cancer immunotherapy and the emerging ... immunotherapy and the emerging...market share among...
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IV INTERNATIONAL MEETING OF THE EGF VACCINE, Havana City 2011
CANCER IMMUNOTHERAPY AND THE EMERGING PARADIMGS IN CLINCAL RESEARCH
CANCER TREATMENT IMMUNOTHERAPY CANCER
VACCINES
Denis Diderot1713-1784
“…..étudier l´esprit de ton pays, connaitre sa pente; de façon qu´il ne laisse jamais ton travail en arrière; sinon qu´il le rencontre en avance….¨
¿WHERE ARE WE GOING?:
GUESS THE TRENDS:
CANCER TREATMENT
IMMUNOTHERAPYCANCERVACCINES
1.
Clinical Trial paradigm shift
1.
Regulatory evolution
1.
Tolerance2.
Exhaustion of the immune response
3.
Links between immunity and inflamation
4.
The dual role of immunity5.
Complexity
IV INTERNATIONAL MEETING OF THE EGF VACCINE, Havana City 2011
CANCER IMMUNOTHERAPY AND THE EMERGING PARADIMGS IN CLINCAL RESEARCH
1- Biotechnology is opening the way to cancer immunotherapy
2-
Biotechnology beyond products: Emerging concepts in cancer treatment.
3-
The dominant paradigm in clinical cancer research, and its limitations.
4-
The emerging paradigm and its impact in clinical research
5-
To follow or to innovate? : The double axis of clinical research .
BIOTECHNOLOGY: MANUFACTURING BIOTECHNOLOGY: MANUFACTURING PROCESSES WITH GENETICALLY PROCESSES WITH GENETICALLY
MODIFIED CELLS MODIFIED CELLS
Biologic conversion
CellsRaw material Final Product
A E
FIGURA 1. EL TAMAÑO DE LAS MOLECULAS BIOLOGICAS. La figura compara en igual escala, de izquierda a derecha, el tamaño de la molecula de Tetraciclina, el del Interferon alfa, y el de un anticuerpo monoclonal.
A DIFFERENT KIND OF MOLECULE
PhRMA-Surveys: BIOTECHNOLOGY MEDICINES
EvaluatePharma Alpha – helping you to find value in the pharma and biotech sector. World Preview 2016.
15%
31%
48%
90% 89% 88% 87% 86% 84% 83% 83% 82% 81% 80% 79% 78% 77% 77%
10% 11% 12% 13% 14% 16% 17% 17% 18% 19% 20% 21% 22% 23% 23%
0
10
20
30
40
50
60
70
80
90
100
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Conventional/Unclassified Biotechnology
SHARE IN THE PHARMACEUTICAL MARKET
Share Among Top-100
Selling Drugs
FOR WHAT IS BIOTECH BEING USED FOR WHAT IS BIOTECH BEING USED ??
PhRMA Report 2011
BIOTECHNOLOGY MEDICINES•900 Products
•352 for Cancer•170 M-Antibodies•97 Vaccines
352
188
EXPERIMENTAL IDENTIFICATIO
N OF POTENTIAL TARGETS
MAKING AN ANTIBODY
PRECLINICAL EVALUATION CLINICAL
TRIALS
EXPANDED USE IN MEDICAL PRACTICE
THE BOTTLENECK OF CLINICAL RESEARCH
6 months 4 months 5 YEARS
CANCER IMMUNOTHERAPY: WHAT IS GOING ON?
1.
Experimental evidence about the action of the immune system on tumors accumulate. Better understanding of the DUAL ROLE
2.
Monoclonal Antibodies enter definitively into cancer pharmacopeia. At least two (Rituximab, Trastuzumab) with clinically relevant effect.
3.
First antibody targeting immune system regulation gets registration (Ipilimumab-2011) for Melanoma
4.
More than 150 antibodies accumulate in the pipeline
5.
First cancer vaccine gets registration (Sipuleucel-2010). Clinical relevance still in debate
6.
More than 100 cancer vaccines accumulate in the pipeline
7.
Major failures
also accumulate (in the transition Phase II III)
8.
Emerging evidence on combinations
with chemo-radiotherapy
MAbs in cancer
2011IPILIMUMAB
13
141 therapeutic cancer vaccines in clinical development…
Phase Of
development
Phase I(56)
Phase II(72)
Phase III(12)
PR(1)
Therapeutic cancer vaccines pipeline overview
Source: Datamonitor
PR = Preregistration
S
Market Summary Pipeline DynamicsUnmet needs
FDA Approves Prostate Cancer Treatment NBC Nightly News
(4/29 -2010) reported that "the FDA has
approved" Provenge (sipuleucel-T),“
a vaccine for prostate cancer
In 4 weeks
Journal of Thoracic Oncology 6:1763 (Oct 2011)
L‐BPL‐25 (Stimuvax) Mucin MUC1 peptide in liposomes
Phase III
TG 4010 Viral vector (Ankara) expressing MUC 1 and IL2Phase II
MAGE‐A3 Peptide Phase IIIBelagenpumatucel‐L Allogenic cells transfected
with TGF‐B antisensePhase III
SRL172 Heat‐Killed Mycobacterium V.
Phase III
Racotumumab Anti‐Idiotipic antibody Phase III multinationalCIMAVAX‐EGF Fusion protein rec‐EGF and
P64 prot.of NeisseriaRegistered in Cuba ‐Peru. Filed Brasil‐Argentina.
Clinical Trial in Europe
CETUXIMAB IN CRC
THE IMPACT OF BIOTECHNOLOGY IN CANCER TREATMENT: BEYOND PRODUCTS.
1-
BIOMARKERS ESTRATIFICATION
2-
CANCER AS A “CHRONIC DISEASE”(long term treatment, even beyond
progression)
3-
THE “REAL”
PATIENT (unfit patients)
4-
THE ROLE OF PRIMARY CARE SETTING(complex health interventions)
5
COMBINED
IMMUNOTHERAPY
WHICH ARE THE CONSEQUENCES FOR CLINICAL RESEARCH ?
1-THE GROWING COMPLEXITY OF PROGNOSTIC STRATIFICATION
Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
Mutations found in 54% (280/516) of tumors completely tested (95% CI: 50% to 59%)
Referral to appropriate biomarker‐driven clinical trial based on patient‐specific analysis
Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas
No Mutation Detected KRAS
22%
EGFR 17%EML4‐AKL
7%
Double Mutants 3%
BRAF 2%PIK3CA 2%HER2MET AMPMEK1NRASAKT1
If you torture the data long enough it will start to confess…
Joost De Damhoudere, Praxis Rerum Criminalium, Antwerp, 1556
WITH ᾳ= 0.05, and 10 ex-post subgroup analysis, probability of false positive es 22.4% !!!
22--THE TRANSITION TO CHRONICITY:THE TRANSITION TO CHRONICITY:
DIAGNOST.LEVEL
TUMORLOAD
TERMINALCANCERRELAPSERELAPSEDIAG.
DFI PROGRESSING DISEASE
COMPLETE or PARTIAL REMISSION
Attacktreatment
1st
line treatment of the advanced disease
CHRONIC EVOLUTIVENEOPLASTIC DISEASE
TRENS IN SURVIVAL OF RECURRENT BREAST CANCER.Cancer Vol.100, 1 Pages: 44‐52
ADVANCED CANCER IS TRANSITING TO CHRONICITY
CALLING FOR A NEW PARADIGM IN CLINICAL RESEARCHCALLING FOR A NEW PARADIGM IN CLINICAL RESEARCH
A “Paradigm” is a universally recognized scientific achievement that for a time provides model problems and solutions to a community of practitioners.From paradigms spring particular coherent traditions of scientific research.
Thomas S. KuhnThe Structure of Scientific Revolutions1962
THE DOMINANT ONCOLOGY DRUG DEVELOPMENT PARADIGM
• Maximizing dose
should maximize efficacy• Pharmacokinetics
is relevant to dose finding
• Objective response
predicts survival and clinical benefit• Tumor shrinkage is expected to happen soon• Objective progression is treatment failure. Drugs are not
active if the tumor is growing• Drugs to be tested in combinations
must be active individually
• Select for clinical trials a patient population
as homogeneous as possible
• Drugs are tested first in advanced disease, and moved soon to the “adjuvant setting”
(seeking cures)
THIS IS THE BASIS OF CURRENT CLINICAL TRIAL PRACTICES AND REGULATIONS
• Maximizing dose
should maximize efficacy
• Pharmacokinetics
is relevant to dose finding
• Objective response
predicts survival and clinical benefit
• Tumor shrinkage is expected to happen soon
• Objective progression is treatment failure. Drugs are not active if the
tumor is growing• Drugs to be tested in combinations
must be active individually• Select for clinical trials a patient
population
as homogeneous as possible
• Drugs are tested first in advanced disease, and moved soon to the
“adjuvant setting”
(seeking cures)
• 1906: FDA• -----1940: CLINICAL
RESEARCH WITHOUT CONTROL GROUPS OR HYPOTHESIS TESTING
• 1962: AMENDMENT OF FDA ACT-Requirement to show effectiveness
• 1979: WHO HANBOOK FOR REPORTING RESULTS OF CANCER TREATMENT
• 2000: RECIST-Response Evaluation Criteria in Solid Tumors
WHY IS THE CURRENT DRUG DEVELOPMENT PARADIGM NOT WORKING WELL
SIX REASONS:
1.
Maximal Tolerated Dose is not optimal dose for biologics
2.
Objective response is not a good predictor of survival
3.
Therapeutic benefit could be delayed
in time4.
Biologics could be active even beyond progression
5.
Combinations
can be effective using drugs which are not active individually
6.
Selected patient populations included in clinical trials often do not represent “real patients”
OBJECTIVE RESPONSE DOES NOT PREDICT SURVIVAL IMPROVEMENT
SORAFENIB in Renal Cell CarcinomaPhase III (903p)
PR = 10%CR 1/451
PFS doubled12 24 wp= 0.00001
High vs Low dose IL2
RR HD 21%LD 13%p=0.048
No statistically significant difference in survival
POLEMICS AROUND THE “ENDPOINTS”
WHAT SHOULD WE MEASURE ?:
•Response Rate
•Disease Control Rate
•Time to Progression
•Overall Survival
?
RESPONSE RATE IS NOT A GOOD ENDPOINT FOR BIOLOGICALS
DISEASE CONTROL RATE CAN PREDICT SURVIVAL
Clin Cancer Res 2007;13(5)March 1, 2007
ASSOCIATION BETWEEN TIME TO PROGRESSION AND SURVIVAL CAN BE POOR
THERAPEUTIC EFFECTS CAN BE DELAYED IN TIME Delayed Separation of curves – Sipuleucel-T
Finke et al., Vaccine (2007), 25S: B97-109
Separation of curves at ~8 months
Sponsor: Dendreon
Agent: autologous dendritic cell vaccine
Disease: metastatic prostate cancer
(intent-to-treat analysis)
DELAYED SEPARATION OF CURVES
: EGF Cancer Vaccine.
VaccineGroup(n= 45)
ControlGroup(n= 21)
Mean(months)
18.67 14.11
Median(months)
17.90 12.33
Funciones de supervivencia
Sobrevida desde Inclusion
403020100-10
Sup
ervi
venc
ia a
cum
1,2
1,0
,8
,6
,4
,2
Grupo de Tratamiento
B
B-censurado
A
A-censurado
Log Rank 1,91 1 ,1664
Funciones de supervivencia
Sobrevida desde Inclusion
403020100
Sup
ervi
venc
ia a
cum
1,2
1,0
,8
,6
,4
,2
Grupo de Tratamiento
B
B-censurado
A
A-censurado
Grupo Vacuna(n= 27)
Grupo Control(n= 17)
Mean(months)
21.84 16.23
Median(months)
- 13.87
Log Rank 3,18 1 ,0743
More than 5 doses
DELAYED SEPARATION OF CURVES Nimotuzumab + RT: GBM
Survival Functions
OS
3020100
Cum
Sur
viva
l
1,2
1,0
,8
,6
,4
,2
0,0
Tratamiento asignado
Nimotuzumab
Nimotuzumab-censored
Control
Control-censored
Junio 2006
Mayo 2007
EORTC‐NCI‐AACR Annual Meeting, Geneva, 2008
Long Lasting Disease Control
GBM GroupGBM Group MeanMean
(months)(months)
MedianMedian
(months)(months)
Nimotuzumab Nimotuzumab 13.8813.88 8.408.40
ControlControl 9.269.26 7.887.88
SV rateSV rate
6 months6 months
SV rateSV rate
24 months24 months
Nimotuzumab Nimotuzumab 64.3 %64.3 % 28.57 %28.57 %
ControlControl 61.5 %61.5 % 8.97 %8.97 %
Figure 5Mathematical illustration of a delayed separation of curves. Example of a two‐arm study with an ultimate hazard ratio of 0.7. The control
arm has an exponential survival distribution with median survival of 18 months (red dashed curve). The form of the delayed separation is
specified by a hazard ratio function (HR(t), solid gray line) that has the value 1.0 for 3 months and then decreases linearly between 3 and 6
months to become 0.7 at 6 months and then remains constant. The experimental arm survival distribution (solid blue line) is the
consequence of mathematically blending the control arm survival distribution function and the hazard ratio function.
Bevacizumab Beyond First Progression in BRiTE
Observational Study
J Clin Oncol 26: 5326 (2008)
IMMUNOTHERAPY CAN PRODUCE CLINICAL BENEFIT BEYOND PROGRESSION
LONG TERM USE OF THE ANTIBODY NIMOTUZUMAB :
(SCCHN:6 doses vs. maintenance vs. control)
20,0015,0010,005,000,00
Su
pe
rviv
en
cia
ac
um
1,0
0,8
0,6
0,4
0,2
0,0
Expanded Access-censurado
Placebo-censuradohR3-censuradoExpanded AccessPlacebohR3
Grupo Tto
Funciones de supervivencia
SV rate 6
months
SV rate12 months
SV rate18 months
SV rate24 months
RTP + placebo
n=29
76.9 % 44.2 % 23.1 % 19 %
RTP + nimo (6 doses)n=40
75.9 % 53.7 % 36.9 % 29 %
RTP + nimo(maintenance)n=16
94.1 % 94.1 % 84.7 % 84.7 %
% of GAR
1
10
100
1000
10000
100000
0 14 21 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480
Time (days)
log
1/se
radi
lutio
n
Patient 1Patient 2
LONG TERM VACCINATION WITH THE EGF-VACCINE, CIMAVAX
VQV
0 100 200 300 400 500 600 700100
1000
10000
100000
Anti-EGFTiter
EGF concentration
0
1000
2000
3000
time (days)
log
of th
e iv
erse
of
Ab
titer
EGF concentration
(pg/mL)
(CHEST 2000; 117:1239–1246)
Only 22% of NSCLC patients received chemotherapy at some point of their evolutionFraction of adult patients participating in a clinical trial is 2/5%. Of these, elderly patients are <10%
3-THE
“REAL WORLD PACIENTS”
: THERE IS A HUGE PATIENT POPULATION OUTSIDE “STATE-OF THE-ART TREATMENTS”
The choice: BIAS vs GENERALIZABILITY(Internal vs External validity)
POPULATION OF PATIENTS
STUDY POPULATION
TTO A
TTO B
TWO KINDS OF CLINICAL TRIALEXPLANATORY TRIAL
• Tests causal hypothesis• Internal validity: Efficacy• Controlled conditions• Academic institutions• Selected homogeneous
population• Inflexible intervention• Intensive follow‐up• Many measurements• Subrogate intermediate
endpoints (RR, Biomarkers)
PRAGMATIC TRIAL
• Tests choice between options• External validity: Effectivenes• Real world conditions• Community hospitals• Wide inclusion criteria
• More flexible intervention• Routine practice follow‐up• Few measurements• Patient‐oriented endpoints
(survival , QoL)
4-THE ROLE OF PRIMARY CARE
A POTENTIATION BETWEEN BIOTECHNOLOGY AND PRIMARY CARE
SIMPLE SANITARY INTERVENTIONS•Example: Vaccines and New Drugs
•It is possible to design for the “isolation” of the effect.•Classical design: RANDOMIZED CLINICAL TRIAL
•BUT BE careful !!!:-Statistical significance
does not mean medical relevance
-Trial sample does not extrapolate to real population
COMPLEX SANITARY INTERVENTIONS•MRC: ..”include separate components which seem essential for the result, but the “active and effective component” is difficult to specify”
•Implemented through the interfase between primary and secondary health care.•Often include changes in human behavior•Non linear results•Randomized experimental evaluation often not possible
•BUT WE ALWAYS MUST EVALUATE !!!
BIOTECHNOLOGY IN THE TREATMENT OF ADVANCED CANCER: A PARADIGM SHIFTTHE CLASIC PARADIGM:
•ACUTE TREATMENTS
•THE GOAL IS “CURE” OR NOTHING
•HIGHLY TOXIC TREATMENTS
•QUALITY OF LIFE DAMAGED BY THE DISEASE AND BY THE TREATMENT
•AGED PATIENTS WITH COMORBIDITIES NOT ELEGIBLE FOR “STATE OF THE ART” TREATMENTS
•PROTAGONISM OF SPECIALIZED HOSPITALS
THE EMERGING PARADIGM:
• LONG TERM TREATMENTS
•THE GOAL IS LONG TERM CONTROL
•LOW TOXICITY TREATMENTS
•QUALITY OF LIFE PRESERVED
•AGED PATIENTS WITH COMORBITIES ACCESING “STATE OF THE ART”
•TREATMENT AT PRIMARY CARE CENTERS IS FEASIBLE
BIOTECHNOLOGY IN THE TREATMENT OF ADVANCED CANCER: A PARADIGM SHIFT
THE EMERGING PARADIGM:
• LONG TERM TREATMENTS
•THE GOAL IS LONG TERM CONTROL
•LOW TOXICITY TREATMENTS
•QUALITY OF LIFE PRESERVED
•AGED PATIENTS WITH COMORBITIES ACCESING “STATE OF THE ART”
•TREATMENT AT PRIMARY CARE CENTERS IS FEASIBLE
CONSEQUENCES FOR CLINICAL TRIALS ?
•Move to survival as primary endpoint (instead of response rate)
•Randomize since Phase II ( II/III ?)
•Adopt “immune-related”
response criteria (instead of RECIST)
•Foresee delayed separation of survival curves in the statistical design
•Widen inclusion criteria to include (stratified) aged and unfit patients
•Validate trials in real conditions
TRANSLATING SCIENCE INTO REGULATIONS
• -----1940: CLINICAL RESEARCH WITHOUT CONTROL GROUPS OR HYPOTHESIS TESTING
• 1962: AMENDMENT OF FDA ACT-Requirement to show effectiveness
• 1979: WHO HANBOOK FOR REPORTING RESULTS OF CANCER TREATMENT
• 2000: RECIST-Response Evaluation Criteria in Solid Tumors
• 2009: irRC-Immune related response criteria
• 2009: FDA guide CLINICAL CONSIDERATIONS FOR THERAPEUTIC CANCER VACCINES
• 2011: Strategic Plan for ADVANCING REGULATORY SCIENCEAT FDA
August 2011
“While the world of drug discovery and development has undergone revolutionary change (shifting from cellular to molecular and gene-based approaches) FDA evaluation methods have remained largely unchanged over the last half-century”
Priority Areas:
•Modernize Toxicology•Stimulate Innovation in Clinical Evaluation•New approaches to improve product manufacturing•Readiness to evaluate innovative technologies•Information Sciences
WHAT COMES AFTER “PROOF OF CONCEPT”
?
Survival Distribution Function
0.00
0.25
0.50
0.75
1.00
days
0 200 400 600 800 1000 1200
STRATA: Arm=CT+RT Censored Arm=CT+RTArm=h-R3+CT+RT Censored Arm=h-R3+CT+RT
MANUFACTURING AND MARKETING
IMPACT IN PUBLIC HEALTH1.Prospective observational studies2.Expanded use programs3.Unfit patients4.Disease-oriented combinations5.Evaluation of complex health interventions6.“Quality Control”
in
medical practice
1. CLINICAL TRIALS PHASE I
2. PHASE-II3. PHASE-III4. PHARMACOL-
SURVEILLANCE
WHAT COMES AFTER “PROOF OF CONCEPT”
?
Survival Distribution Function
0.00
0.25
0.50
0.75
1.00
days
0 200 400 600 800 1000 1200
STRATA: Arm=CT+RT Censored Arm=CT+RTArm=h-R3+CT+RT Censored Arm=h-R3+CT+RT
MANUFACTURING AND MARKETING
IMPACT IN PUBLIC HEALTH1.Prospective observational studies2.Expanded use programs3.Unfit patients4.Disease-oriented combinations5.Evaluation of complex health interventions6.“Quality Control”
in
medical practice
1.
CLINICAL TRIALS PHASE I
2.
PHASE-II3.
PHASE-III
4.
PHARMACOL- SURVEILLANCE
?
TWO PERSPECTIVES OF THE INTERACTION BIOTECH-HEALTH
FROM THE TECHNOLOGIES:
•Product-oriented research•Isolated evaluation•Evaluation in controlled conditions•Statistical significance
FROM THE HEALTH PROBLEM:
•Disease-oriented research•Evaluation inside the context of other interventions•Evaluation in REAL conditions•Statistical significance + Medical Relevance.
ST
RE
NG
TH
OF
EV
IDE
NC
E
PILOT STUDY
PHASE III
PHASE IIRANDOMIZ
PHASE II
METAANALYSIS
HOW MUCH EVIDENCE DO WE NEED TO SWITCH TO A DISEASE-ORIENTED STUDY ?
TIME
TIME is what Science needs;But TIME is what Patients lack
A SCIENTIFIC CULTURE ALL AROUND MEDICAL PRACTICE
EVIDENCE BASEDAND QUALITY CONTROLLED MEDICAL PRACTICE
RANDOMIZED CLINICAL TRIAL
CLINICAL RESEARCH•Retrospective•Prospective observational study
IV INTERNATIONAL MEETING OF THE EGF VACCINE, Havana City 2011
CANCER IMMUNOTHERAPY AND THE EMERGING PARADIMGS IN CLINCAL RESEARCH
1- Biotechnology is opening the way to cancer immunotherapy
2-
Biotechnology beyond products: Emerging concepts in cancer treatment.
3-
The dominant paradigm in clinical cancer research, and its limitations.
4-
The emerging paradigm and its impact in clinical research
5-
To follow or to innovate? : The double axis of clinical research .
SH
IFT
IN
“S
TA
TE
OF
AR
T”
POPULATION COVERAGE(and universal training of Health Professionals)
(+)
CLINICAL RESEARCH IN CONTROLED CONDITIONS
EXCELLENCE: ADVANCED
HEALTH PROGRAMS
(-) MEDIOCRITYELEMENTAL
HEALTH PROGRAMS
(-) (+)
¿ ? CIMAVAX-2011: INTERROGATE OUR DATA 1. What is the strength of our evidence of clinical activity?
2. Is age a correlate of clinical activity or of insufficient immunization?
3. Do we have a subrogate marker of clinical activity in antibody titers of EGF concentration?
4. Which is the available evidence for the effect of chronic vaccination?
5. Is there evidence for response exhaustion at some point?
6. Do we have evidence of clinical benefit for patients unfit for chemo?
7. Have we already reached the optimal biological dose?
8. Which is the available evidence about dose-dependence?
9. What do we know about interaction of vaccination with chemotherapy?
10.Which are the provisional basis for the insertion of CIMAVAX in the complex management of advanced lung cancer?
¿ ? CIMAVAX-2011: INTERROGATE OUR DATA 1. What is the strength of our evidence of clinical
activity?2. Is age a correlate of clinical activity or of insufficient
immunization?3. Do we have a subrogate marker of clinical activity in
antibody titers of EGF concentration?4. Which is the available evidence for the effect of
chronic vaccination?5. Is there evidence for response exhaustion at some
point?6. Do we have evidence of clinical benefit for patients
unfit for chemo?7. Have we already reached the optimal biological dose?8. Which is the available evidence about dose-
dependence?9. What do we know about interaction of vaccination with
chemotherapy?10.Which are the provisional basis for the insertion of
CIMAVAX in the complex management of advanced lung cancer?
AND:
WHICH SHOULD BE THE PRIORITIES FOR 2012 ?