Presented at PhUSE 2013 The evaluation of efficacy in oncology studies, in particular for solid tumors, is pretty standard and well defined by several regulatory guidance (e.g. EMA and FDA), including some specific cancer type guidance (e.g. NSCLC from FDA). Although some references will be also given for non-solid tumors, the paper will mainly focus on solid tumors efficacy endpoints. Overall Survival, Best Overall Response as per RECIST criteria, Progression Free Survival (PFS), Time to Progression (TTP), Best Overall Response Rate are some of the key efficacy indicators that will be discussed.

1. 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

2. 2
Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Disclaimer
The information contained in this
presentation is based on personal
research of the author and does not
necessarily represent Cytel Inc..
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

3. 3
Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Introduction
Oncology Endpoints in Drug Development
 Early Phase
 Safety and Evidence of Drug Activity
 Identification of possible indications
 Late Phase
 Seeks for Clinical Benefit
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

4. 4
Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Introduction
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
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Overall Survival (OS)
Geneva Branch
Introduction
The «Gold» standard for demonstrating clinical benefit
Overall Survival
Surrogate Endpoints
Definition
Pros
Time from randomization until death
from any cause
• 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
Regulatory Req.
Data Management
Analysis
Conclusions

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Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
History of (FDA) Drugs Approval
‘70: Objective (tumor) Response Rate (ORR)
‘80: More evidence of clinical benefit:
Survival, QoL, Physical functioning, Tumorrelated 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.
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
A surrogate endpoint is an alternative endpoint that if validated
allows inference on the effect of an intervention on a true
endpoint often requiring a shorten observaion period
 Surrogate ‘efficacy’ endpoints in oncology aim to replace OS,
the endpoint to ‘predict’
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Endpoints used for
basis of oncology drug
approvals
(FDA 1990–2002)
Primary endpoints in randomized controlled
trials of treatments for advanced breast
cancer 2000-2007)

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Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
The concept of Tumor (e.g. solid) Response and Progression in
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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
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 (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’ measurements (mm)
 An increase / prgression of any non-target lesion or new lesion identified
after study entry determines also the progression
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
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.
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
The concept of Tumor Response and Progression in Solid Tumors
Lesion
Baseline Timepoint 1 Timepoint 2
Timepoint 3
Timepoint 4
T1 (mm)
T2 (mm)
T3 (mm)
(Sum of Lesion mm)
(Response Target Lesions)
NT1
New Lesion
10
25
15
50
7
5
15
27
PR
Stable
No
10
5
20
35
PD
Stable
No
PR
PD
NA
NA
10
15
15
40
SD
Stable
No
SD
5
5
15
25
PR
Stable
No
PR
PR
EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 –247
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Cytel Inc. - Confidential
Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
The concept of Progression and Response
Overall Survival
Surrogate Endpoints
PD
Decrease with
respect to baseline...
Regulatory Req.
Data Management
PR
PR
SD
Analysis
…but also increase
with respect to prior
reduction showing
the «re-growth» of
the tumor and
therefore the
possible failure of
the treatment
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
The concept of Progression and Response
data respT;
set SOLD;
by USUBJID VISITNUM;
retain NADIR BASE;
PD
if first.USUBJID then do;
NADIR=.;
BASE=SOLDMM;
end;
PR
PCTBASE=((SOLDMM-BASE)/BASE)*100;
PCTNADIR=((SOLDMM-NADIR)/NADIR)*100;
if SOLDMM=0 then NTRESP=‘CR’;
else if PCTNADIR>20 then NTRESP=‘PD’;
else
PR if abs(PCTBASE)>30 then NTRESP=‘PR’;
else SOLDMM ne . Then NTRESP=‘SD’;
else NTRESP=‘NE’;
output;
SOL
BA
NADIR=min(NADIR,SOLDMM); Timepoint
DMM SE
SD
run;
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Time to Tumor Progression (TTP)
Definition
Pros
Time from randomization until radiolagical
tumor progression
• 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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Progression Free Survival (PFS)
 A variant of TTP where deaths are also counted as events
 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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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

17. 17
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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Objective Response Rate (ORR)
Definition
Proportion of patients with tumor size reduction
of 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
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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Efficacy Endpoint – Example 1
 Responder
 Progressing
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
RAN
SD
SD
PR
CR
PD
Death /
Alive
Analysis
Conclusions
ORR
PFS
TTP
Response Duration
OS

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Efficacy Endpoint – Example 2
 Non Responder
 Non Progressed
 Death
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
RAN
SD
SD
SD
Off TRT
TTF
TTP
PFS
OS
Death

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
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 is 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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
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.
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
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
of 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..
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Quality of Life
 Only used in support of primary endpoints
 Several ‘validated’ questionnaires available for
different indications
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
http://groups.eortc.be/qol/eortc-modules

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Efficacy Endpoints in Oncology
Surrogate Endpoints
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)
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
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

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Efficacy Endpoints in Oncology
Surrogate Endpoints
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Regulatory Requirements
FDA Clinical Trial Endpoints for the Approval of Cancer
Drugs and Biologics (2007)
 General regulatory requirements for efficacy
 Detailed description of endpoints and how these 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
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Regulatory Requirements
Geneva Branch
Introduction
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 noncytotoxic 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.
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Data Management Issues
Geneva Branch
Introduction
 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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Analysis
ORR Analysis with proportion and %CI
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Analysis
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
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Analysis
Survival Analysis
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

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Efficacy Endpoints in Oncology
Analyisis
Subgroup Analysis with Forest Plot
Geneva Branch
Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Bursac, Z, "Creating Forest Plots from Pre-computed Data using PROC SGPLOT and Graph Template Language,“
In SAS Global Forum, 2010

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Efficacy Endpoints in Oncology
Analyisis
Geneva Branch
Introduction
Tumor Shrinkage with Waterfall Plot
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
NJ Pandya, "Waterfall Charts in Oncology Trials - Ride the Wave,"
In PharmaSUG, 2012

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Efficacy Endpoints in Oncology
Conclusions
Geneva Branch
Introduction
 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
Overall Survival
Surrogate Endpoints
Regulatory Req.
Analysis
Data Management
Conclusions

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Efficacy Endpoints in Oncology
Questions
New Geneva offices – November 2012
Geneva Branch