Biotechnology in Fighting Fatal Disease Cancer

National Biotechnology Symposium 2012Innovations in Biotechnology: From Education to IndustrySep 1, 2012, AMA, Ahmedabad

Dr. Chirag Desai, MD, DM (Oncology)Hemato-oncology Clinic, Vedanta, Ahmedabad

Chiragdesai.oncology@gmail.com

Metastatic colon cancer (unresectable)1970s Only 5-FU survival of 6 mths1980s Leucovorin/5-FU survival of 9 mths1990s Only 5-FU Addition of oxaliplatin/Irinotecan/capecitabine - survival of 18 mths2000s Avastin - survival of 21 mthsNow Erbitux survival of 25 mthsSurvival

Increased

4 folds

In

30 years

Breast Cancer stage II1960s Only surgery - 40% cured1970s CMF - 50% cured1980s CMF and Tamoxifen - 60% cured1990s Anthracyclines and taxanes - 67% cured2000s Aromatase inhibitors - 73% curedNow Herceptin - 80% cured ??Cure

Rate

Doubled

In

40

years

Biotechnology in Cancer:Translational ResearchBench to bedside

The biological revolution of 20th century totally reshaped all fields of biomedical study -- cancer research being only one of them.

Biotechnology helps in elucidating the normal cellular functioningAnd the derangements thereof resulting in diseaseIncluding cancer.andThe ways to tackle these derangements

Chronic Myeloid LeukemiaOne cancerOne geneOne TreatmentOne chromosome

Most CancersEach cancerMultiplegenesMultipleTreatmentsMultiple chromosomes

InitiationNormal CellPre-Cancerous CellCancer CellInvasionAngiogenesisMetastasesSignal transductionMigrationSeed/SoilImmune SurveillancePromotion

Prevention/early detectionDiagnosis/prognosisTreatment

Biotechnology techniques and processes (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of PT vol. 1, 3rd edn.)

Growth FactorGrowth Factor receptorSignal Transduction

Research and development network

Examples of Biologicals:Growth Factors:

EGFVEGFFGFIGFPDGFReceptors:

EGFRHer-2VEGFRPDGFRER/PRSTIs:

TKIsmTORICDKIFTIsOthers

Mabs:

RituximabAvastinHerceptinErbituxBiomab

clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine

Evolution From Empiric to Personalized Therapy in NSCLCAdapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.

FactorsAgent AffectedClinicalAsian, never-smoker, femaleErlotinib, gefitinibUntreated CNS metastases, no hemoptysis, uncontrolled hypertensionBevacizumabHistologicAdenocarcinoma Erlotinib, gefitinibNonsquamousBevacizumab, pemetrexedThymidylate synthasePemetrexedMolecularEGFR mutationErlotinib, gefitinibERCC1/RRM1PlatinumRRM1GemcitabineKRAS mutationErlotinib, gefitinib EGFR by FISHErlotinib? Gefitinib? EGFR by IHCCetuximab?EML4-ALK fusionCrizotinib

Patient Selection Improves Treatment Results in NSCLCMedian survival (months)1970s1980s19902005BSC:24 monthsCisplatin-based regimens: 68 monthsPlatinum-based doublets (3rd gen): 810 months2005Bevacizumab + platinum-based doublet:>12 months282420161284020082008Pemetrexed+ platinum:>12 months

Bevacizumab + platinum:>14 monthsNon-squamousAdeno-onlyAdeno-onlyMolecular selection.EGFR-mut+Erlotinib alone>27 months2009/10No selection Clinical selection

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VEGF in clinicAntibody Bevacezumab (Avastin)Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell Carcinoma, Brain Tumors, Breast Cancer

Tyrosine kinase Inhibitors:Sunitinib, Sorafenib, Pazopinib, Axitinib, Dovitinib, others

Renal Cell Cancer, Neuro-endocrine tumors, Liver cancers, GIST, Sarcoma

Biologicals are effective in:

Lung cancerColon cancerBreast cancerHead and neck cancerLeukemias/LymphomasRenal/Liver cancersOthers

Biologicals help in the treatment of >80% of cancers either curatively or in advanced cancers

Challenges in the development of biologicals

RBF Symposium Feb 2011A Nobel Prize by Chance

Start at the topFormulate testable hypothesisMake the plan / design the study

clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine

Phase I(~ 18 mos)Phase II(~ 18 mos)Phase III(~ 36 mos)Preclinical(~ 18 mos) Total Time~ 90 mosor 7.5 yrsBiomarker IntegrationN = 30N = 300N = 1600DrugApprovalConfirm target

Assay developmentIntegrate biomarker

Assay performancePhases of Development of New Biomarker linked to New DrugBiomarkerinformative?

AssayperformanceClinical validation

CoprimaryendpointClinicalapplicationofbiomarkerGandara D, et al. NCI CAPR Workshop. 2011. Printed with permission.New Therapeutic Agent: Development Phases

A large number of biologically/molecularly acting drugs are under developmentTraditional end points are less relevantNew end points requiredOS still is a gold standard end pointSurrogate end points need to be re-definedEven though response rate is less important, exact definition of response is criticalOngoing analysis of tissue/blood based biomarkers is critical

Surrogate End points with targeted Therapies:

TraditionalPFSQoLOSPharmacoeconomicsOthers

ExploratoryTarget inhibitionTissue levelBlood levelPharmacogeneticTissue basedBlood based

clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine

Primary endpoint: 8-wk disease control rate; 30% assumedKim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.BATTLE: Phase II NSCLC Biomarker StudyUmbrella protocolCore biopsyEGFRKRAS/BRAF VEGFRXR/CyclinD1Biomarker profileRandomization: Equal AdaptiveErlotinib Equal (n = 25) Adaptive (n = 33)Vandetanib Equal (n = 23) Adaptive (n = 29)Erlotinib + Bexarotene Equal (n = 21) Adaptive (n = 15)Sorafenib Equal (n = 26) Adaptive (n = 72)

clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine

Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.BATTLE: Phase II NSCLC Biomarker StudyDiscovery Platform

Who should do this?Academic institutions

Corporate hospitals

Individual practitioners

Medical associations

Collaborative effort

Who should do this?

Innovationschiragdesai.oncology@gmail.com

Future:

Tests like Oncotype Dx21 in breast cancerDrugs like Imatinib in CMLOutcome like sequential use of chemo and targeted drugs in myelomaMaking cancer a chronic Disease

**CNS, central nervous system; FISH, fluorescent in-situ hybridization; IHC, immunohistochemistry; NSCLC, non-small-cell lung cancer.**NSCLC, non-small-cell lung cancer.NSCLC, non-small-cell lung cancer.**