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Biotechnology in Fighting Fatal Disease –
Cancer
National Biotechnology Symposium 2012
Innovations in Biotechnology: From Education to Industry
Sep 1, 2012, AMA, Ahmedabad
Dr. Chirag Desai, MD, DM (Oncology)
Hemato-oncology Clinic, Vedanta,
Ahmedabad
[email protected]
Metastatic colon cancer
(unresectable)
1970s – Only 5-FU – survival of 6 mths
1980s – Leucovorin/5-FU – survival of 9 mths
Survival
Increased
1990s – Only 5-FU – Addition of oxaliplatin/
Irinotecan/capecitabine - – survival of 18 mths
4 folds
In
2000s – Avastin - – survival of 21 mths
Now – Erbitux – survival of 25 mths
30 years
Breast Cancer – stage II
1960s – Only surgery - 40% cured
Cure
Rate
1970s – CMF - 50% cured
1980s – CMF and Tamoxifen - 60% cured
Doubled
1990s – Anthracyclines and taxanes - 67% cured
In
40
2000s – Aromatase inhibitors - 73% cured
years
Now – Herceptin - 80% cured ??
Biotechnology in Cancer:
Translational
Research
Bench 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 functioning
And the derangements thereof resulting in
disease
Including cancer…….and
The ways to tackle these derangements
Chronic Myeloid Leukemia
One
cancer
One
chromosome
One
gene
One
Treatment
Most Cancers
Each
cancer
Multiple
chromosomes
Multiple
genes
Multiple
Treatments
Initiation
Normal Cell
Promotion
Pre-Cancerous Cell
Cancer Cell
Signal transduction
Migration
Seed/Soil
Immune Surveillance
Invasion
Angiogenesis
Metastases
Prevention/early
detection
Diagnosis/
prognosis
Treatment
Biotechnology techniques and processes
(Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of
PT vol. 1, 3rd edn.)
Growth Factor
Growth Factor
receptor
Signal Transduction
Research and development
network
Examples of Biologicals:
Growth
Factors:
EGF
VEGF
FGF
IGF
PDGF
Receptors:
EGFR
Her-2
VEGFR
PDGFR
ER/PR
STIs:
TKIs
mTORI
CDKI
FTIs
Others
Mabs:
Rituximab
Avastin
Herceptin
Erbitux
Biomab
Providing Personalized Care in an Era of Molecular Medicine
clinicaloptions.com/oncology
Evolution From Empiric to Personalized
Therapy in NSCLC
Clinical
Histologic
Molecular
Factors
Agent Affected
Asian, never-smoker, female
Erlotinib, gefitinib
Untreated CNS metastases, no hemoptysis,
uncontrolled hypertension
Bevacizumab
Adenocarcinoma
Erlotinib, gefitinib
Nonsquamous
Bevacizumab, pemetrexed
Thymidylate synthase
Pemetrexed
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 Improves
Treatment Results in NSCLC
No selection
Molecular selection….
Clinical selection
28
Erlotinib
alone
>27 months
Median survival (months)
24
20
16
12
8
4
BSC:
2–4
months
Cisplatinbased
regimens:
6–8 months
Bevacizumab
+ platinum:
>14 months
Bevacizumab
+ platinumbased doublet:
>12 months
Pemetrexed
+ platinum:
>12 months
8–10
months
Nonsquamous
Adenoonly
Adenoonly
1990–2005
2005
2008
2008
Platinumbased
doublets
(3rd gen):
EGFRmut+
0
1970s
1980s
2009/10
VEGF in clinic
Antibody – 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 cancer
Colon cancer
Breast cancer
Head and neck cancer
Leukemias/Lymphomas
Renal/Liver cancers
Others
Biologicals help in the treatment of >80% of cancers either curatively or in
advanced cancers
Challenges in the development of
biologicals
RBF Symposium Feb 2011
A Nobel Prize by Chance
Start at the top
1. Formulate testable hypothesis
2. Make the plan / design the study
Generate Hypothesis
Design study
Develop new theory
Collect information
Analyse and interprete finding
Providing Personalized Care in an Era of Molecular Medicine
clinicaloptions.com/oncology
New Therapeutic Agent: Development
Phases
Biomarker
Integration
N = 30
Preclinical
(~ 18 mos)
Phase I
(~ 18 mos)
N = 300
Phase II
(~ 18 mos)
N = 1600
Phase III
(~ 36 mos)
Drug
Approval
Total Time
~ 90 mos
or 7.5 yrs
Phases of Development of New Biomarker linked to New Drug
Confirm
target
Integrate
biomarker
Biomarker
informative?
Clinical
validation
Assay
development
Assay
performance
Assay
performance
Coprimary
endpoint
Gandara D, et al. NCI CAPR Workshop. 2011. Printed with permission.
Clinical
application
of
biomarker
A large number of biologically/molecularly
acting drugs are under development
Traditional end points are less relevant
New end points required
OS still is a gold standard end point
Surrogate end points need to be re-defined
Even though response rate is less important, exact
definition of response is critical
Ongoing analysis of tissue/blood based biomarkers
is critical
Surrogate End points with
targeted Therapies:
Exploratory
Traditional





PFS
QoL
OS
Pharmacoeconomics
Others

Target inhibition
Tissue level
Blood level

Pharmacogenetic
Tissue based
Blood based
Providing Personalized Care in an Era of Molecular Medicine
clinicaloptions.com/oncology
BATTLE: Phase II NSCLC Biomarker Study
Umbrella protocol
Core biopsy
EGFR
VEGF
KRAS/BRAF
RXR/CyclinD1
Biomarker
profile
Randomization:
Equal  Adaptive
Erlotinib
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)
Primary endpoint: 8-wk disease control rate; 30% assumed
Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.
Providing Personalized Care in an Era of Molecular Medicine
clinicaloptions.com/oncology
BATTLE: Phase II NSCLC Biomarker
Study—Discovery Platform
Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.
Who should do this?
•Academic institutions
Generate Hypothesis
•Corporate hospitals
Design study
Develop new theory
Collect information
Analyse and interprete finding
•Individual practitioners
•Medical associations
•Collaborative effort
Who should do this?
Generate Hypothesis
Design study
Develop new theory
Collect information
Analyse and interprete finding
Innovations
[email protected]
Future:
Tests like Oncotype Dx21 in breast cancer
Drugs like Imatinib in CML
Outcome like sequential use of chemo and
targeted drugs in myeloma
Making cancer a chronic Disease