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Oncology endpoints:
An unexpected journey
Waseem Jugon & Mijanur Rahman
Disclaimer
The views expressed in this paper are
those of the authors and do not
necessarily reflect those of Roche or any
other organization that may be cited for
reference in this presentation
Introduction
•  What is oncology?
•  What is an endpoint?
•  What statistical analyses are done?
•  How is an endpoint interpreted?
•  The evolution of a programmer
•  Summary
What is oncology?
•  The term oncology means a branch of science that deals with tumours
and cancers.
•  Cells grow out of control forming abnormal tissue growth, they may
become cancerous. This is known as cell mutation and can form
tumours in the body.
Image Reference: http://eschooltoday.com/cancer/what-is-cancer.html
Types of cancer
•  Benign tumours
–  Non-cancerous cells that can be removed.
•  Malignant tumours
–  Cancerous tumor cells that can spread.
•  Solid and non-solid tumours
–  Non-solid tumour resulting from defective blood cells (e.g. Leukemia).
–  Solid tumours are excess tissues made up of cancer cells. (E.g. Breast,
Lung)
•  Over 200 different types of cancer:
–  Breast, lung, bowel (colorectal) and prostate - make up over half of all new
cases (approx 54%).
–  The most common cancer type for men is prostate cancer.
–  The most common cancer type for women is breast cancer.
Evaluation of cancer therapies
•  Medical professionals who specialise in cancer are referred to as
oncologists and can help diagnose and recommend and evaluate
therapies.
•  RECIST - Response Evaluation Criteria in Solid Tumours
–  A set of rules first published in February 2000 but revised in 2008.
Respond
Stable
Progress
•  The evaluations of tumours are often collected as lesions.
•  These can be Target or Non-Target; however the presence of New
Lesions may occur at subsequent tumour assessments.
Complete
Partial
Response
(PR)
(CR)
Progressive
StableResponse
Disease
Disease
(SD)
(PD)
Oncology Endpoints
•  Defined as a measure of evaluating cancer therapies.
•  Primary endpoint of a study must be able to provide a valid and
reproducible measure of clinical and statistical benefit.
•  Specified in the protocol of the clinical trial and the methods of
interpreting the data of how to calculate these are contained within a
statistical analysis plan.
•  Some endpoints may be referred to as a surrogate endpoint.
–  Indication to predict clinical benefit.
–  Accelerated approval, less expensive, Novel treatments to patients
faster.
“As payers seek to keep pace with groundbreaking changes in the oncology
arena, it is critical that they have a solid understanding of how oncology
clinical trial endpoints can or should be used to guide decisions about the
care that patients receive.”
Kogan, A. J, & Haren, M - Translating Cancer Trial Endpoints Into the Language of Managed Care.
Types of Oncology Endpoints
Statistical Endpoint
Definition
Limitation
Overall survival (OS)
Time from randomization until death from any cause; most
commonly used endpoint in phase 3 trials and trials for
regulatory approval and is considered the gold standard
used to determine patient benefit. The reason this endpoint
is preferred is that it is not subject to any investigator bias.
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Requires randomized trial with lengthy
follow-up.
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Can be affected by subsequent therapies
A surrogate endpoint for OS. Time from randomization to
objective tumour progression or death. Unlike time to
progression (TTP), PFS includes death from any cause as
well as progression. Like TTP, it is unaffected by
subsequent therapies. FDA prefers PFS rather than TTP as
regulatory endpoint.
A surrogate endpoint for OS. Defined as time from
randomization until objective tumour progression. Unlike
PFS, it does not include deaths, but if most deaths are not
cancer-related TTP can be acceptable endpoint. Like PFS,
it is unaffected by subsequent therapies.
• 
Not statistically validated as surrogate for
survival in all treatment settings
Not precisely measured subject to
assessment bias particularly in openlabel studies
Definitions vary among studies
Frequent radiological or other
assessments
Involves balanced timing of assessments
among treatment arms
Progression-free
survival (PFS)
Time to progression
(TTP)
Objective response
rate (ORR)
A surrogate endpoint for OS. A proportion of patients with
reduction in tumour size by a predefined amount (using
standardized criteria, such as RECIST). Directly attributable
to drug effect.
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Patient Reported
Outcomes (PRO)
Patient-reported outcomes, such as quality of life (QOL),
complement information from traditional endpoints,
generating the patient’s global assessment of the direct
clinical benefit of a drug
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Not a direct measure of benefit
Not a comprehensive measure of drug
activity
Only a subset of patients who benefit
Blinding often is difficult
Data frequently are missing or
incomplete
Clinical significance of small changes is
unknown
Multiple analyses
Lack of validated instruments
Definitions are as per the FDA guidelines for Clinical Oncology
endpoints
Novel Endpoints and The Future
•  OS is still considered the gold standard in terms of determining
treatment benefit.
Why do we need different endpoints?
•  OS can take many years to prove any clinical benefit.
•  If a surrogate endpoint can be used to gain accelerated regulatory
approval, more novel therapies can reach patients faster.
–  PFS has been an example of a surrogate that has been used as
the primary endpoint for a novel targeted therapy treatment in
breast cancer.
•  Continuing to learn about the effect of cancer treatments
A Novel Endpoint: Pathological Complete
Response (pCR)
•  Pathological complete response (pCR) — The Food and Drug
Administration (FDA) defines pCR as no evidence of disease in the
breast or lymph nodes as examined by a pathologist.
•  The FDA recently published a draft guidance document for the use of
Pathological Complete Response (pCR) in Neoadjuvant Treatment
(before surgery) of High Risk Early-Stage Breast Cancer.
•  FDA approval granted - major breakthrough for treatment in early
breast cancer and achieve a common goal of bringing treatment to
patients quicker and safer.
Understand primary endpoint data
Investigator assessed PFS
No New Lesions
•  The tumour does increase from baseline, but not by 20%.
•  Tumour increase is only 9.8%
•  Incorrectly assessed as PD
Statistical Analysis
•  Survival analysis - In clinical trials, the effect of an intervention is
evaluated by measuring the number of patients survived after that
intervention over a period of time.
•  Key terms in Survival Analysis
–  Response Rate
–  Median Survival
–  P-value
–  Censoring
–  Hazard Ratio
–  Odds Ratio
Kaplan - Meier Curve
•  Definition: The Kaplan – Meier (KM) curve is a graphical
representation of a time to event analysis showing when a patient
reaches a trials survival endpoint.
•  Can be summarised by observing the median survival.
•  Median survival is the measure of how long patients will live on average
with a certain disease or treatment, and corresponds to the point on the
KM curve where the survival probability equals 0.5.
•  The KM estimate describes the probability of surviving in a given length
of time while considering time in many small intervals depicted as
steps, occurring at the time of each new event.
•  Censoring - Certain situations can occur in a study such as patients
refuse to remain in the study, or loss of contact with the patient etc.
These are labelled as censored observations.
Kaplan - Meier Curve
Cox Regression
•  Definition: The Cox regression model provides us with estimates of the effect
that different factors event (e.g. age, weight, sex etc.) have on the time until the
end.
•  The hazard ratio (HR) is the relevant risk of experiencing an event being
measured (e.g. death) between two groups.
–  HR = 1: indicates no difference
–  HR <1 : indicates there was a reduced risk in one of the treatment arms.
–  HR > 1: indicates an increased risk in one of the treatment arms.
Log Rank Test
•  Definition: The Log rank test is a hypothesis test and provides no
direct information on how different the treatment groups are but can be
used to compare the KM survival distributions between 2 groups.
•  This test is commonly used in clinical trials to give an indication of the
efficacy of a new treatment to standard of care.
•  The P-value can tell us if the difference between the survival
distributions is statistically significant.
Odds Ratio
•  Definition: This is the ratio of an event happening compared to an
event not happening in the sampled population.
Cox Regression – Time to event
1. Responders
2. Time to Event
3. Hazard Ratio
4. Truncated Analyses
Nearly 60% of patients in the control arm were deemed to have had an
event compared to approximately 48% in the experimental arm.
The experimental arm shows an improvement of PFS by approximately
6.1 months. A P-Value calculated using a log rank test of less than
0.0001 indicates that this is statistically significant.
A Hazard ratio of 0.63 indicates that there is 37% lower risk of a PFS
event occurring in the experimental arm compared to the control arm.
More patients have not experienced an event in the experimental arm.
Objective Response Rates
1. Responders
2. Treatment Group
comparison
3. Odds Ratio
4. Response Rate
Approximately 77% of the patients respond to treatment in the
experimental arm in comparison to approximately 68% in the control
arm.
The difference in the response rates between the 2 treatment arms is
approximately 9.2 %. P-value shows there is a statistically significant
difference between the 2 treatment groups.
An Odds ratio of 1.60 indicates that the likelihood of achieving a
response is 1.6 times higher in the experimental arm compared to the
control arm.
The number of responses for each observed tumour response is
calculated as a percentage out of the population N. The associated 95%
Forest Plots
•  Definition: Shows the corresponding magnitude of benefit and
confidence limits of each subgroup analyzed.
•  Forest plots are extremely useful when it comes to displaying or trying
to identify the treatment effect in different subgroups of patients.
•  Forest plots are usually created for exploratory analyses as many
clinical trials are not always designed to show treatment benefits in
many different subgroups.
Forest Plots
Evolution of Programmers
Summary
•  Oncology is the most significant therapeutic area in terms of R&D
•  Knowledge of the clinical endpoint helps with:
–  Understanding the science to challenge analyses
–  Reviewing the key data points to ensure accuracy
–  Interpreting the statistical analysis to ensure the correct message
is being delivered
•  Programmers need to up-skill in order to add value
The role of a programmer is constantly
ING
EVOLV
Reading Recommendations
Oncology Endpoints
•  Genentech USA, I. (2011). The Ongoing Evolution Of Endpoints in Oncology. Retrieved
from NAMCP Medical Directors: http://www.namcp.org/institutes/cancer/Oncology
%20Endpoints.pdf
•  Oncology, A. (2009). CLINICAL DRUG TRIALS IN CANCER: STUDY ENDPOINTS –
WHAT DO THEY REALLY MEAN? Retrieved 2013, from PR Newswire: http://
multivu.prnewswire.com/mnr/astrazeneca/38570/docs/38570ClinicalTrialsEndpointFactsheet.pdf
RECIST
•  Eisenhauera, E., Therasseb, P., Bogaertsc, J., Schwartzd, L., Sargente, D., Fordf, R., et
al. (2008, October 28). New response evaluation criteria in solid tumours: Revised
RECIST guideline (version 1.1). Retrieved 2013, from EUROPEAN JOURNAL OF
CANCER: http://www.eortc.be/Recist/documents/RECISTGuidelines.pdf
Statistics
•  Harris, M., & Taylor, G. (2008). Medical Statistics Made Easy. Scion Publishing Limited.
•  Machin, D., Campbell, M. J., & Walters, S. J. (2007). Medical Statistics: A Textbook for
The Health Sciences. John Wiley & Sons Ltd.