Biotechnology in Fighting Biotechnology in Fighting FatalFatal Disease – Disease – CancerCancer

National Biotechnology Symposium 2012National Biotechnology Symposium 2012Innovations in Biotechnology: From Education to IndustryInnovations in Biotechnology: From Education to Industry

Sep 1, 2012, AMA, AhmedabadSep 1, 2012, AMA, Ahmedabad

Dr. Chirag DesaiDr. Chirag Desai, , MD, DM (Oncology)MD, DM (Oncology)

Hemato-oncology Clinic, Vedanta, Hemato-oncology Clinic, Vedanta, AhmedabadAhmedabad

Chiragdesai.oncology@gmail.com

Metastatic colon cancer Metastatic colon cancer (unresectable)(unresectable)

1970s – Only 5-FU – survival of 6 mths

1980s – Leucovorin/5-FU – survival of 9 mths

1990s – Only 5-FU – Addition of oxaliplatin/Irinotecan/capecitabine - – survival of 18 mths

2000s – Avastin - – survival of 21 mths

Now – Erbitux – survival of 25 mths

Survival

Increased

4 folds

In

30 years

Breast Cancer – stage IIBreast Cancer – stage II

1960s – Only surgery - 40% cured

1970s – CMF - 50% cured

1980s – CMF and Tamoxifen - 60% cured

1990s – Anthracyclines and taxanes - 67% cured

2000s – Aromatase inhibitors - 73% cured

Now – Herceptin - 80% cured ??

Cure

Rate

Doubled

In

40

years

Biotechnology in Cancer:Biotechnology in Cancer:

Translational Research

Bench to bedside

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

Biotechnology helps in elucidating the Biotechnology helps in elucidating the normal cellular functioningnormal cellular functioning

And the derangements thereof resulting in And the derangements thereof resulting in diseasedisease

Including cancer…….andIncluding cancer…….and

The ways to tackle these derangementsThe ways to tackle these derangements

Chronic Myeloid LeukemiaChronic Myeloid LeukemiaOne

cancer

One gene

One Treatment

One chromosome

Most CancersMost CancersEach

cancer

Multiplegenes

MultipleTreatments

Multiple chromosomes

InitiationNormal Cell

Pre-Cancerous Cell

Cancer Cell

Invasion

Angiogenesis

Metastases

Signal transduction

Migration

Seed/Soil

Immune Surveillance

Promotion

Prevention/early detection

Diagnosis/prognosis

Treatment

Biotechnology techniques and processes Biotechnology techniques and processes (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of

PT vol. 1, 3PT vol. 1, 3rdrd edn.) edn.)

Growth Factor

Growth Factor receptor

Signal Transduction

Research and development Research and development networknetwork

Examples of Biologicals:Examples of Biologicals:

Growth Growth Factors:Factors:

EGFEGF

VEGFVEGF

FGFFGF

IGFIGF

PDGFPDGF

Receptors:Receptors:

EGFREGFR

Her-2Her-2

VEGFRVEGFR

PDGFRPDGFR

ER/PRER/PR

STIs:STIs:

TKIsTKIs

mTORImTORI

CDKICDKI

FTIsFTIs

OthersOthers

Mabs:Mabs:

RituximabRituximab

AvastinAvastin

HerceptinHerceptin

ErbituxErbitux

BiomabBiomab

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

Evolution From Empiric to Personalized Therapy in NSCLC

Factors Agent Affected

Clinical

Asian, never-smoker, female Erlotinib, gefitinib

Untreated CNS metastases, no hemoptysis, uncontrolled hypertension

Bevacizumab

Histologic

Adenocarcinoma Erlotinib, gefitinib

Nonsquamous Bevacizumab, pemetrexed

Thymidylate synthase Pemetrexed

Molecular

EGFR mutation Erlotinib, gefitinib

ERCC1/RRM1 Platinum

RRM1 Gemcitabine

KRAS mutation Erlotinib, gefitinib

↑ EGFR by FISH Erlotinib? Gefitinib?

↑ EGFR by IHC Cetuximab?

EML4-ALK fusion Crizotinib

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.

Patient Selection Patient Selection Improves Treatment Improves Treatment

Results in NSCLCResults in NSCLCM

edia

n su

rviv

al (

mo

nth

s)

1970s 1980s 1990–2005

BSC:2–4

months

Cisplatin-based

regimens:6–8 months

Platinum-based

doublets (3rd gen):

8–10 months

2005

Bevacizumab + platinum-

based doublet:>12 months

28

24

20

16

12

8

4

02008 2008

Pemetrexed+ platinum:>12 months

Bevacizumab + platinum:>14 months

Non-Non-squamoussquamous

Adeno-Adeno-onlyonly

Adeno-Adeno-onlyonly

Molecular selection….

EGFR-EGFR-mut+mut+

Erlotinib alone

>27 months

2009/10

No selection Clinical selection

VEGF in clinicVEGF in clinic

Antibody – Bevacezumab (Avastin)Antibody – Bevacezumab (Avastin) Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell

Carcinoma, Brain Tumors, Carcinoma, Brain Tumors, Breast CancerBreast Cancer

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

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

Biologicals are effective in:Biologicals are effective in:

Lung cancerLung cancer

Colon cancerColon cancer

Breast cancerBreast cancer

Head and neck cancerHead and neck cancer

Leukemias/LymphomasLeukemias/Lymphomas

Renal/Liver cancersRenal/Liver cancers

OthersOthers

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

Challenges in the development of Challenges in the development of biologicalsbiologicals

RBF Symposium Feb 2011RBF Symposium Feb 2011

A Nobel Prize by ChanceA Nobel Prize by Chance

Start at the topStart at the top

1.1. Formulate testable hypothesisFormulate testable hypothesis

2.2. Make the plan / design the studyMake the plan / design the study

Generate Hypothesis

Design study

Collect information

Analyse and interprete finding

Develop new theory

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 yrs

Biomarker Biomarker IntegrationIntegration

N = 30 N = 300 N = 1600 DrugApproval

Confirm target

Assay development

Integrate biomarker

Assay performance

Phases of Development of New Biomarker linked to New Drug

Biomarkerinformative?

Assayperformance

Clinical validation

Coprimaryendpoint

Clinicalapplication

ofbiomarker

Gandara D, et al. NCI CAPR Workshop. 2011. Printed with permission.

New Therapeutic Agent: Development Phases

A large number of biologically/molecularly A large number of biologically/molecularly acting drugs are under developmentacting drugs are under development

Traditional end points are less relevantTraditional end points are less relevant

New end points requiredNew end points requiredOS still is a gold standard end pointOS still is a gold standard end point

Surrogate end points need to be re-definedSurrogate end points need to be re-defined

Even though response rate is less important, exact Even though response rate is less important, exact definition of response is criticaldefinition of response is critical

Ongoing analysis of tissue/blood based biomarkers Ongoing analysis of tissue/blood based biomarkers is criticalis critical

Surrogate End points with Surrogate End points with targeted Therapies:targeted Therapies:

TraditionalTraditional PFSPFS QoLQoL OSOS PharmacoeconomicsPharmacoeconomics OthersOthers

ExploratoryExploratory Target inhibitionTarget inhibition

Tissue levelTissue level

Blood levelBlood level PharmacogeneticPharmacogenetic

Tissue basedTissue based

Blood 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 Study

Umbrella protocol

Core biopsy

EGFR KRAS/BRAFVEGF RXR/CyclinD1

Biomarkerprofile

Randomization:Equal Adaptive

ErlotinibEqual (n = 25)

Adaptive (n = 33)

VandetanibEqual (n = 23)

Adaptive (n = 29)

Erlotinib + BexaroteneEqual (n = 21)

Adaptive (n = 15)

SorafenibEqual (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 Study—Discovery Platform

Who should do this?Who should do this?

Generate Hypothesis

Design study

Collect information

Analyse and interprete finding

Develop new theory

•Academic institutions

•Corporate hospitals

•Individual practitioners

•Medical associations

•Collaborative effort

Who should do this?Who should do this?

Generate Hypothesis

Design study

Collect information

Analyse and interprete finding

Develop new theory

InnovationsInnovations

chiragdesai.oncology@gmail.com

Future:Future:

Tests like Oncotype Dx21 in breast cancerTests like Oncotype Dx21 in breast cancer

Drugs like Imatinib in CMLDrugs like Imatinib in CML

Outcome like sequential use of chemo and Outcome like sequential use of chemo and targeted drugs in myelomatargeted drugs in myeloma

Making cancer a chronic Disease