EFFICACY ENDPOINTS IN ONCOLOGY IS01 Bruxelles 13-16/10/2013 - - PowerPoint PPT Presentation

Geneva Branch

EFFICACY ENDPOINTS IN ONCOLOGY

– IS01 Bruxelles 13-16/10/2013 Angelo Tinazzi Cytel Inc., Wilmington Del. USA Succursale de Meyrin – Geneva – Switzerland angelo.tinazzi@cytel.com

Geneva Branch

Cytel Inc. - Confidential 2

Efficacy Endpoints in Oncology

Disc Disclaimer laimer

The information contained in this presentation is based on personal research

• f the author. The author may or may not

be experts in the field. Cytel Inc. does not guarantee for the correctness of the displayed information.

Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions

Geneva Branch

Cytel Inc. - Confidential 3

Efficacy Endpoints in Oncology

Intr Introduction

• duction

Introduction

Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions

Oncology Endpoints in Drug Development

§ Early Phase

§ Safety and Evidence of Drug Activity § Identification of possible indications

§ Late Phase

§ Seek for Clinical Benefit

Geneva Branch

Cytel Inc. - Confidential 4

Efficacy Endpoints in Oncology

Intr Introduction

• duction

Introduction

Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions

Key Requirements for Drugs Approval

§ Demonstration of efficacy with acceptable safety in

adeguate and well-controlled studies

§ Benefits/Risks asssessment

§ Longer Life § Better Life (Quality) § Safety § Cost

“Clinical Trials Enpoints for the Approval of Cancer Drugs and Biologics” Guidance for Industry, FDA, May 2007

Geneva Branch

Cytel Inc. - Confidential 5

Efficacy Endpoints in Oncology

Ov Over erall Sur all Survival (OS) vival (OS)

Introduction

Overall Survival

Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions

Definition Time from randomization until death from any cause Pros

• Measure of direct benefit
• Easy to measure (Unbiased)

Cons

• It may require large population and follow-up
• It includes deaths unrelated to cancer
• It may be affected by crossover or subsequent

therapies Censor

• Last date subjects was seen alive

The «Gold» standard for demonstrating clinical benefit

Geneva Branch

Cytel Inc. - Confidential 6

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

History of (FDA) Drugs Approval

§

‘70: Objective (tumor) Response Rate (ORR)

§

‘80: More demonstration of clinical benefit: Survival, QoL, Physical functioning, Tumor- related symptoms

§

’90: use of Surrogate endpoints predicting clinical benefits

§ 1992: FDA adopted accelerated drug approval

• J. McCain, "The Ongoing Evolution of Endpoints in Oncology," 2010.

Geneva Branch

Cytel Inc. - Confidential 7

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

A surrogate endpoint is an alternative endpoint that if validated allows conclusions to be made about the effect of an intervention

• n a true endpoint often requiring a shorten observaion period

§

Surrogate ‘efficacy’ endpoints in oncology aim to replace OS, the endpoint to ‘predict’

Primary endpoints in randomized controlled trials of treatments for advanced breast cancer 2000-2007) Endpoints used for basis of oncology drug approvals (FDA 1990–2002)

Geneva Branch

Cytel Inc. - Confidential 8

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Tumor Response and Progression in Solid Tumors

§ Change in Tumor Mass

§ Shrinkage (Response) § Growth (Progression)

§ Instrumental Evaluation / Radiological Evaluation (e.g. CT-Scan) § Periodic and Regular Assessments

Source: Gonçalves et al. BMC Cancer 2008 8:169 doi:10.1186/1471-2407-8-169

Geneva Branch

Cytel Inc. - Confidential 9

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Tumor Response and Progression in Solid Tumors

§ Standard set of Criteria (RECIST)

§ Identification and Classification of Tumor Lesions

§ Measurable (Target) vs Non Measurable (Non-Target)

§ Periodicity (e.g. CT-Scan every 6 or 8 weeks) § Response evaluated vs Baseline (assessment prior to study

entry)

§ A 30% decrease in the sum of all lesions measurement (mm)

§ Progression evaluated vs Nadir (best response prior to current

assessment)

§ A 20% increase in the sum of all lesions measurement (mm) § An increase / prgression of any non-target lesion or new lesion identified after study entry determines also the progression

Geneva Branch

Cytel Inc. - Confidential 10

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Tumor Response and Progression in Solid Tumors

§

Standard set of Criteria (RECIST) - Cont

§ 5 Overall Response Criteria

§ CR – Complete Response § PR – Partial Response § SD – Stable Response § PD – Progressive Disease § NE – Not Evaluable

§ Best Overall Response as the best response (criteria) assessed since the

subject is on-study (on-treatment)

• P Therasse et al, "New response evaluation criteria in solid tumors: Revised RECIST

guideline (version 1.1)," European Journal of Clinical Oncology, pp. 45: 228-247, 2009. ¡

• MB Mayakuntla, PM Nidamathy, "RECIST and programming challenges," in IASCT, 2012. ¡
• Ji Yu, P Slagle, "Objective tumor response and RECIST criteria in cancer clinical trials," in

MWSUG, 2011. ¡

Geneva Branch

Cytel Inc. - Confidential 11

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Tumor Response and Progression in Solid Tumors

EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 –247

Lesion Baseline Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4

T1 (mm) 10 10 5 7 10 T2 (mm) 25 15 5 5 5 T3 (mm) 15 15 15 15 20 (Sum of Lesion mm) 50 40 25 27 35 (Response Target Lesions) SD PR PR PD NT1 NA Stable Stable Stable Stable New Lesion NA No No No No

PR SD PR PD PR SD PD

Geneva Branch

Cytel Inc. - Confidential 12

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Progression and Response

PD PR PR SD

Decrease with respect to baseline... …but also increase with respect to prior reduction showing the «re-growth» of the cancer and therefore the failure

• f the treatment

Geneva Branch

Cytel Inc. - Confidential 13

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Progression and Response

PD PR PR SD

data respT; set SOLD; by USUBJID VISITNUM; retain NADIR BASE; if first.USUBJID then do; NADIR=.; BASE=SOLDMM; end; PCTBASE=((SOLDMM-BASE)/BASE)*100; PCTNADIR=((SOLDMM-NADIR)/NADIR)*100; if SOLDMM=0 then NTRESP=‘CR’; else if PCTNADIR>20 then NTRESP=‘PD’; else if abs(PCTBASE)>30 then NTRESP=‘PR’; else SOLDMM ne . Then NTRESP=‘SD’; else NTRESP=‘NE’;

• utput;

NADIR=min(NADIR,SOLDMM); run;

Timepoint SOL DMM BA SE PCTB ASE NA DIR PCTN ADIR NTRE SPT Baseline 50 Timepoint 1 40 50

• 20

50

• 20

SD Timepoint 2 25 50

• 50

40

• 37.5

PR Timepoint 3 27 50

• 46

25 8 PR Timepoint 4 35 50

• 30

25 40 PD

Geneva Branch

Cytel Inc. - Confidential 14

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

The concept of Progression and Response in non Solid Tumors (e.g. Acute Multiple Lymphoma)

atlasgeneticsoncology.org

Geneva Branch

Cytel Inc. - Confidential 15

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Definition Time from randomization until radiolagical tumor progression Pros

• Requires smaller sample size
• Not affected by crossover or subsequent

therapies

• Based on objective and quantitative assessment

Cons

• Measurement may be subject to bias
• Requires frequent radiologic assessment (e.g.

every 6 weeks) and same or similar among treatment arms

• In some settings can be difficult to validate

Censor

• Last date radiological tumor assessment

Time to Tumor Progression (TTP)

Geneva Branch

Cytel Inc. - Confidential 16

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Progression Free Survival (PFS)

§

A variant of TTP where death are also counted as event

§

In some protocols Death as event can be limited if occurred within ‘xx’ weeks from last tumor assessment (e.g. 12 weeks)

§

Applicable to study with patients with advanced cancer Disease Free Survival (DFS)

§

Same as PFS but it assumes patients are disease-free at study entry

§

Applicable to study testing adjuvant therapies with patients where the disease (cancer) was previously surgically removed Time to Treatment Failure (TTF)

§

Time from randomization to discontinuation of treatment for any reason

§

TTF not reccomended as regulatory endpoint for approval; «a regulatory endpoint should clearly distinguish the efficacy of the drug from toxicity, patient or physichian withdrwal or patient intolerance»

Geneva Branch

Cytel Inc. - Confidential 17

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Definition Proportion of patients with tumor size reduction

• f a predefined amount and for a minumim time
• period. FDA has defined ORR as the sum of

Complete and Partial Responses Pros

• Can be assessed in single-arm studies
• Can be assessed earlier and in smaller studies
• Effect attributable to drug, not natural history

Cons

• Not a direct measure of benefit
• Only a subset of patients who benefit

Objective Response Rate (ORR) Response Duration (DR)

§ Time from first assessment of CR or PR until date of

progression or last tumor assessment

§ Applicable only to patients with ORR

Geneva Branch

Cytel Inc. - Confidential 18

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Efficacy Endpoint – Example 1

§

Responder

§

Progressing

RAN SD SD PR CR PD Response Duration ORR OS PFS TTP Death / Alive

Geneva Branch

Cytel Inc. - Confidential 19

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Efficacy Endpoint – Example 2

§

Non Responder

§

Non Progressed

§

Death

RAN SD SD SD Off TRT OS TTP Death PFS TTF

Geneva Branch

Cytel Inc. - Confidential 20

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Sensitivity Analysis in Tumor Response based endpoint

§ Use of Per Protocol Population § Include clinical progressions § Different Censoring/Event Date Methods

§ Backdating event date when tumor assessment are not performed within

the pre-defined interval

§ Censoring at the date of subsequent cancer therapy if occurred before

progression

§ Use of Independent Review of Tumor Endpoints

§ Can minimize bias in readiographic interpretation of the radiological

findings (investigator)

§ Often Primary endpoints in non-blinded studies

Geneva Branch

Cytel Inc. - Confidential 21

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Modified Response / PFS Criteria e.g. Prostate Cancer according PCWG2 criteria Where disease progression is defined as the presence of at least one of the following conditions:

§ Bone Lesions Progression § Soft-Tissue Lesions Progression (RECIST) § Presence of Skeletal Events

HI Scher, "End Points and Outcomes in Castration-Resistant Prostate Cancer: From Clinical Trials to Clinical Practice," J Clin Oncol, 2011. ¡

Geneva Branch

Cytel Inc. - Confidential 22

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Other endpoints: Time to symptom progression (TTSP) e.g. TTSP in Lung Cancer Trials as per the Lung Cancer Symptom Scale (LCSS)

§ Symptomatic progression defined as an increase

(worsening) of the average symptomatic burden index (ASBI, i.e., the mean of the six major lung cancer specific symptom scores [fatigue, pain, dyspnoea, cough, anorexia and hemoptysis])

§ The worsening is defined as an at least 10% increase

• f the scale breadth (i.e., at least 10 mm increase on

the 100 mm scale) from the baseline score.

Hollen PJ, Gralla RJ, Kris MG, et al. Quality of life assessment in individuals with lung cancer: Testing the lung cancer symptom scale (LCSS). Eur J Cancer. 1993;29A(1):51-8.. ¡

Geneva Branch

Cytel Inc. - Confidential 23

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Quality of Life

§

Only used in support of primary endpoints

§

Several ‘validated’ questionnaires available for different indications

http://groups.eortc.be/qol/eortc-modules

Geneva Branch

Cytel Inc. - Confidential 24

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Duration of Complete Response in Leukemia Considered established endpoint of clinical benefit in leukemia

§ Less infection § Less Bleeding § Less use of blood product support (e.g. transfusion)

D Cheson et al, "Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia," Journal of Clinical Oncology, pp. Vol 21, No 24: pp 4642-4649, 2003 ¡

Geneva Branch

Cytel Inc. - Confidential 25

Efficacy Endpoints in Oncology

Sur Surroga

• gate Endpoints

te Endpoints

Introduction Overall Survival

Surrogate Endpoints

Regulatory Req. Data Management Analysis Conclusions

Geneva Branch

Cytel Inc. - Confidential 26

Efficacy Endpoints in Oncology

Re Regulatory Re Requirements

Introduction Overall Survival Surrogate Endpoints

Regulatory Req.

Data Management Analysis Conclusions

FDA Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007)

§ General regulatory requirements for efficacy § Detailed description of endpoints and how they can be

used in various clinical settings

§ Pros and Cons § Protocol and SAP design requirements § Data Collection for Tumor Measurement § Issue to consider in PFS analysis

§ Progression and Censore Date § How to handle Missing Data § Lesions evaluation § Sensitivity Analysis

++

Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Cancer Drugs and Biologics, FDA, 2011 Cancer Drug Approval Endpoints

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/CancerDrugs/ucm094586.htm

Geneva Branch

Cytel Inc. - Confidential 27

Efficacy Endpoints in Oncology

Re Regulatory Re Requirements

Introduction Overall Survival Surrogate Endpoints

Regulatory Req.

Data Management Analysis Conclusions

EMA Guideline on the evaluation of anticancer medical products in man

§ Guidance on all stages of clinical drug development for

the treatment of malignancies

§ The current version of the guidance cover also non-

cytotoxic compounds and additional indication for exploratory studies.

§ Completed by a set of specific appendices covering

methodologial aspects related

§ Methodological Consideration for using Progression Free Survival

(PFS) and Disease Free Survival (DFS) in confirmatory trials

§ Confirmatory Studies in Haematological Malignancies § Condition specific Guidance such as NSCLC, Prostate

§ The EMA is also planning to provide an additional

appendix for Quality of Life/Patient Reported Outcome.

Geneva Branch

Cytel Inc. - Confidential 28

Efficacy Endpoints in Oncology

Da Data ta Mana Management gement Issues Issues

Introduction Overall Survival Surrogate Endpoints Regulatory Req.

Data Management

Analysis Conclusions

§ Tumor Response

§ Missing Assessments § Consistent Lesions Reporting

§ Type, Site

§ Assessment of method used § Disappeared Tumor Lesions (0mm) § Consisteny between lesions details (sum of diamaters

for target lesions) and overall response

§ Independent Review Committee

§ Keep follow-up up-to-date § CDISC SDTM 3.1.3 Tumor Response Domains

++

• Overcoming Difficulties in Implementing RECIST criteria, PhUSE 2013, G. Ruhnke
• CDISC Journey on Solid Tumor Studies using RECIST 1.1., PhUSE 2013, K. Lee

Geneva Branch

Cytel Inc. - Confidential 29

ORR Analysis with proportion and %CI

Efficacy Endpoints in Oncology

Anal Analysis ysis

Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management

Analysis

Conclusions

Geneva Branch

Cytel Inc. - Confidential 30

Survival Analysis § Unadjusted (Kaplan Meier & Log-Rank Test)

§ SAS Proc LIFETEST

§ Adjusted (Cox proportional hazards regression model)

§ SAS Proc PHREG § Selection of covariates to be used depends on the indication and

treatment setting. E.g. type and/or response to prior therapy

§ Examples of other possible covariates

Efficacy Endpoints in Oncology

Anal Analysis ysis

Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management

Analysis

Conclusions

Geneva Branch

Cytel Inc. - Confidential 31

Survival Analysis

Efficacy Endpoints in Oncology

Anal Analysis ysis

Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management

Analysis

Conclusions

Geneva Branch

Cytel Inc. - Confidential 32

Subgroup Analysis with Forest Plot

Efficacy Endpoints in Oncology

Anal Analyisis yisis

Bursac, Z, "Creating Forest Plots from Pre-computed Data using PROC SGPLOT and Graph Template Language,“ In SAS Global Forum, 2010

Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management

Analysis

Conclusions

Geneva Branch

Cytel Inc. - Confidential 33

Efficacy Endpoints in Oncology

Anal Analyisis yisis

Tumor Shrinkage with Waterfall Plot

NJ Pandya, "Waterfall Charts in Oncology Trials - Ride the Wave," In PharmaSUG, 2012

Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management

Analysis

Conclusions

Geneva Branch

Cytel Inc. - Confidential 34

Efficacy Endpoints in Oncology

Conc Conclusions lusions

Introduction Overall Survival Surrogate Endpoints Regulatory Req.

Analysis Data Management

Conclusions

§ Despite its complexity, “stable” standards exist for

efficacy evaluation

§ Use of efficacy indicators may be different from an

indication to another

§ Managing, deriving and analyzing efficacy endpoints

in oncology requires a clear understanding of the disease

§ The use of efficacy endpoints in drug approval may

change again with the idea of targetting the therapies based on molecular profiling

Geneva Branch

Cytel Inc. - Confidential 35 New Geneva offices – November 2012

Efficacy Endpoints in Oncology

Ques Questions ions