medicine Associate Director, Clinical Research Co-Chair GI Oncology USC/Norris Comprehensive Cancer Center
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How to Use Predictive or Prognostic Biomarkers
When (Prognostic) With what (Predictive) How much (Predictive) What combination (Predictive)
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Colon Cancer is More Than One Disease
50-60% 40-50% KRAS Wild-Type KRAS Mutant + EGFR Agents 15-20% - EGFR Agents 80-85% MSI-High MSS ? No 5FU ~80% of CRC patients have FAP genetics ~20% have different (MSI/HNPCC) genetics HNPCC patients do not benefit from 5-FU and may actually be harmed by it 3
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MSI-H and Adjuvant 5FU Sargent D, et al. J Clin Oncol. 2008; 26(suppl). Abstr
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MSI-H and Adjuvant 5FU Sargent D, et al. J Clin Oncol. 2008; 26(suppl). Abstr
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ECOG 5202 Therapy Based on Genetics
Stratify: Stage IIA or IIB MSS or MSI 18qLOH Low-Risk: MSS or MSI-L with retention of 18q alleles; MSI-H High-Risk: MSS/18qLOH or MSI/18qLOH Randomize to: Observation only FOLFOX6 FOLFOX6+BEV Primary endpoint: 3-year DFS Secondary endpoints: OS, toxicity, correlation between tumor biology and survival 6
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Decision Algorithm in Adjuvant Therapy
Resected colon cancer Stage II Stage III Low-risk stage II High-risk stage II a dMMR pMMR FOLFOX Based on the results of the pooled molecular analysis, stratification of patients based on MMR status provides a more specified approach to determining type of adjuvant therapy. The data indicates that a patient with stage II disease should be assessed for MMR status to determine whether no therapy or chemotherapy will provide the best outcome. a 5-FU/LV or capecitabine No therapy aPatients not considered candidates for oxaliplatin.
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Key Takeaways dMMR validated as a prognostic marker in untreated patients No suggestion of benefit from 5-FU based treatment in dMMR patients Significant OS decrement to 5-FU based treatment in stage II patients Increased Sensitivity to CPT-11 In conclusion, this international prospectively specified pooled analysis of data from randomized clinical trials has validated dMMR as a marker prognostic of patient outcome in the absence of treatment. Both datasets individually and the pooled data provide no suggestion of a benefit from 5-FU based treatment in patients with dMMR tumors, and in the pooled dataset a significant decrement was observed in overall survival in stage II patients treated with 5-FU based regimens. Sargent et al., 2008.
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Tailored therapy to improve outcomes in mCRC
CRYSTAL FOLFIRI + Cetuximab OPUS FOLFOX + Cetuxiamb KRAS wild-type status is predictive of Cetuximab efficacy Wild-type Mutant Response rate (%) n=105 n=172 n=52 n=61 1. Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl.) [Abstract no. 2]; Bokemeyer C, et al. J Clin Oncol 2008;26(Suppl.) [Abstract 4000}
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Personalize therapy to improve outcomes in mCRC
1.0 CRYSTAL KRAS wild-type: HR=0.68; p=0.017 0.9 0.8 0.7 KRAS wild-type status is predictive of Cetuximab efficacy 0.6 PFS 0.5 0.4 0.3 32% risk reduction for progression 0.2 0.1 Reduced tumor progression reported for patients with KRAS wild-type tumors 2 4 6 8 10 12 14 16 18 Time (months) 1.0 0.9 OPUS KRAS wild-type: HR=0.57; p=0.016 0.8 0.7 0.6 PFS 0.5 0.4 43% risk reduction for progression 0.3 Cetuximab + chemotherapy 0.2 Chemotherapy alone 0.1 2 4 6 8 10 12 Time (months) 1. Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl.) [Abstract no. 2]; Bokemeyer C, et al. J Clin Oncol 2008;26(Suppl.) [Abstract 4000} 12 12
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KRAS status: Predictive or Prognostic
NCIC CTG C0.17 CRYSTAL 1.0 0.4 0.2 0.0 0.6 0.8 8 2 4 6 10 16 12 14 0.2 0.4 0.6 0.8 1 2 4 6 8 10 12 14 16 18 FOLFIRI wild-type PFS estimate FOLFIRI mutant Proportion alive [%] HR % CI (0.74,1.37) Log rank p-value: 0.97 HR=0.97 (p=0.87) Mutated Wild type Time from randomization [months] Time [months]
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Possible Mechanisms for Resistance of KRAS Mutated Tumors to EGFR Inhibitors
Ras-induced up-regulation of VEGF Zachary & Gliki: Cardiovasc Res 49: , 2001 Activation of Ras terminal differentiation and tumor stem cell population KM Haigis et al: Nature Genetics 40: , 2008 K-Ras mutation DNA methylation expression of tumor suppressor and apoptotic genes SK Patra: Exp Cell Res 314: , 2008 K-Ras mutation expression or activity of DNA repair genes Lenz et al, ASCO 2009
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Overall survival according to KRAS mutation and skin toxicity
2 good prognostic factors (wild type and grade 2-3 skin toxicity) 1good prognostic factors (wild type or grade 2-3 skin toxicity) 1.00 0 good prognostic factors (KRAS mutant and grade 0-1 skin toxicity) 0.75 15.6 months (95%CI, ) 10.7 months (95%CI, ) Survival probability 0.50 5.6 months p = (95%CI: ) 0.25 0.00 10 20 30 Months Uses colours from showfile part 1 in L:\Medi Cine International\Merck - NEW\cetuximab\Completed\Meetings\MK th EAN, Nov 07\Deliverables\Slides\SHOWFILES AND FINAL SLIDES
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Not eligible for randomization Skin toxicity 2/3
EVEREST: Study design Control standard cetuximab regimen (250 mg/m2/w) Cetuximab (400 mg/m2initial dose then 250 mg/m2/w) + irinotecan (180 mg/m2 q2w) Day 22 Randomization Skin toxicity 0/1 Screening Dose-escalation cetuximab dose increases of 50 mg/m2 q2w up to maximum 500 mg/m2/w Not eligible for randomization Skin toxicity 2/3 Non-randomized standard cetuximab regimen (250 mg/m2/w) Central to this presentation is understanding the design of the everest study, a complex design aimed at looking at the impact of dose increase of cetuximab in patients that develped no or only slight skin reactions on standard dose cetuximab. On the left we see all pt initially enrolled that were treated with standard dose cetuximab for three weeks, and were then assesed for skin toxicity. Patients with a skin tox of grad 2 or higher by week 3, were not randomized and continued on standard dose. Patients with no (grade0) or slight grade 1 skin reaction by week 3 were randomized to either continuing standard dose (here caled control Arm) or to dose increase up to 500 mg/M2 untill response or unacceptable toxicity. (dose escalation arm) All patients continued to receive irinotecan Treatment until disease progression, unacceptable toxicity or withdrawal of consent Skin and tumor biopsy at baseline, week 3 and, in dose-escalation arm, at maximum cetuximab dose Van Cutsem E et al, Ann Oncol 2007; S Tejpar et al, Proc ASCO 2007 16
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EVEREST: Efficacy results
RR DCR Median duration of response 16% 58% 5.8 months 30% 71% 6.9 months 25% 62% 7.0 months Patients (%) As a reminder, in the whole Everest population, unstratified by KRAS status, an increased response rate was observed in the dose increase arm (ie low skin tox patients receiving dose increase) versus the control arm (ie low skin toxicity patients with standard dose cetuximab. RR = response rate; DCR = disease control rate 17
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How many febrile events?
Fuchs data to be here
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Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 Genotypes
Author n/N (%) Est. Odds Ratio 95% CI 7/7 6/6 + 6/7 Innocenti 3/6 (50%) 3/53 (6%) 16.7 Rouits 4/7 (57%) 10/66 (15%) 7.5 Marcuelloa 4/10 (40%) 18/85 (21%) 2.5 Andob 22/111 (20%) 5.4 aGr 3+ neutropenia. bGr 4 leukopenia and/or Gr 3+ diarrhea. From Parodi et al, FDA Subcommittee presentation, November, 2004
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Revised Camptosar® label
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Potential Predictive Markers for Colon Cancer Treatment
Drug Marker Fluoropyrimidines TS, DPD*, TP, MSI, MTHFR expression/polymorphisms Irinotecan UGT polymorphisms*, MSI, transporter polymorphisms Oxaliplatin ERCC1, GST P1, XPD expression, transporter polymorphisms EGFR Antibodies gene amplification/polymorphism, RAS mutation, BRAF mutation, ligand expression, PTEN expression, VEGF levels VEGF inhibitors VEGF polymorphisms, ICAM polymorphisms/levels, E-selectin levels, HIF1, Glut-1, VEGFr gene expression General Circulating tumor cells *FDA-recognized Meropol ASCO 2008
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Pre-clinical studies showing ERCC1 to be a determinant of platinum efficacy
Youn et al Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based Anticancer Agents Cancer Res 2004:64,
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Customizing Cisplatin
Treatment Selection using ERCC1 Increases Response Rate Results: Patient Selection for Therapy Significantly Increased Response Rate. Please adjust the graphics to accommodate the section header. If needed add bar, or move logo. Control PGx Selected p<0.02, Genotypic vs Control 25
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Colorectal Cancer and ERCC-1
ERCC1 gene expression and survival in CRC patients treated with 5-FU/Oxali Therapy Shirota, Y. et al. J Clin Oncol; 19: Low ERCC1 High ERCC1 p<0.001 n=40 n=10
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Biomarkers and Median Overalll Survival in mCRC
Treated First Line with FOLFOX or FOLFIRI
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How to Use Predictive or Prognostic Biomarkers
When (Prognostic) With what (Predictive) How much (Predictive) What combination (Predictive)
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Genetic Testing Today Kras for EGFR inhibitors
UGT1A1 for Irinotecan Toxicity MSI for 5-FU chemotherapy for stage II colon cancer
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Sharon Carpenter Laboratory
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