1. Early tumor shrinkage (ETS) and depth of response (DpR) to anti-EGFR in (m)CRC helpful surrogates or meaningless endpoints?
Marc Peeters MD, PhD
Coordinator Multidisciplinary Oncological Center Antwerpen (MOCA)
Head of the Oncology Department UZA, Professor in Oncology UA

2. well-controlled arterial hypertension
Demographics
female patient, 56 years
well-controlled arterial hypertension
Current History
invitation for flemish colorectal screening program
iFOB test : positive
Oncological History
total colonoscopy : semicircular lesion at the splenic flexure
pathology : moderately differentiated adenocarcinoma
staging :
CEA – 5.6 µg/l (3.5 µg/l)
thoracic/abdominal CT – no distant metastases
non-metastatic adenocarcinoma of the left colon, pG2T3N0(0/16)cM0

3. colonoscopy after 1 year : no lesions
Follow-up
colonoscopy after 1 year : no lesions
every 3 months – clinical evaluation and CEA-level determination
every 6 months – liver ultrasound/thoracic radiology
2013
Date
CEA (µg/L)
11/01
2,3
24/04
2,7
09/07
2,5
23/10
3,2
2014
07/01
5,7
21/02
11,2

4. colonoscopy: stenotic tumor at 25 cm (sigmoid)
Hemoglobin
(g/dl)
Alk. Phosph.
(U/l)
AST
ALT
LDH
CEA
(µg/l)
12.4
( )
173
(53-141) 34
(< 31) 43
(< 34)
1367
(84-246)
14507
(< 3.0)
colonoscopy: stenotic tumor at 25 cm (sigmoid)
biopsy: moderately differentiated (G2) adenocarcinoma

5. mCRC – (clinical) heterogenuous population
Metastatic
Limited
Resectable
Neo-Adjuvant
Potential Resectable
Induction
Diffuse
Palliative
Control
Response

6. EGFR inhibitors in mCRC – combination therapy
Treatment
PFS, mo
OS, mo
Chemo + bevacizumab
Chemo + anti-EGFR
FIRE-3
Chemo + bev vs
10.2
10.4
25.6
33.1
CALGB 80405
11.3
11.4
31.2
32.0
Adapted from Cremolini et al. Nat Rev Clin Oncol. 2015;doi: /nrclinonc

7. Douillard JY et al. N Engl J Med 2013;369:1023-1034

8. Assessment of Efficacy in First line mCRC
- PFS
Influenced by toxicity of the regimen and size of the tumour lesion, favouring larger lesions
- OS
Influenced by 2nd and subsequent lines of treatment
With longer post-progression survival, the influence of further treatment lines becomes greater
- ORR:
Influenced by RECIST measurements
Used as an endpoint in Phase 2 studies
Slide courtesy of S. Stintzing

9. Tumor characteristics Patient characteristics
Efficacy
Safety
Histopathology
Tumor characteristics
Patient characteristics
Previous treatment
Patient preference
Goals of therapy
Biomarkers

10. Response – continuous measure based on RECIST
Tumour change, %
SD range: ‒29 % to +19 % 20 SD
- 30
ORR
Slide courtesy of V. Heinemann
SD = stable disease

11. Surrogate endpoint = Earlier Measurement Smaller Sample Size
a biomarker intended to substitute for a clinical endpoint (NIH, 2001)
a laboratory measurement or physical sign used as a substitute for a clinical meaningful endpoint that measures directly how a patient feels, functions, or survives and that is expected to predict the effect of the therapy (FDA, 1992)
Earlier Measurement
Smaller Sample Size
Zhoa F. J Clin Oncol 2016;34: Editorial

12. ETS – % decrease in tumour load at a given time
8 weeks
Baseline
= 100%
ETS = % decrease (8 weeks)
With a 20% cut-off, this results in a categorical decision:
Early tumour shrinkage (ETS)
Non-early tumour shrinkage (non-ETS)
Heinemann V et al. Eur J Cancer 2015;51:

13. + molecular markers e.g. CEA, CA19-9
Additional (response) assessments – parameters (1)
Time since start of treatment OS
ETS
Tumour nadir
PFS
Tumour load at baseline
Lethal tumour load
TTG
+ molecular markers e.g. CEA, CA19-9
DpR
Heinemann V et al. Eur J Cancer 2015;51:
DpR, depth of response; TTG, time to tumour growth

14. Additional (response) assessments – clinical (2)
ETS:
Rapidly predicts sensitivity to treatment1−5
Potential to relieve tumour-related symptoms5
May increase possibility of resection/chance of cure in some patients with initially unresectable metastases5
ETS, DpR:
Potentially prognostic for PFS/OS4−6
1. Giessen C, et al. Cancer Sci 2013;104:718−24; 2. Piessevaux H, et al. Ann Oncol 2009;20:1375–82; 3. Piessevaux H, et al. J Clin Oncol 2013;31:3764−75; 4. Stintzing S, et al. Ann Oncol 2014;25(Suppl 5):v1–v41:abstract LBA11 (and oral presentation); 5. Douillard JY, et al. Eur J Cancer 2015;51:1231−42; 6. Petrelli F, et al. Eur J Cancer 2015;51:800−7

15. FOLFIRI+Cmab FOLFIRI FOLFOX+Cmab FOLFOX
Piessevaux H et al. J Clin Oncol 2013;31:

16. Piessevaux H et al. J Clin Oncol 2013;31:3764-3775

17. Douillard JY et al. Eur J Cancer 2015;51:1231-42

18. PRIME – ETS for PFS and OS
Panitumumab + FOLFOX4
FOLFOX4
ETS at Week 8, RAS wild type
< 20%
≥ 20%
n (%)†
61 (28)
158 (72)
96 (43)
125 (57)
Median PFS, months (95% CI)
6.7 (5.4–9.9)
13.6 (12.0–15.7)
6.1 (5.3–8.0)
9.9 (8.0–11.1) HR
(95% CI)
P-value
0.62
(0.45–0.85)
0.0031
0.67
(0.50–0.88)
0.0040
Phi coefficient‡
0.31
Median OS, months (95% CI)
12.6 (9.3–18.2)
32.5 (28.3–37.6)
15.2 (11.4–17.2)
26.0 (22.1–31.3)
0.47
(0.34–0.65)
<
0.50
(0.37–0.66)
Phi coefficient§
0.34
Douillard JY et al. Eur J Cancer 2015;51:

19. PRIME – change in EQ-5D health scores (baseline to discontinuation)
WT RAS: symptomatic†
Mixed effect model
ETS ≥ 30%
ETS < 30%
Difference
P-value
HSI
LS means
(95% CI)
(n = 84)
0.096
(0.049, 0.142)
(n = 109)
0.025 (‒0.020, 0.071)
0.070
(0.013, 0.127)
0.02
OHR
(n = 82)
4.164 (1.405, 7.824)
0.300
(‒2.822, 3.422)
4.314 (0.636, 7.993)
†Patients with tumour-related symptoms at baselinedefined as EQ-5D pain/discomfort scale score > 1.. EQ-5D, EuroQoL 5-domain; HSI, health state index;LS, least squares; OHR, overall health rating.
In patients with tumour symptoms at baseline, there were statistically significant improvements in QoL in those with ETS vs those without
These data add to the idea that achieving early reductions in tumour load is associated with symptomatic benefits for patients
Siena S, et al. ESMO Open 2016;1:e000041

20. PRIME – ETS, conclusions
Whole population vs. Individuals
ETS in symptomatic patients & in conversion
Douillard JY et al. Eur J Cancer 2015;51:

21. Median tumour diameter (95% CI) of patients not PD, %
FIRE-3 – median tumour diameter over time
WT RAS
100 75
Median tumour diameter (95% CI) of patients not PD, % 50
Bevacizumab + FOLFIRI
Cetuximab + FOLFIRI 6 12 22 32
Week
103 95
Cetuximab + FOLFIRI
Bevacizumab + FOLFIRI
109
126 79 99 45 43
Stintzing S, et al. Ann Oncol 2014;25(Suppl 5):v1–v41:abstract LBA11 (and oral presentation)

22. FIRE-3 – additional response assessments
Cetuximab + FOLFIRI
(n = 199)
Bevacizumab + FOLFIRI
(n = 201)
HR/OR (95% CI) P-value
Median PFS, months
10.3
10.2
HR = 0.97 (0.78–1.20) P = 0.77
Median OS, months
33.1
25.0
HR = (0.54–0.90) P =
ORR,† %
(n = 157)
72.0
(n = 173) 56.1
OR = 2.01 (1.27−3.19) P = 0.003
(n = 173)
P-value
ETS ≥ 20% at Week 6, %
68.2
49.1
OR = 2.22
(1.41−3.47) P =
ETS < 20% at Week 6, %
31.8
50.9 -
Median DpR, %
48.9
32.3
P <
CEA reduction2#
Maximum − median, %
≥ 75%, %
(n = 230)
83.0
63.0
(n = 242)
72.3
47.9
P = 0.003
P = 0.005
*RAS ascertainment rate: 80.2%; †Primary endpoint; #WT KRAS exon 2 population.
1. Stintzing S, et al. Ann Oncol 2014;25(Suppl 5):v1–v41:abstract LBA11 (and oral presentation); 2. Michl M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3592 (and poster)

23. PEAK – ETS ≥ 30% at Week 8 (1) 64% OR = 1.99 (95% CI, 0.99−4.10)
WT RAS
64%
OR = 1.99 (95% CI, 0.99−4.10)
P = 0.052
45%
ETS ≥ 30% at Week 8, %
Panitumumab + mFOLFOX6 (n = 80)
Bevacizumab + mFOLFOX6 (n = 74)
Rivera F, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2014 (and poster).

24. PEAK – Depth of Response, DpR (2)
WT RAS
65%
P = †
46%
DpR, %
Panitumumab + mFOLFOX6 (n = 88)
Bevacizumab + mFOLFOX6 (n = 81)
Rivera F, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2014 (and poster).

25. Mean change (95% CI) from baseline, %
PEAK – % change from baseline in tumour load over time (3)
WT RAS
−20
−40
Mean change (95% CI) from baseline, %
−60
−80
Bevacizumab + mFOLFOX6
Panitumumab + mFOLFOX6
−100 8 16 24 32 40 48 56
Weeks
Pmab + mFOLFOX6 88 80 70 62 53 41 38 33
Bev + mFOLFOX6 81 74 66 56 44 33 23 18
Rivera F, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2014 (and poster).

26. Cremolini et al. Ann Oncol 2015;26:1188-94

27. Impact: yes, but… FOLFOXIRI + Bev FOLFIRI + Bev
Cremolini et al. Ann Oncol 2015;26:

28. ETS & PFS, OS – overview of the literature (1)
Heinemann V et al. Eur J Cancer 2015;51:

29. ETS & PFS, OS – overview of the literature (2)
Heinemann V et al. Eur J Cancer 2015;51:

30. ETS, DpR & PFS, OS – randomised trials
Heinemann V et al. Eur J Cancer 2015;51:

31. ETS – summary ETS reflects the velocity of response to therapy
It is measured at the earliest time point of CT evaluation
ETS indicates sensitivity to treatment
Addition of anti-EGFR agents to chemotherapy increases the number of patients with ETS and enhances the velocity of response
Slide courtesy of V Heinemann

32. Time since start of treatment
DpR – summary
Δ OS SD
Lethal tumour load PR
Δ OS
100%
Tumour size, %
70%
ETS is an early predictor of sensitivity to treatment
DpR correlates with OS PR
Deepest response
Time since start of treatment
Adapted from: Stintzing S, et al. Ann Oncol 2014;25 (Suppl 5):v1–v41:abstract LBA11 (and oral presentation).

33. Additional response assessments – conclusions
- ETS is associated with prolonged survival and is an early predictor of sensitivity to treatment in mCRC
- Based on ETS and DpR, anti-EGFR therapy may show a benefit over anti-VEGF therapy in 1st-line WT RAS mCRC
knowledge of the radiologist in standard setting
global population vs. individual decision

34. The Multidisciplinary Oncology Team at Antwerp University Hospital
UZA
DIAMOND
HARBOR
DESIGN
The Multidisciplinary Oncology Team at Antwerp University Hospital
I wish to thank