EXTENT OF TUMOR RESPONSE: DOES IT MATTER?
WHAT DOES EARLY TUMOR SHRINKAGE (ETS)
MEAN?
Elena Elez, MD, PhD
Gastrointestinal Cancer and Developmental Therapeutics Program
Vall d’Hebron Institute of Oncology
[email protected]
WHY TALKING ABOUT ETS
•
Resources must be optimized for
succesful development of better
treatment options in mCRC
•
Need to develop better efficacy
endpoints
that
could
provide
guidance wether it is fair to continue
developing a new drug or treatment
based on the data generated in
small proof-of-efficacy
•
PFS realy correlates with OS?
Discordant data obtained from large
phase III trials
Tabernero J, venook A. J Clin Oncol 2014
Einstein discovers that time is
actually money
DRUG DEVELOPMENT CHANGING PARADIGM
o
o
o
o
Phase I
Phase II
Phase III
Safety, tolerability
Pharmacokinetics
Pharmacodynamics
Preliminary antitumor
activity
o Efficacy observed in
selected tumor types,
e.g. ORR, TTP, PFS
o Meaningful benefit obtained in
a randomized setting against
existent standard e.g. OS
Phase 1 trials
Proof of Mechanism
Proof of Concept
Early
Late
o Safety, tolerability – on target
and off target effects
o Predictive biomarkers
explored
o Predictive biomarkers
confirmed
o Preliminary antitumor activity
o Antitumor activity seen
using surrogate
endpoints e.g. ORR,
TTP or PFS
o Proof of concept using a
validated clinical
endpoint e.g. OS
o Evidence of target engagement
in valid pharmacodynamic
biomarkers
Adapted slide courtesy J Rodon
ETS IS NOT A NEW CONCEPT
ETS IS NOT A NEW CONCEPT
• Evaluation Responders (CR, PR) vs non responders (PD, SD).
• Stable disease would include a tumor shrinkage from 0 to 29% and a PD
from 1 to 19%
Grothey et al. J Clin Oncol 2008
ETS IS NOT A NEW CONCEPT
• ARCAD group database analysis
of Early Objective Tumor
Response:
– 11.987 patients analyzed
across 15 front line randomized
trials
– Significantly longer mOS in ETS
patients at 6, 8 and 12 weeks
– Suggest early objective tumor
response as a predictor for PFS
and OS.
Sommeijer DW et al. ASCO 2013
ETS IS NOT A NEW CONCEPT
Total tumor burden assessed by RECIST 1.0 in 468 patients every 6 weeks (+/3weeks)
Zhao et al. ASCO 2013
ETS: CONCEPT
BASELINE = 100%
% DECREASE
6-8 WEEKS
TUMOR LOAD
ETS =
6 – 8 WEEKS
TIME
•
ETS is a continuous parameter that represents the percent decrease of tumor load at a given
time (week 6-8)
•
It can be categorized by introducing a cut-off value that has been published as 10% or 20%
depending on the trial, evaluation performed or therapeutical agents used (chemotherapy,
biologicals)
Piessevaux H et al. Ann Oncol 2009, Suzuki C et al. Ann Oncol 2011
ETS AND CHEMOTHERAPY
N = 201; ETS: 94 (47%), non-ETS 107 (53%)
It has been described that ETS correlates with chemosensivity and better survival
Von Weikersthal et al. EJC 2011, Giessen et al. ESMO 2012
ETS AND BIOLOGICALS
•
ETS analysis in the CRYSTAL and OPUS mCRC trials KRAS exon 2 wild
type population.
•
Radiologic assessments at week 8 were used to calculate the relative
change in the sum of the longest diameters of the target
•
Values for PFS and survival were higher (p.001) in those receiving
chemotherapy plus cetuximab versus chemotherapy alone, indicating a
stronger predictive value of ETS for long-term outcome in these patients
Piessevaux et al. J clin Oncol 2013
OPUS: +/-CTX
CRYSTAL: +/-CTX
ETS AND BIOLOGICALS
ETS AND BIOLOGICALS
PRIME study (ETS and response) PFS and OS by ETS (20% cut-off) at Week 8
Panitumumab + FOLFOX4
FOLFOX4
ETS
< 20%
≥ 20%
< 20%
≥ 20%
n (%)†
61 (28)
158 (72)
96 (43)
125 (57)
6.7
(5.4–9.9)
13.6
(12.0–15.7)
6.1
(5.3–8.0)
9.9
(8.0–11.1)
Median PFS, months
(95% CI)
HR
(95% CI)
P-value
0.62
(0.45–0.85)
0.0031
0.67
(0.50–0.88)
0.0040
Phi coefficient‡
Median OS, months
(95% CI)
HR
(95% CI)
P-value
Phi coefficient§
0.31
12.6
(9.3–18.2)
32.5
(28.3–37.6)
15.2
(11.4–17.2)
0.47
(0.34–0.65)
< 0.0001
26.0
(22.1–31.3)
0.50
(0.37–0.66)
< 0.0001
0.34
Douillard JY, et al. Eur J Cancer 2015;51:1231−42.
ETS AND BIOLOGICALS
ETS AND BIOLOGICALS
PFS outcomes by tumour shrinkage at week 8
Tumour shrinkage at week 8
≥20%
<20%
Panitumumab +
mFOLFOX6
Bevacizumab +
mFOLFOX6
Panitumumab +
mFOLFOX6
Bevacizumab +
mFOLFOX6
n (%)
20 (25)
28 (38)
60 (75)
46 (62)
Median PFS, months
(95% CI)
9.4 (4.2–13.1)
9.5 (7.3–12.7)
13.2 (10.9–16.2)
11.1 (9.0–13.4)
HR (95% CI);a
p-value
0.93 (0.48–1.80);
0.8294
0.69 (0.423–1.113);
0.1271
Tumour shrinkage at week 8
≥30%
<30%
n (%)
Median PFS, months
(95% CI)
HR (95% CI);a
p-value
Panitumumab +
mFOLFOX6
Bevacizumab +
mFOLFOX6
Panitumumab +
mFOLFOX6
Bevacizumab +
mFOLFOX6
29 (36)
41 (55)
51 (64)
33 (45)
9.8 (6.0–13.2)
9.7 (7.4–12.7)
13.1 (10.9–16.2)
10.1 (7.9–17.2)
0.86 (0.49–1.49);
0.5851
0.73 (0.42–1.27);
0.2646
Rivera F et al. J Clin Oncol 2015;33(Suppl 3): Abstract 660 & Poster (D2).
NON-ETS CONCEPT
Early progression
NON-ETS
TUMOR SIZE
SD/Minor shrinkage
ETS
TIME
Giessen et al. Cancer Science 2013. Picture adapted from Heinemann ESMO GIC 2013
ETS AND DPR
Adapted from Heinemann. ESMO-WGIC 2013
REDEFINING TUMOR ASSESSMENTS
• Relation between RECIST and volume
• Volume assesment provides a steeper response for tumor
shrinkage than RECIST
• Logarithmic approaches proposed.
• Technology not available
Mansmann et al. ASCO 2012
REDEFINING OBJECTIVES
Time to tumor growth captures benefit from bevacizumab in first line treatment
Claret L et al. J Clin Oncol 2013
TO CONCLUDE...
Is ETS so complicated?
It seems to be obvious: More reponse: better prognosis!
ETS: STRENGHTHS, CAVEATS AND PITFALLS
STATEMENTS
CONCERNS
ETS is a novel strategy to predict high sensivity to
treatment and a potential predictor for DpR.
Yes, consistent across studies
RECIST assessments have some limitations even
to predict survival. ETS would constitute an
alternative aim.
Relevant topic, not sure if the answer is “yes”,
needs further evaluation.
If relevant and consistent: Is it routinely
applicable?
Not now. Technology required, mandatory
radiologists implication. And: What to do with nonETS patients
Potential biomarker for accelerating drugs
efficacy: “go-don’t go” decisions
It is consistent enough to include it as an
objective specially in early clinical trials
What about novel therapeutics? Immunotherapy
strategies
Its role with other targeted therapies to be
elucidated
Imbrication with other potential evaluations
Contextualization with novel techniques such as
liquid biopsies
THANK YOU FOR YOUR ATTENTION
Elena Elez, MD, PhD
Gastrointestinal Cancer and Developmental Therapeutics Program
Vall d’Hebron Institute of Oncology
[email protected]