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 ?