Download James Yang, MD, PhD

Clinical Trial Endpoint Selection in
Oncology: What Can Make a
Difference?
James CH Yang, MD, PhD
Conflicts of Interest
• James Chih-Hsin Yang received honoraria for speeches or for participated in
compensated advisory boards of Boehringer Ingelheim, Eli Lilly, Bayer,
Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis,
Clovis Oncology, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, and
Ono Pharmaceutical, and uncompensated advisory board of AstraZeneca
Outline
• Brief overview of regulatory authorities and their approval processes
• Brief discussion of regulatory perspectives on clinical trial endpoints
What Makes a Good Endpoint?
CHARACTERISTIC
MEANING
Relevant
Clinically important/useful
Quantifiable
Measured on an appropiate scale
Valid
Measures the intended effect
Objective
Interpreted effect yields consistent measurements
Reliable
Same effect yields consistent measurements
Sensitive
Respond to small changes in effect
Specific
Unaffected by extraneous influences
Precise
Small variability
Other
Tradition, cost, time…
Surrogate endpoint : firmly established endpoint to predict a clinically meaningful outcome
or to predict an established endpoint
Clinical Trial Endpoint Selection in Last Two Decades
• Strict legal requirements to demonstrate benefit
– Randomised controlled trials (how many are necessary?)
– Primary endpoint: Valid and reliable measure that provides the most clinically
relevant and convincing evidence
– Wrong design or lack of efficacy the most important reason for rejection
• The commonly used endpoints are based on
OS: Historically viewed as the most effective way, as it addresses
biology of tumour and the natural history of the disease
SURVIVAL
TUMOUR
RESPONSE
SYMPTOM
ASSESSMENT
OS = overall survival; PFS = progression-free survival.
PFS: Progression is associated with tumour growth, assesses
tumour shrinkage and stabilisation of disease
• Response rate: Objective demonstration of drug effect,
durability of response is also taken into consideration
• Breakthrough designation and fast tract approval are usually
based on tumour response
Clinical Trial Endpoint Selection in Phase III Trials
• Statistically significant
• Clinically meaningful
Phase III, confirmatory studies, interim
analyses/data maturity
• OS as primary endpoint, not response rate
• Possible: PFS when clinically relevant,
symptom control, or could be viewed as a
surrogate of OS benefit when OS difference
cannot be achieved due to crossover, or
long-term waiting
• Reflective of patient benefit
– Survival
– Progression-free survival (PFS)
plus some measure of symptom
relief or quality of life (QoL)
– Symptom relief
For accelerated approval: must predict
clinical benefit over available therapy
– QoL
• Overall response rate and response
duration have been the most commonly
• Surrogate endpoints
•
used surrogate endpoint in accelerated
approval
PFS is also acceptable under some
conditions
OS: Still the Gold Standard for Demonstrating Clinical Benefit
• OS should be the primary endpoint in most phase III trials
• If OS is a secondary endpoint, trials should be better powered for assessing survival
ACCURATE
NOT PRONE TO
INVESTIGATOR OR
ASSESSMENT BIAS
OBJECTIVE
“Overall survival is
accepted as the
gold standard for
efficacy evaluation
in clinical trials of
oncology agents.”
Soria JC, Massard C, Le
Chevalier T. Ann Oncol.
2010;21:2324.
READILY
COMPARED
ACROSS
DISEASES
CLINICALLY
SIGNIFICANT
UNAMBIGUOUS
Cheema and Burkes. Curr Oncol. 2013;20:e150-60.
EASILY
MEASURED
Advanced NSCLC: Why Overall Survival?
In Advanced NSCLC
• Most relevant to patient
• Most objective endpoint
– Clear and accurate endpoint
– Usually easy to get this information
• Relevant for other reasons
– It is easier to decide upon a treatment
when its impact on survival
is known
– Reimbursement issues
– Assessment in earlier disease stages
– Impact on drug development in general
OS as primary end point (or powered
for survival)
−
−
−
Adjuvant chemotherapy trials; eg, IALT
Chemoradiotherapy in NSCLC stage III
Most phase lll trials in advanced NSCLC
• Pemetrexed
• Bevacizumab (ECOG);
Cetuximab (FLEX); Necitumumab
(SQUIRE)
• Maintenance trials (pemetrexed,
erlotinib, gefitinib)
• Nintedanib
• Ramucirumab
• Nivolumab
• Pembrolizumab
A Trial That Looks for OS…
•
•
•
•
•
Takes too long
Requires large sample sizes
Is influenced by post-trial therapy if subsequent treatments are effective or detrimental
Is complex to analyse if there are too many salvage agents after trials
Is more expensive
• Reminder:
– RCTs only require large sample sizes when one is looking for small treatment
effects
– Larger trials can stop early with formal interim analysis if the treatment effect is
surprisingly large, and can also be stopped early if the success possibility is too low
(futility)
Korn E. J Clin Oncol. 2012.
Overall Survival Challenges
• Magnitude of the benefit
– Hazard ratio of 0.7-0.8
– Median benefit of 2-3 months
– Should be realistic and achievable
• Impact of further treatment (post-study therapy)
– Cannot be excluded
– Treatment lines beyond first line have fewer benefits
– No major imbalances in subsequent treatments among the arms in large
phase lll trials
• Role of crossover
– Is it really unethical to avoid crossover ?
ASCO Consensus: “OS Endpoint Is Important”
• OS is a feasible endpoint, though the OS benefit may be clouded by
subsequent therapies
• Clinical trials should aim to improve OS by >25%
ASCO stresses the use of the OS endpoint.
Agents not expected to provide such OS gain would no
longer be needed in clinical practice.
• Consensus (esp. the degree of benefit or HR) was arbitrarily determined by a
sample of clinical investigators, patient advocates, biostatisticians, US FDA
oncologists, industry oncologists. However, there is a lack of the sampling process
and a demonstration that the expert panel is representative of the general user or
beneficiaries of the treatment (excluding the financial beneficiaries).
http://www.asco.org/practice-research/clinically-meaningful-outcomes
ASCO Consensus: “OS Endpoint Is Important”
• OS is a feasible endpoint, though the OS benefit may be clouded by
subsequent therapies
• Clinical trials should aim to improve OS by >25%: Agents not expected to
provide such OS gain would no longer be needed in clinical practice
Ellis et al. J Clin Oncol. 2014.
ASCO Consensus: “OS Endpoint Is Important”? Exceptions
“Although OS was selected as the primary end point by all working
groups, this does not diminish the value of progression-free survival (PFS) and
other surrogate end points as valid end points in certain clinical situations.
“We are now able to identify secondary mutations that drive tumor growth after
progression during first-line targeted therapies. Although this information
provides an opportunity for success in second-line therapies, it also makes OS
a more difficult end point to attain. Thus, the use of PFS as a clinically
meaningful end point may be appropriate in particular disease settings and
has, in fact, been accepted by regulatory authorities on many occasions
already.”
http://www.asco.org/practice-research/clinically-meaningful-outcomes
How Recent New Agents Granted Approval in NSCLC? US FDA’s Decision
OS
Docetaxel
X
Pemetrexed
X
PFS
2nd L vs placebo, HR:0.484, +2.4M
RR, RD
+3.9 wks
Non-inferiority
X
Gefitinib
Erlotinib
X
2nd L vs placebo, HR:0.7, +2M
Afatinib
Bevacizumab
First line, non-inferiority
X
X (1st L)
No OS benefit shown in 1st line EGFR mut
X (1st L)
OS benefit only in subset (EGFR del19)
HR: 0.77, +2.3M
Only in one study
X
Crizotinib
No OS benefit shown, orphan drug designation
No OS benefit shown
Ceritinib
X
No OS benefit shown
Alectinib
X
No OS benefit shown
Osimertinib
X
Accelerated approval
Necitumumab
X
HR: 0.84, +1.6M
+0.2M
Ramucirumab
X
HR: 0.86, +1.4M
+1.5M
Nintedanib
X
HR: 0.75, +3 M (subset)
+0.7M (ITT)
Nivolumab
X
HR: 0.59, +3.2M (CM017)
HR: 0.73, +2.8M (CM057)
Pembrolizumab
X
HR: 0.61, +4.2M (10 mg/kg)
HR: 0.71, +1.9M (2 mg/kg)
Subset (adeno, progression <9M)
Accelerated approval first in PDL1+
OS: overall survival, PFS: progression-free survival, RR: response rate, RD: response duration
Nivolumab Second Line
OS, Total Population
Treatment Arm
Median
Rate at
(95% CI), mo
1y
HRa
(95% CI)
P
Pembro
2 mg/kg
10.4
(9.4-11.9)
43.2%
0.71
(0.58-0.88)
0.00076
Pembro
10 mg/kg
12.7
(10.0-17.3)
52.3%
0.61
(0.49-0.75)
<0.00001
Docetaxel
8.5 (7.5-9.8)
34.6%
—
—
Analysis cut-off date: September 30, 2015.
aComparison of
pembrolizumab vs docetaxel.
Moving on to Surrogates for OS…
 A measurement used in trials as an early
and adequate substitute for OS, like ORR
or PFS
Advantages of surrogate
markers:
– Can be measured earlier
– Convenient or less invasive
 An endpoint that is a surrogate for OS
would be helpful in addressing the
limitations of OS but must first be
validated by satisfying statistical criteria
 A growing belief in the oncology
community that delaying progression in
metastatic disease is a worthy goal, even
if OS is not improved
– Can be measured more frequently
– Can accelerate the approval process
– May reduce the size of clinical trials
– May shorten the duration of clinical
trials
– May reduce the cost of clinical trials
PFS as an Endpoint Has Potential Advantages
• Progression events occur early and more frequently than death events
• Less influenced by competing causes of death
• PFS is not influenced by post-progression therapy
• Faster time to drug approval
• Faster receipt by patients of novel therapies
• Less cost to manufacturer or sponsor
In Advanced NSCLC
PFS as primary endpoint (prolonged
PFS):
- Tyrosine kinase inhibitor trials in
selected patients
Saad, Katz. Ann Oncol. 2009; Burzykowski et al. JCO. 2008;
Shi et al. Int J Clin Oncol. 2009.
Use of PFS in the Contemporary Era
200
11
150
35
2
100
50
0
47
107
167
137
0
1975-1984
1985-1994
1995-2004
2005-2009
No. PUBLISHED RCT
Booth C. J Clin Oncol. 2012.
PFS AS PRIMARY ENDPOINT
Can PFS be Considered a Strong and Robust Surrogate Endpoint?
• Is a treatment that improves PFS really an advance for patients even if OS is not improved?
• How does PFS relate to patient benefit?
• Or is it only lowering the bar to declare efficacy and accelerate drug approval?
Buyse M. Stat Methods Med Res. 2008.
Booth C. J Clin Oncol. 2012.
Disadvantages of Using PFS
ASSESSMENT BIAS
The investigator may declare a patient in the control arm a progressor to get a patient on an active
experimental therapy ASAP
EVOLUTION-TIME BIAS
A suspected progression may be formally evaluated at a later time when patients are in one arm
rather than the other arm
THE EXACT TIME OF PROGRESSION IS UNKNOWN
It requires frequent radiologic assessment, which introduces imprecision
ATTRITION BIAS
More patients may withdraw from one arm than from the other arm
Challenges With PFS in Trials for Advanced NSCLC
• Placebo-controlled, double-blind studies are required but sometimes
impossible (eg, in cases of rash)
• Other challenges
– Progression without radiologic documentation
– Clinical deterioration without radiologic progression
– Missing data
• Sensitivity analyses are required to assess whether the results are robust
(Bhattacharya S et al. J Clin Oncol. 2009;27:5958)
• Problems are more pronounced when PFS is short
• Relevant for patient ?
– Only if associated with improved QoL (symptom relief) and absence of relevant
toxicity
– Magnitude of improvement in QoL becomes an issue
– Overall PFS is a soft endpoint
Phase III Trials Comparing TKI vs Conventional CT in
EGFR Mutation–positive NSCLC
Study
Control arm
Ethnicity
Rx evaluation
Independent review
PFS
LUX-Lung 3
(n=345)
Afatinib vs
Cis/Pem
Asian (71%)
Caucasian
6w
Yes
13.6 vs 6.9
11.1 vs 6.9
LUX-Lung 6
(n=364)
Afatinib vs
Cis/Gem
Asian
6w
Yes
11 vs 5.6
EURTAC
(n=174)
Erlotinib vs
CT
Caucasian
6w
Yes
10.4 vs 5.4
OPTIMAL
(N=165)
Erlotinib vs
Carb/Gem
Asian
6w
No
13.1 vs 4.6
WJTOG
(n=172)
Gefitinib vs
Cis/Doc
Asian
8w
No
9.6 vs 6.3
NEJ002
(n=230)
Gefitinib vs
Carb/Pacl
Asian
8w
Yes
10.8 vs 5.4
IPASS
(n=261)
Gefitinib vs
Carb/Pacl
Asian
6w
No
8.4 vs 6.7
SIGNAL
(n=42)
Gefitinib vs
Cis/Gem
Asian
9w
Yes
9.5 vs 6.3
Afatinib
Erlotinib
Gefitinib
Lines of Targeted Therapy and Overall Survival
Results From the IPASS Trial: Subgroup of EGFR Mutation-positive Pts (n=261)
Carboplatin/
paclitaxel (doublet
chemo) arm
Gefitinib
arm
2
PFS: 9.5 months
(median, 2010)
(median, 2008)
Chemotherapy
Months
EGFR TKI
PFS: 6.3 months
1
(median, 2008)
Months
PFS: HR 0.48, 95% CI 0.36-0.64, p<0.001
OS: HR 1.00, 95% CI 0.76-1.33
1. Mok et al. 2008.
2. Yang et al. 2010.
OS: 21.6 months
1
OS: 21.9 months
(median, 2010)
2
First Line Use of Afatinib vs Chemotherapy and
Survival in EGFR Del19 Subgroup
LUX-Lung 3
LUX-Lung 6
Afatinib Pem/Cis
n=112
n=57
Median,
months
HR
(95%CI),
p-value
Estimated OS probability
0.8
33.3
1.0
21.1
0.54 (0.36–0.79),
p=0.0015
0.6
0.4
HR
(95%CI),
p-value
18.4
0.64 (0.44–0.94),
p=0.0229
0.4
0.2
0
0
3 6
31.4
0.6
0.2
0
Median,
months
0.8
Estimated OS probability
1.0
Afatinib Gem/Cis
n=124
n=62
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45
Time (months)
Time (months)
No of patients
No of patients
Afatinib
112 108 105 102 96 93 83 80 72 62 58 51 34 30 21
6
1
0
Afatinib
124 122 118 115 106 99
90
80
73
69
59
39
16
8
1
0
Pem/Cis
57 55 50 46 43 37 33 27 25 22 20 16 10
1
0
0
Gem/Cis
62
30
28
26
21
18
11
4
3
0
0
Presented by: James Chih-Hsin Yang
6
1
58
53
49
44
35
Yang JC et al. Lancet Oncology. 2015
What Is the True Definition of Meaningful Clinical Benefit?
• 68 year old lady, T3N1M0, diagnosed with T3N1M0IIIA adenocarcinoma of
lung in 2004, after surgery, she received 4 cycles of paclitaxel and carboplatin
• Recurrence in 2007/Oct with multiple lung mets, EGFR L858R+
• Afatinib started 2007/Oct/15 (Lux-Lung-2), progression 2015/July/10, cycle
101
• Afatinib continued beyond progression until 2015/Dec/14
2007/Oct
2015/July/10
2015/Dec/14
PATIENT-REPORTED OUTCOMES (PRO)
Are PRO Measures Underappreciated and Underused in Oncology?
• PRO address more than just symptoms
• Direct measures of patient benefit, they can be considered independent
endpoints
• This approach is especially useful in trials of drugs for patients with incurable
cancers, in which one of the main goals is to improve palliation of symptoms
• Only 1/3 of phase III breast cancer trials registered with US NIH have collected
or are presently collecting PRO
For more on PROs, stay tuned
for Dr. Silvia Novello’s talk
Wilson et al. Lancet Oncol. 2015.
Some Recent Observations and Future Trends
• PFS is proving more challenging to employ as a regulatory endpoint
– However, it will continue to have a future potential role in oncology drug registration
if rigorous acceptance criteria and standards are met
• There will be increasing regulatory pressure to link or associate PFS benefits
with other clinical trial outcomes that show direct clinical benefit (e.g. QoL
benefits, disease-related symptom benefits, OS positive trends)
– PFS may have its best future applications in symptomatic disease settings and/or
where delay in disease progression correlates with delay in symptom onset
– Benefit of delay of progression may also be measured by assessing QoL benefits
pre- vs post-progression, independent of study arm
New Challenges in Endpoint Selection for New Therapies
• INMUNOTHERAPY
– Pseudo-progression effect: go vs no-go decision
– Survival benefit in the absence of significant responses, or very significant PFS
• PERSONALISED THERAPIES
– Intra-patient heterogeneity
– How to deal with
• Brain mets
• Single-site progression
• Benefit beyond progression
• WILL WE BE ABLE TO DEFINE THE BEST SEQUENCING?
Accelerated Approval for Breakthrough Medications
•
•
•
•
•
Orphan drug designation
Breakthrough treatment designation (based on scientific and clinical evidence)
Expedited review
Accelerated approval (based on response and response duration)
Full approval (based on phase III studies comparing PFS, OS)
Development of Reliable Endpoints to Allow an Early Recognition of Clinical
Benefit
Wilson et al. Lancet Oncol. 2015.
3rd G Osimertinib: EGFR TKI failure T790M+ NSCLC Patients
Specific Inhibitor to T790M and Activating Mutations
AURA Ph I
80
40
20
0
–20
–40
–60
–80
–100
100
Best percentage change from baseline in
target lesion size (%)
Best percentage change from baseline in
target lesion size (%)
100
AURA pooled Ph II
80
60
40
20
*********
0
–20
Complete response
Partial response
Stable disease
Progressive disease
Not evaluable
–40
–60
–80
–100
Complete response
Partial response
Stable disease
Progressive disease
Not evaluable
AURA Ph I (80 mg)
N=61
Confirmed ORR
71%
(95% CI 57, 82)
Disease control rate†
93%
(95% CI 84, 98)
Best objective response
Complete response
Partial response
Stable disease ≥6 weeks
Progressive disease
1
42
14
2
• AURA Ph I data cut-off 4 January 2016;
population: evaluable for response set;
assessment: investigator assessed;
• AURA pooled Ph II data cut-off 1
November 2015; population: evaluable
for response set; assessment: BICR
• *Represents imputed values: if it is
known that the patient has died, has
AURA pooled Ph II (80 mg)
new lesions or progression of nonN=397
target lesions, has withdrawn due to
• disease progression, and has no
66%
evaluable target lesion (before or at
(95% CI 61, 71)
progression) assessments, best
change will be imputed as 20%.
91%
†
(95% CI 88, 94) • Complete response, partial response,
stable disease ≥6 weeks.
•
6
ORR, objective response rate; CI,
256
confidence interval.
99
25
EUROPEAN LUNG CANCER CONFERENCE 2016
Yang JC et al.
When to Use 3rd-Generation EGFR TKI?
(Targeted Therapy)
Gefitinib
Erlotinib
Afatinib
Pemetrexed 2nd-line CT
platinum
Docetaxel
3rd-generation
EGFR TKI
AURA-ext; AURA2
AURA-ext; AURA2
AURA3; ELUXA2
Other EGFR TKI+
cMETi or anti-PD1
1st-line
3rd-generation EGFR TKI
FLAURA, SOLAR
Resistance
Mechanism
Overall Survival?
Phase IIb/III Trial of Afatinib (BIBW 2992) + Best Supportive Care (BSC) vs Placebo +
BSC in Patients Failing 1–2 lines of CT and Erlotinib/Gefitinib (LUX-Lung 1)
Endpoints
Patients
• Chemo-naïve
• Life
expectancy
≥12 weeks
• PS
BIBW2992
BSC
IIIB/IV disease
2:1 randomisation
• Failed
1 or 2 lines of
chemotherapy
• Failed
Placebo
• Used
BSC
to gefitinib or
erlotinib
gefitinib or erlotinib
for more than 3 months
Miller VA, Yang JC. Lancet Oncol. 2012;13(5):528-38.
• Overall Survival Time
Secondary
0-2
• Stage
Primary
Progression-free Survival Time
Objective Response Rate (according
to RECIST)
Duration of Clinical Benefit (CR,
PR, SD)
Time to Objective Response
Duration of Objective Response
Safety of BIBW 2992
PK parameters
Health-related Quality of Life
LUX-Lung 1: Afatinib vs Placebo in 3rd/4th-line
Efficacy Shown in PFS, but Salvage Agents Were Equally Effective
Overall Survival
Miller VA, Yang JC. Lancet Oncol. 2012;13(5):528-38.
PFS
LUX-Lung 5, 4th/5th-line Study
Afatinib + Paclitaxel vs Chemotherapy
PFS
Schuler M et al. Annals of Oncology, 2016;27:417-423.
OS
MOLECULAR ONCOLOGY…NEW TRIAL ENDPOINTS
Buyse M. et al. Nat Rev Clin Oncol. 2010.
TREATMENTS
ENDPOINTS
Signal transduction
inhibitors
Effect on molecular
target
Gene expression
modulators
Circulating tumour cells
Angiogenesis inhibitor
Circulating tumour DNA
Immunotherapies
Functional imaging
Key Guidelines for Clinical Trial Endpoint Selection
The decision should always be related to:
• The patient subpopulation of interest
• The stage of disease (depends on the type of cancer)
• The characteristics of the treatment (toxicity, efficacy)
• The aims of the trial (superiority/noninferiority/safety)
• The other treatments already available to that group of patients
• Ethics
• Practical feasibility (costs, logistics…)