Challenges and pitfalls in designing clinical
trials in the CNS metastases field.
Dr. Thierry Gorlia, PhDEORTC Lead
Statistician
Factors influencing the choice of endpoints
• Patients with solid tumors may differ in prognosis and competing risk of extracranial progression.
• The trial setting (Phase II (response) vs Phase III trials (PFS/OS)
• Type of intervention (CNS-directed vs systemic therapies, RT vs CT)
Requiring ad hoc end points.
Soffietti R. et al. CNS Oncol. 2017 Oct;6(4):243-246.
Specifics of trials for brain metastases
• Goal is rarely improvement in survival, as most patients die of extracranial disease
• Most assessed treatments are local treatments targeting the brain disease• Prophylactic treatment (e.g. PCI in M0) à goal is to prevent occurrence of brain metastases• Palliative treatment (brain metastases in place) à goal is often to preserve function and/or reduce the risk of
progression of brain disease
Specifics of trials for brain metastases
• Other disease sites (primary or other metastases)• either in place (and controlled)• or removed prior to entry in the trial
àCompeting risks: progression elsewhere in the body may cause the patient to die (of cancer) without disease evolution inside the brain
àHeterogeneity of outcomes according to the type of primary & by treatments given to control other sites of PD (often assumed not to cross BB-barrier)
• Small risk that the patient dies of a cause unrelated to cancer (rare)
Specific role of prognostic factors
• The knowledge of prognostic factors is critical in order to identify subgroups of patients with different outcomes
• As stratification factor or inclusion criteria or adjustment factors in analyses.
Sperduto PW et a. JAMA Oncol. 2017;3(6):827-831.
Lung-molGP
Key issues in imaging brain metastases
• Modalities and frequency of assessment, • Type and magnitude of change used to define response or
progression of disease, • The incorporation of steroid use and neurological
symptoms/signs• The ability to differentiate tumor-related and treatment-related
changes• The interlesional variability of response to treatment can render
problematic the evaluation of response in multiple metastasesSoffietti R. et al. CNS Oncol. 2017 Oct;6(4):243-246.
Past experience within EORTC
• EORTC 22993-08993: PCI in ED NSCLC (Slotman et al. NEJM 2007 &
JCO 2008)
• EORTC 22952-26001: WBRT for 1-3 brain mets from solid tumor after
resection or radio-surgery (Kocher JCO 2011, Soffietti submitted to JCO)
• Design of SIB trial (22111-26111)
• Design for testing Sunitinib combined with WBRT in brain mets of breast
cancer not suitable for resection (10095)
• Earlier phase II studies by Postmus et al. (08841, 08873…) in SCLC
(WBRT, Teniposide, Etoposide); PCI study with EULINT group…
Possible endpoints
« Global » endpoints• Overall survival• Progression-free survival (all disease sites)
« Brain-specific » endpoints• Incidence of (symptomatic) brain mets (if prophylactic)• (Symptomatic) progression of metastases (if therapeutic)
« Quality of living » endpoints• Survival with WHO PS ≤ 2 (or KPS≥70) “independent life”• Neurological function scores• Quality of life, ...
? Sensitivity to brain trt effects
? Relevance if no effect on symptoms/QoL
? Reliability of measurements, drop outs, biases
EORTC 22993-08993: Phase III of PCI* in Extensive Disease SCLC
l Cytologically or histologically proven SCLCl Response after 4 to 6 cycles of initial
chemotherapyl No evidence of brain metastases
or leptomeningeal metastasesl No prior radiotherapy to the brain and head and
neck areal No use of corticosteroidsl 18 £ Age£ 75 years, WHO PS £ 2
l Primary endpoint: time to symptomatic brain metastases
l Secondary endpoint: l Quality of life and MMSEl OSl Time to extracranial PDl FFS** (any PD or death)l Acute toxicity
PCI*
No furtherradiotherapy
RandomInduction
Chemotherapy(4-6 cycles)
Response
5 weeks*PCI: Prophylactic cranial irradiation; **FFS: Failure Free Survival
Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Protocol statistical considerations
• It is expected that without PCI, 40% of the patients develop brain metastases within 3 year.
• To demonstrate decrease in rate of symptomatic brain metsfrom 40% at 3 years to 20% (HR=0.44, 2-sided a=0.05, power 80%) à 50 events of symptomatic BM needed.
• Anticipating 40% death rate by year 3à 287 patients are planned to enter to get the 50 events needed.Visits after baseline: at 6 wks, 3 months, 6 months, 9 months and 12 months
then q6 months + QLQ-C30 and BN20 at each visitSlotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Overall Survival in control group
(months)0 4 8 12 16 20 24 28 32 36
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment125 143 90 43 15 3 2 1 0 0 Control
At 6 m44.6%
At 1 y13.3%
Control At 3 y.. 0%
Assumed 40% dead by year 3àway too optimistic à40% dead by month 4!
%
Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Symptomatic BM in control group
(months)0 4 8 12 16 20 24 28 32 36
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment59 143 74 36 11 2 1 1 0 0 Control
At 6 m32.0%
At 1 yr40.4% Control
Assumed 40% by year 3à 40% reached by year 1 already!
Flat because nobody alive without PD elsewhere
%
Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Follow-up schedule
(months)0 3 6 9 12 15 18 21 24
0102030405060708090
100
O N Number of patients at risk : Treatment125 143 115 58 36 15 3 2 1 Control
à QoL analyzable only to month 9à More exams in 3-9m would have been useful
%
Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Compliance to QoL: drop outs!
N alive/arm
% forms completed
Baseline 140 93.7%At 6 weeks 60.0%At 3 months 110 54.5%At 6 months 60 60.8%At 9 months 35 46.3%At 1 year 15 48.9%
Missing/drop outs ~ 40%Upon symptomatic BM?
Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Cumulative incidence of symptomatic BM
(months)0 4 8 12 16 20 24 28 32 36
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment59 143 74 36 11 2 1 1 0 024 143 97 48 24 12 5 3 2 2
ControlPCI
PCI
Control
• More exams early when trt effect on BM appears• Study should have been monitored more closely, à we may have done with less patients as events accumulated faster than planned
%
Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.
Failure-free survival
(months)0 3 6 9 12 15 18 21 24 27
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment
137 143 62 20 8 1 1 0 0 0129 143 79 30 13 6 3 3 2 1
ControlPCI
Hazard Ratio: 0.76 (95%CI: 0.59, 0.96)Median: 12.2w à 14.8w (+2.6w)
15.5%
At 6 m23.4%
Logrank P=0.022
PCI
Control
à More meaningful to patients?à Less sensitive to treatment effects,à esp.if PD at other sites before sympt BM
%
EORTC 22952-26001: No RT vs WBI for 1-3 brain metastases from solid tumor after surgical
resection (Sx) or radiosurgery (RSx). l Primary endpoint: Time to deterioration of the WHO
PS to WHO PS> 2 (= Survival with WHO PS£2)l Secondary endpoints: OS, QoL, PFS, Time to
neurological progressionEligibility:l 1 or 2 (or 3) BM within 3 weeks of (radio)surgeryl Stable systemic cancer for the last 3 months (= absence
of symptomatic and radiologic progression outside the brain)ORAsymptomatic synchronous primary tumor without metastases outside the CNS, or patients with unknown primary tumor
• Complete resection of brain mets or for RS, mets than can be radioresected
RadioSurg
No further RT
WBI
Surgery
No further RT
WBI
OR
R
R
Kocher M et al. J Clin Oncol. 2011 Jan 10;29(2):134-41
EORTC 22952-26001:Trial sample size and objectives
l To show that WBI improves the survival with PS £ 2 @6m from 50% to 61% (HR=0.71)
à 280 events (death OR WHO PS>2)
l However, as the event rate in the control arm was LOWER than anticipated (40% @6m instead of 50%), the total number of patients was increased from 340 in the original protocol to 359 (to observe the total number of events).
Adequate study monitoring à identified drop outsà prevented to close the trial with only few patients in follow-up, having to wait trial results “forever”à 280/340 : little room for the happy few and drop outs
Kocher M et al. J Clin Oncol. 2011 Jan 10;29(2):134-41
22952-26001: Survival results
HR = 0.96 (CI: 0.76–1.20)P=0.71
63.0% (95%CI: 55.4-69.6)66.9% (95%CI: 59.4-73.2)
HR = 0.98 95%CI: 0.78–1.24)P=0.89
66.2% (95%CI: 58.8-72.7)70.2% (95%CI: 62.9-76.4)
(months)0 6 12 18 24 30 36 42 48 54 60 66
0
10
20
30
40
50
60
70
80
90
100
Treatmentno RTWBI
Survival with PS<=2
%
(months)0 6 12 18 24 30 36 42 48 54 60 66
0
10
20
30
40
50
60
70
80
90
100Overall Survival
%
Treatmentno RTWBI
66.9% OS with PS£2 vs 70.2% OS and 63.0 % OS with PS£2 vs 66.2% OS
àWHO PS>2 accounts for
only 3-4% of events @6m
àMissing reports of WHO
PS at last visits? Infrequent
visits?
Kocher M et al. J Clin Oncol. 2011 Jan 10;29(2):134-41
= first event ofWHO PS>2Death with PS£2
Time to intracranial progressionCompeting Risks: death, extracranial progression
Time to extracranial progressionCompeting Risks: death
22952-26001:Time to intra/extra cranial PD
(months)0 6 12 18 24 30 36 42 48 54 60 66
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment100 179 47 21 13 10 6 5 4 3 2 260 180 75 36 24 17 14 11 8 8 5 3
no RTWBI
CI of 22952: Time to intracranial progressionCompeting Risks: Death, Extracranial progression
%
Gray test: p<0.0001
54.2% (95%CI: 46.9-61.5)
31.2% (95%CI: 24.3-38.0)
(months)0 6 12 18 24 30 36 42 48 54 60 66
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment111 179 75 40 22 16 11 8 7 6 4 2110 180 87 51 35 23 17 13 9 8 5 3
no RTWBI
CI of 22952: Time to systemic progressionCompeting Risk. Death
%
Gray test: p=0.96
60.5% (95%CI: 53.2-67.8)
60.3% (95%CI: 53.0-67.5)
à Relevant endpoint if symptoms not relieved? (no QOL benefit seen)
à Extracranial PD very early àalso impacts WHO PS and OS.
Kocher M et al. J Clin Oncol. 2011 Jan 10;29(2):134-41
Progression Free Survival
Meaningful to patients ?Sensitive to trt effects, (if PD at other sites first)?
26.3%
42.2%
WBI
no RT
HR = 0.71 (CI: 0.58 – 0.88), P=0.002
Median: 20.0w (95%CI: 17.0-.26.5)Median: 14.8w (95%CI: 13.5-17.0)
=+5weeks
(months)0 6 12 18 24 30 36 42 48 54 60 66
0
10
20
30
40
50
60
70
80
90
100
%
PFS = first event ofIntracranial PDExtracranial PDDeath in absence of PD
Sequence of events in 2295210-14% death as first event32-46% with PD outside brain as first eventà 40-50% « other events »à Will not be affected by BM treatmentà sets a “cap” on benefit that can be expected
PFS-6 will never be > 50-60% even if eradicating BM.
Same mechanism for alive with WHO PS£2
Important elements to consider for TTE endpoints
• Frequency of assessment should be min Δmedians/2 (eg: to detect a 3 month shift: 6 weekly assessments)
• Impact of compliance to schedule à systematic deviations from schedule may cause artificial differences in survival curves
• Open label studies à risk of bias towards earlier assessments and diagnosis of PD (WHO PS worsening) in the arm with no/less treatment of the brain?
Impact of deviations from schedule
Both treatment groups are scheduled to have outcome assessments every 8 weeks; however, Drug B has an average delay of 5 days at each assessment time. Both groups have an actual median progression-free survival (PFS) of 18 weeks; however, the reported PFS of Drug B is clearly better, only because of the increased time to each assessment
BA
Gignac GA et al. Cancer 2008; 113(5): 966-74
“Quality endpoints”
• Subjective endpoints: QOL, WHO PS, Neurological function?• Blinding not possible
Assessment by a staff unaware of the treatment received?• Inter-rater variations? (eg: WHO>2 vs KPS<70 vs NFS?)• Influence of factors other PD and protocol treatment? (steroids,
anti epileptics on NF etc..)• Most sensitive and specific tools? (not MMSE)
• Neurologic Assessment in Neuro-Oncology (NANO) or PRO approach, such as the MD Anderson Symptom Inventory Brain Tumor Module.
• Prospective collection on seizures.
“Quality endpoints”
• Patient’s drop off before assessment• Eg: 22952: paradoxical impression that worse WHO PS at
baseline à better compliance (because QOL until endpoint reached, and endpoint includes WHO PS…)
• Impact of tumor site and disease load at baseline à different baseline scores, different timing of event à stratification needed
Design of new studies
• Stratification factors: RPA, site of primary, tumor load• Endpoints:
• Clinically meaningful• Uniformly assessed (as much as can be)• Keep biases away (by “pseudo-blinding”)
• Frequency of assessment: more intense early on, less than the difference to detect.
Design of new studies
• Compliance to scheduled assessments is crucial!• Assumptions underlying sample size & target difference
• Mind the “cap effect” due to competing risks• Monitor hypotheses, drop outs and competing risks during
study
Thank you
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