Colorectal Cancer: What’s New and What’s on the Horizon
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Colorectal Cancer: What’s New and What’s on the Horizon

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Every summer, the American Society for Clinical Oncology (ASCO) brings together internationally renowned cancer researchers, doctors and medical professionals to discover and discuss the latest in ...

Every summer, the American Society for Clinical Oncology (ASCO) brings together internationally renowned cancer researchers, doctors and medical professionals to discover and discuss the latest in cancer research and patient care. This webinar, scheduled for June 19 2013 is presented by Dr. John Marshall, and will highlight the key colorectal cancer findings from the 2013 meeting and what these advances mean for you.

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    Colorectal Cancer: What’s New and What’s on the Horizon   Colorectal Cancer: What’s New and What’s on the Horizon Presentation Transcript

    • Save the date for our 10th NationalPatient ConferenceLearn more or register:www.ccalliance.org or 1-877-422-2030
    • Presented by:
    • Fight Colorectal CancerMissionFight Colorectal Cancer demands a cure for colon and rectalcancer. We educate and support patients, push for changesin policy that will increase and improve research, andempower survivors to raise their voices against the status quo.Monthly Patient Webinar Series3rd Wednesday every monthFightColorectalCancer.orgFight CRC Toll-free Answer Line 1.877.427.2111Join One Million StrongCRCMillionStrong.orgJoin us in March 2014 for Call on Congress
    • Fighting a Smarter War On Colon Cancer:John L. Marshall, MDThe Biomarker DivideTel: (202) 444-0275Fax: (202) 444-1229http://lombardi.georgetown.edu/GI
    • Stakeholder MotivationStakeholders• FDA• CMS/Payers• NCI/CTEP• PhRMA• Community Onc• Academic Onc• PatientsPriority/Agenda• Safety and Efficacy• Cost Control/Value• Cure Cancer• Markets, ROI• Efficient/Quality Care• Clinical Trial Accrual• Cure/Benefit/Altruism
    • Gastrointestinal (GI) Cancers Facts GI cancers represent the most common and fatal cancers in the world 2009: 275,720 new diagnosis of GI Cancers and 135,830 deaths in theUS alone Anal Cancer Colorectal Cancer Esophageal Cancer Gallbladder Cancer Liver Cancer Pancreatic Cancer Small Intestine Cancer Stomach/Gastric CancerNo two cancers are alike and treatments must be selected based on anindividual’s tumor characteristics, by personalized medicine
    • Breast Cancer Nation
    • Why Not Brown?
    • Our Current Model of Colon Cancer
    • Antoni van Leeuwenhoek(1632-1723)Invented the microscopearound 166810
    • The view from 35,000 feetEverything looks the same from up here
    • 12Management of MCRC:An Evolving Treatment AlgorithmDiagnosis of MCRCResectable UnresectableAdjuvant therapySurgeryNeo-adjuvant/Pre-operativetherapyFirst-LineSecond-LineThird-LineBorderline/PotentiallyResectableFourth-LineTreatmentcontinuum
    • 13Advances in the Treatmentof Colorectal Cancer2000 2005 2008 2012CapecitabineOxaliplatinCetuximabIrinotecan5-FUPanitumumabTargetedtherapiesBevacizumabKRASAfliberceptRegorafanib
    • 2012 ESMO Guidelines:Sequence of Treatment by LineSchmoll et al. Ann Oncol. 2012;23:2479-2516.
    • 15EGFR: One of Many Signaling Modulesin Cancer CellsHanahan, Weinberg, Cell 100:57, 2000
    • 16Proliferation MetastasisAngiogenesisApoptosisResistanceShcPI3-KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1What is the Role of the Epidermal Growth FactorReceptor (EGFR) in Cancer?Cell MembraneEGFRSignalingProteinsCellResponseto Signaling
    • 17A. Friedman and N. Perrimon, Cell 128, January 26, 2007Pathway vs. Network signalingNetwork“Chaotic”Pathway“Newtonian”
    • The Nature of the Disease
    • 19ShcPI3-KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1Proliferation MetastasisAngiogenesisApoptosisResistanceEGFRSignalingProteinsCellResponseto Signaling
    • 20ShcPI3-KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1Which Target?
    • 21Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer CenterSos-1RasMEKK-1MEKShcPI3-KRafMKK-7Grb2AKTJNKERK
    • 22Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer CenterSos-1RasMEKK-1MEKShcPI3-KRafMKK-7Grb2AKTJNKERKWhere’s the target?The EGF Receptor Interactome638 Genes
    • 23Colon Cancer Has Many BiologicSubsets That Differ in Response toEGFR-Targeted AgentsBRAFKRASEREG or AREGPI3K PTENEGFRPIP1PIP3Signaling to the nucleusLow expression of EGFR ligands→ decreased response to EGFRtargeted agentsMutant BRAF →decreased response toEGFR-targeted agentsPTEN loss of expression→ decreased responseto EGFR-targeted agentsMutant KRAS →decreased response toEGFR-targeted agents
    • 24Q: Is More Always Better?
    • 25Correlation Between Survival andPercentage of Patients Receiving ThreeDrugs in Phase 3 Trials3 drugs: 5-FU/LV, irinotecan, oxaliplatin.Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.12131415161718192021220 10 20 30 40 50 60 70 80Patients with three drugs (%)MedianOS(months)
    • TRIBE Study DesignR508 mCRC pts1st lineunresectablestratified by center PS 0/1-2 adjuvant CTFOLFIRI+bev(up to 12 cycles)FOLFOXIRI+bev(up to 12 cycles)5-FU/LV+Bev5-FU/LV+BevPDINDUCTION MAINTENANCE
    • Toxicity Profile – Safety populationG3/4 adverse events,% patientsFOLFIRI + bevN=254FOLFOXIRI + bevN=250pNausea 3 3 1.000Vomiting 3 4 0.492Diarrhea 11 19 0.012Stomatitis 4 9 0.048Neutropenia 20 50 <0.001Febrile neutropenia 6 9 0.315Neurotoxicity 0 5 <0.001Hypertension 2 5 0.157Venous Thrombosis 6 7 0.593Arterial Thrombosis 2 1 1.000Bleeding 1 1 1.000
    • Secondary endpoint: Response rate (updated) - ITT populationBest Response, %FOLFIRI + bevN = 256FOLFOXIRI + bevN = 252pComplete Response 3% 5%Partial Response 50% 60%Response Rate 53% 65% 0.006Stable Disease 32% 25%Progressive Disease 11% 6%Not Assessed 4% 4%
    • Median follow up: 32.3 mosFOLFIRI + bev: N = 256 / Progressed = 226FOLFOXIRI + bev: N = 252 / Progressed = 213FOLFIRI + bev, median PFS : 9.7 mosFOLFOXIRI + bev, median PFS : 12.1 mosUnstratified HR: 0.77 [0.64-0.93]p=0.006Stratified HR: 0.75 [0.62-0.90]p=0.003Primary endpoint: PFS (updated) – ITT populationFOLFIRI/bev 256 203 94 46 26 14 7 3 0 0FOLFOXIRI/bev 252 208 125 74 35 21 11 5 2 1Progression-freesurvivalprobabilityF-up time (months)FOLFIRI + bevFOLFOXIRI + bev
    • Secondary endpoint: OS (preliminary) – ITT populationFOLFIRI/bev 256 233 216 172 109 69 36 15 5 0FOLFOXIRI/bev 252 234 205 175 119 70 35 15 4 0OverallsurvivalprobabilityF-up time (months)FOLFIRI + bevFOLFOXIRI + bevMedian follow up: 32.3 mosFOLFIRI + bev: N = 256 / Died = 155FOLFOXIRI + bev: N = 252 / Died = 131FOLFIRI + bev, median OS : 25.8 mosFOLFOXIRI + bev, median OS : 31.0 mosUnstratified HR: 0.83 [0.66-1.05]p=0.125Stratified HR: 0.79 [0.63-1.00]p=0.054
    • Contrast of Appearance vs.Expression PhenotypingMicroarray Low Risk High RiskMicroscope Low Grade High GradeTreatmentAdvice31
    • We need to be careful withour conclusions
    • pmTOR-immunostaining (Ventana)Critical: Postsurgical ischemia
    • 34Colon Cancer is more than one diseasekRAS Wild Type kRAS mutantMSI-High MSS+ EGFR Agents - EGFR Agents? No 5FU50-60% 40-50%15-20% 80-85%And of course it is very many more than the4 sub-groups above
    • Clinical Research 2.0
    • Agent HR $ Cost/Month(÷100)Toxicity(G1+2) * (G3+4)# PatientsQOL/Utility ScorePass/FailImatinib vs IFNCML0.17 55.90 0.67Nilotinib vs ImatCML0.8 76.40 0.17ImatinibGIST0.4 55.90 1.22Erlotinib vsChemoMut NSCL0.75 52.80 0.71ErlotinibPancreas0.82 52.80 11.9Bevacizumab 2ndline CRC0.74 22.90 0.8Aflibercept2nd line CRC0.79 ????- 3.0Value Metric
    • Finding Value• Come together• Listen to each other• Respect what we hear• Find the common threads• Weave a new fabric- provide global healthcare with value
    • Engaging the 97%• Better education/information• Incentives for patients and providers– No added incentives for delivering SOC– Honor our “soldiers” in the war on cancer• Recognized the shared investment in research– Docs, hospitals, NCI, Industry, Payers, Patients• Target “substantial therapeutic benefit”– “Breakthrough Designation”• Reduce concept to approval time line• Embrace the emerging markets
    • Fundamental Shifts In Cancer CareYesterday• Consumption• Individual Practices• Rich Countries• Microscope• Safety and Efficacy• Large trials• 1.4 months• QOL• Patient as a “Subject”• Chaotic Data Collection• Institutional IRBs• National ApprovalsTomorrow• Outcomes• Healthcare Systems• All Countries• Gene Profile• Value• Small trials• “Substantial Improvement”• Patient Reported Outcomes• Patient as a “Partner”• Standard Data Collection• Central/National IRBs• Global Approvals
    • Questions & Answers
    • Thank you!Fight Colorectal CancerAnswer Line 1-877-427-2111FightColorectalCancer.orgInfo@fightcrc.orgColon Cancer AllianceHelpline: 1-877-422-2030www.CCAlliance.orginfo@ccalliance.org