Transcript Diapositive 1

Individual Patient Data Analysis of Progression-Free versus Overall Survival as an Endpoint for
Metastatic Colorectal Cancer in Modern Trials: Findings from the 16,700 Patient ARCAD Database
Q Shi1, A de Gramont2, M Buyse3, A Grothey1, H-J Schmoll4, MT Seymour5, R Adams6, L Saltz7, RM Goldberg8, CJA Punt9, J-Y Douillard10, JR Hecht11, H Hurwitz12,
E Diaz-Rubio13, Pr R Proschen14, NC Tebbutt15, C Fuchs16, J Souglakos17, A Falcone18, DJ Sargent1, For the ARCAD Group
1Mayo
Clinic, Rochester MN; 2Hospital Saint Antoine, Paris, France; 3International Drug Development Institute, Louvain-la-Neuve, Belgium; 4Martin-Luther University, Halle, Germany; 5Cancer Rsrch UK Clinical Ctr, Leeds, UK; 6Cardiff University, Cardiff, UK; 7Memory Sloan Kettering Cancer Center, New
York, NY; 8Ohio State University Comprehensive Cancer Center, Columbus, OH; 9Academic Medical Center, Amsterdam, Netherlands; 10Centre R Gauducheau, St Herblain, France; 11David Geffen School of Medicine at UCLA, Los Angeles, CA; 12Duke University Medical Center, Durham, NC; 13Hospital
Clinico San Carlos, Madrid, Spain; 14Klinikum Bremen-Ost, Bremen, Germany; 15Austin Health, Australia; 16Dana Farber Cancer Institution, Boston, MA; 17 University of Crete, School of Medicine, Heraklion, Greece; 18University Hospital “S. Chiara”, Pisa, Italy
ABSTRACT
METHODS
Background:
Progression-free survival (PFS) has previously been established as a
surrogate for overall survival (OS) based on individual patient data
(IPD) from 1st line metastatic colorectal cancer )mCRC) trials
conducted before 1999. As mCRC treatment (trt) has advanced in the
last decade and OS has increased from 1 to 2 years, this surrogacy
required re-examination.
Trial Selection and Patient Characteristics
• 22 trials and 43 comparisons were included
• Two of 24 1st line trials in ARCAD with regimens
identical in both arms before 1st PD were excluded
• Trials with multiple arms were prospectively defined to
generate two-arms comparisons
• Where KRAS available, KRAS wildtype vs. mutated
patients were treated as 2 separate comparisons
• Trials with regimens identical in both arms before 1st
progressive disease (PD) were excluded
• The non-reported cohorts were included and treated as
separate comparisons
• Total of 16,762 patients were included
• Age: 14% < 50; 26% 50 – 59; 35% 60 – 69; 25% ≥ 70
• ECOG PS: 53% 0; 42% 1; 5% 2+
• Gender: 61% male; 39% female
• Regimen: 44% targeted; 56% non-targeted
Endpoint Definitions
• OS – Time from randomization to death due to any cause
• PFS – Time from randomization to 1st PD or death due to
any cause
• When possible, PFS centrally redefined to allow
consistent calculations across trials
Statistical Methods
• Patient level
• Landmark analysis (evaluating prognostic value of
PFS at 6 and 12 months for OS)
• Rank correlation coefficient, ρ, between PFS and OS
(Copula bivariate survival model)
• Treatment arm level
• Correlation between short-term (6 months) PFS rates
and long-term (12 & 18 months) OS rates
• Estimated based on Kaplan-Meier estimates
• Coefficient of determination from weighted least
square (WLS) linear regression, r2WLS
• Trial (i.e. comparison) level
• Correlation between hazard ratios (HRs) on PFS and
OS – Coefficient of determination from linear
regression based on HRs estimated by
• Cox model (& WLS regression), R2WLS
• Copula bivariate survival model, R2Copula
• Concordance of significance of the treatment effect
Methods:
IPD from 16,762 pts, median age 62, 62% male, 53% ECOG PS 0
were available from 22 1st line mCRC studies conducted from 19972006; 12 tested targeted (anti-angiogenic and/or anti-EGFR)
regimens. The relationship between PFS (first event of progression
or death) and OS was evaluated at patient-, trt-arm-, and trial-levels
using correlation (corr.) coefficients and R2 (closer to 1 the better)
from weighted least square (WLS) regression of arm-specific
survival rates and trial-specific hazard ratios (HRs), estimated using
Cox and Copula bivariate models. The concordance of significance
(CoS) of the treatment effects (TEs) on both endpoints was
calculated.
Results:
44% pts received a targeted regimen. Median PFS was 8 and OS
was18 months. The corr. between PFS and OS was modest at all
three levels with low CoS in TE comparisons (see Table). Analyses
limited to trials testing targeted trts, non-strategy trials, or superiority
trials did not improve surrogacy.
Conclusion:
In modern mCRC trials, where survival post-first progression
exceeds time to first progression, PFS TEs do not reliably predict
TEs on OS. Nonetheless, until alternative endpoints of clinical
benefit can be validated, PFS remains a relevant primary endpoint for
1st line mCRC trials, as our data demonstrate that the ability for any
agent to produce an OS benefit from a single line of therapy is
challenging.
HYPOTHESES
• Short-term PFS predicts the clinical benefit
on long-term OS at the patient-level
• Treatment effect measured on PFS predicts
the treatment effect on OS at trial-level
• Type of treatment (targeted vs. non-targeted)
affects the predictive relationship between
PFS and OS
• Superiority trials will have stronger PFS/OS
surrogacy than strategy/non-inferiority trials
RESULTS
Table 1: Trials Included
Comp. Study [Year]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
C97-3 [1997]
N9741 [1999]
AVF2192g [2000]
AVF2107g [2000]
HORG [2000]
GONO [2001]
03-TTD-01 [2002]
AIO22 [2002]
HORIZON II
[2005]
CAIRO1 [2003]
BICC-C [2003]
FOCUS2 [2004]
C: 5FULV+Placebo; E: 5FULV+Bev
C: IFL+Placebo; E: IFL+Bev
C: IFL+Placebo; E: 5FULV+Bev
C: FOLFIRI; E: FOLFOXIRI
C: FOLFIRI; E: FOLFOXIRI
C: FUOX; E: XELOX
C: CAPOX; E: FUFOX
C: FOLFOX/CAPOX+placebo
E: FOLFOX/CAPOX+Cediranib20mg
C: FOLFOX/CAPOX+placebo
E: FOLFOX/CAPOX+Cediranib30mg
C: CapIRICap+Bev; E:
Cap+IRICap+Bev
C: FOLFIRI; E: mIFL
C: FOLFIRI+Bev; E: mIFL+Bev
C: FOLFIRI; E: CapeIRI
C: 5FULV; E: 5FULV+OX
C: Cap; E: Cap+OX
C: FOLFOX4+Bev; E: XELOX+Bev
C: XELOX+placebo; E: XELOX+Bev
C: FOLFOX4+placebo; E: FOLFOX4+Bev
FIRE II [2004]
30
PACCE [2005]
31
32
33
COIN [2005]
34
35
CAIRO2 [2005]
36
37
38
MAX [2005]
39
Macro [2006]
40
PRIME [2006]
41
43
C: FUIRI; E: FU+IRI
C: FUIRI; E: FU+OX
C: FOLFOX4+placebo; E: XELOX+placebo
29
42
C: FOLFIRIFOLFOX6; E:
FOLFOX6FOLFIRI
C: IFL; E: FOLFOX
C: IFL; E: IROX
C: rIFL; E: FOLFOX
C: FOLFOX4; E: XELOX
NO16966 [2003]
HORIZON III
[2006]
Figure 1: Overall Treatment arm and Trial-level Surrogacy
Sample
Strategy
Treatment assignments at randomization size
Regimen type study1 Design2
C: rIFL; E: IROX
FOCUS [2000]
FINDINGS
C: Cetuximab+CAPIRI; E:
Cetuximab+CAPOX
C: Bev+OX (KRAS WT);
E: Bev+OX+Pmab (KRAS WT)
C: Bev+OX (KRAS MT)
E: Bev+OX+Pmab (KRAS MT)
C: Bev+IRI (KRAS WT)
E: Bev+IRI+Pmab (KRAS WT)
C: Bev+IRI (KRAS MT)
E: Bev+IRI+Pmab (KRAS MT)
C: 5FULv/Cap+OX (KRAS WT)
E: 5FULv/Cap+OX+Cetuximab (KRAS WT)
C: 5FULv/Cap+OX (KRAS MT)
E: 5FULv/Cap+OX+Cetuximab (KRAS MT)
C: Cap+OX+Bev (KRAS WT)
E: Cap+OX+Bev+Cetuximab (KRAS WT)
C: Cap+OX+Bev (KRAS MT)
E: Cap+OX+Bev+Cetuximab (KRAS MT)
C: Cap; E: Cap+Bev
C: Cap; E: Cap+Bev+Mitomycin
C: XELOX+BevXELOX+Bev
E: XELOX+BevBev
C: FOLFOX4 (KRAS WT)
E: FOLFOX4+Pmab (KRAS WT)
C: FOLFOX4 (KRAS MT)
E: FOLFOX4+Pmab (KRAS MT)
C: mFOLFOX6+Bev
E: mFOLFOX6+Cediranib20mg
C: mFOLFOX6+Bev
E: mFOLFOX6+Cediranib30mg
220
NT
Y
NI
531
528
304
269
1058
1057
209
813
220
283
244
348
474
NT
NT
NT
NT
NT
NT
ANG
ANG
ANG
NT
NT
NT
NT
N
N
N
N
Y
Y
N
N
N
N
N
N
N
Sup
Sup
Sup
Sup
Sup
Sup
Sup
Sup
Sup
Sup
Sup
NI
NI
860
ANG
N
Sup
432
ANG
N
Sup
803
ANG
Y
Sup
285
117
289
230
229
634
701
699
700
700
NT
ANG
NT
NT
NT
NT
NT
ANG
ANG
ANG
N
N
N
N
N
N
N
N
N
N
NI
NI
NI
Sup
Sup
NI
NI
NI
Sup
Sup
177
EGFR
N
NI
408
ANG + EGFR
N
Sup
262
ANG + EGFR
N
Sup
116
ANG + EGFR
N
Sup
89
ANG + EGFR
N
Sup
729
EGFR
N
Sup
565
EGFR
N
Sup
316
ANG + EGFR
N
Sup
204
ANG + EGFR
N
Sup
313
314
ANG
ANG
N
N
Sup
Sup
480
ANG
N
NI
656
EGFR
N
Sup
440
EGFR
N
Sup
1409
ANG
N
Sup
380
ANG
N
Sup
Abbreviations: C, control arm; E, experimental arm; IRI, irinotecan; OX, oxaliplatin; LV, leucovorin; Bev, bevacizumab; Cap,
capecitabine; Pmab, Pamtumumab; WT, wild type; MT, mutated; T, targeted; NT, non-targeted; ANG, Anti-angiogenic regimen; EGFR,
Anti-EGFR regimen; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; PD, progressive disease
1.Cross-over reflects the actual cross-over from one arm to another due to toxicity, PD and other reasons.
2Strategy trial refers more treatment specified by protocol beyond the first per protocol regimen. For example, a sequence of treatment was
specified per protocol (i.e., the treatment effect of a whole strategy of experimental arm is compared to the control arm), or cross over
after PD was specified per protocol. For these studies, the PFS (1st PD-PFS) with the 1st PD occurred during study follow-up as one of the
events may not be the appropriate endpoint if the regimen before 1st PD was same for both experimental and control arms.
3The design refers to the intended primary comparison between arms, i.e., non-inferiority (NI) or superiority (Sup) comparison. The
statistical sample size/power consideration section may not reflect NI or Sup design.
• Although early PFS rate is a strong predictor of
long-term OS (patient level landmark analysis),
treatment effects observed on PFS at the triallevel do not provide sufficiently accurate
prediction of treatment effect on OS in the firstline advanced CRC trials.
• Trials testing targeted therapies demonstrated
only modestly higher PFS/OS correlations at
patient-, treatment arm, and trial-level between
PFS and OS than non-targeted trials.
• Restricting to non-strategy trials, overall results
remain: correlation measures between PFS and
OS by treatment arm and at trial-level improved
by ~ 0.1 in absolute values.
• Restricting trials with superiority design, the
above results remain.
• Excluding one outlier improved the correlation
measures only slightly
DISCUSSION
Table 2: Surrogacy Estimation
Class (n. of Comp.)
Overall (22)
Patient level
Rank corr. ρ
.51 (.50 - .52)
Treatment arm level [6m PFS vs. 12m OS rates]
r2WLS
.69 (.58 - .79)
Trial level [HRPFS vs. HROS]
R2WLS
.54 (.33 - .75)
R2Copula
.46 (.24 - .68)
Concordance of conclusions
67%
Targeted (12)
Non-strategy (18)
Superiority (16)
.55 (.54 - .56)
.53 (.52 - .54)
.51 (.50 - .52)
.70 (.48 - .91)
.73 (.62 - .83)
.71 (.59 - .83)
.52 (.24 - .80)
.45 (.16 - .75)
64%
.54 (.32 - .76)
.48 (.24 - .71)
68%
.51 (.24 - .77)
.54 (.31 - .78)
63%
• PFS has its own merits as an endpoint, and is
considered by some a clinical benefit endpoint.
However, based on modern trials, PFS treatment
effects do not reliably translate into treatment
effects on OS.
• The lack of association between PFS and OS in
modern trials is likely due to extensive use of
later-line therapies.
• The lack of ability for PFS to predict OS
emphasizes rather than detracts from its
importance as a clinical trials endpoint to
demonstrate activity of a new agent.
• PFS remains a relevant primary endpoint for 1st
line mCRC trials, as our data demonstrate that
the ability for any agent to produce an OS benefit
from a single line of therapy is challenging.