Highlighting the choice of 1st line therapy in metastatic colorectal cancer emphasizing the role of early tumor shrinkage on treatment outcome.

1. mCRC:
The Paradigm of Sequence or
Still Maximum Exposure?
Evidence from RCT
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Asyut Annual Meeting
Merck Serono Lecture
Luxor: 22/02/2017

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD
Speaker Disclosures:

3. Colon Cancer:
Basic Facts & Figures:
• 2nd & 3rd most common cancers in females and males.
• 9% of cancer related deaths.
• 90% occurring around the age of 40 – 50 years.
• OAS for entire patients = 65%.
• Metastatic disease: 5-year OAS = 10%.
• Organ limited metastatic disease (Metastatectomy):
5-year OAS > 40%
• Median survival of metastatic disease > 35 months.
• Improved OAS with exposure to all available drugs.
• Unified global treatment algorhytm is still controversial.

4. Median OS
Months
1980s 1990s 2000s
BSC 5-FU
Irinotecan1
Capecitabine2
Oxaliplatin3
Bevacizumab4
Cetuximab5,6BSC
Panitumumab
7 Aflibercept8
Regorafenib
9
30
25
20
15
10
5
0
1. Cunningham D, et al. Lancet. 1998;352(9138):1413-1418. 2. Van Cutsem E, et al. Br J Cancer.
2004;90(6):1190-1197. 3. Rothenberg M, et al. J Clin Oncol. 2003;21(11):2059-2069.
4. Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342. 5. Cunningham D, et al. N Engl J Med.
2004;351(4):337-345. 6. Van Cutsem E, et al. N Engl J Med. 2009;360(14):1408-1417.
7. Van Cutsem E, et al. J Clin Oncol. 2007;25(13):1658-6164. 8. Van Cutsem E et al. J Clin Oncol.
2012;30(28):3499-3506. 9. Grothey A, et al. Lancet. 2013;381(9863):303-312.
mCRC:
Improved Survival Over Time:

5. Choice of Systemic Therapy:
Old Dogma:
5-Fu/LV
Capecitabine
Oxaliplatin
Irinotecan
Bevacizumab
Cetuximab
Panitumumab
Aflibercept
Regrafinib
Ramucirumab
TAS 102
Survival Improvement
Treatment
Lines &
Combinations

6. mCRC:
Can we do better?
Treatment
INTENTION
Organ Confined
Disease
NAT:
Resectable
Or Convertible
Resection
for Cure
Progressive
Metastatic
Palliative
Treatment
OAS
QoL

7. Can We Do Better?
• MDT
• Predictive Markers  K-RAS Assessment  All RAS
Assessment  SEQUENCE  SMART & STRATEGIC

8. Daily Treatment Scenarios:
Exposure:
• Advancing Cancer 
Chronic Disease.
• Survival  All Active
Agents.
• Sequence isn’t important
Sequence:
• Predictive Markers
• Upfront  Massive Attack.
• Late  still wining cards
• Survival Improvement is modest in 2n & 3rd Lines.
• Losing an Active Agent Out of Upfront Treatment.
Khattak et al. Clinical Colorectal Cancer, Vol. 14, No. 2, 81-90 a 2015

9. ORR, %*
PFS, months*
Importance of 1st line treatment
decision
1st line1-4 2nd line5–7 3rd line8,9
1‡ – 22†
2‡ – 4†
38‡ – 69
9‡ – 13
10† – 41
4† – 9†
Treatment is most effective in the 1st line1–9
Determining RAS status at diagnosis is crucial for maximizing patient
outcomes and planning the course of treatment
1. Saltz LB, et al. J Clin Oncol 2008;26:2013–2019; 2. Lenz HJ, et al. ESMO 2014
(Abstract No. 501O); 3. Pericay C, et al. WCGC 2012 (Abstract No. O-0024);
4. Karthaus M, et al. ECC 2013 (Abstract No. 2262); 5. Langer C, et al. ESMO
2008 (Abstract No. 385P); 6. Peeters M, et al. ASCO GI 2014 (Abstract No.
LBA387);
7. Cohn A, et al. ASCO 2013 (Abstract No. 3616); 8. Grothey A, et al. Lancet
2013;381:303–312; 9. Price TJ, et al. Lancet Oncol 2014;15:569–579
*Range of results for the targeted
treatment arms of key Phase II/III
trials (RAS wt except where
indicated;
†KRAS exon 2 wt; ‡unselected)

10. Predictive Markers:
OPUS, COIN, CRYSTAL, PRIME, 20050181, PICCOLO, 20020408,
FIRE -3, PEAK

11. KRAS WT: Impact of All RAS Testing:
1. PFS
Sorich et al. Annals of Oncology 26: 13–21, 2015

12. KRAS WT: Impact of All RAS Testing:
2. OAS
Sorich et al. Annals of Oncology 26: 13–21, 2015

13. CRYSTAL5
COIN3
PRIME4
NORDICVII2
CO.179
4088
N01471
PFS for EGFR inhibitors improves across lines of
therapy in KRAS dliw-stnetiap epyt:
Hazardratio
1. Alberts, et al. JAMA 2012;2OCJ .la te ,tievT .2012;3tecnaL .la te ,nahguaM .2011
4. Douillard, et al. ASCO 2011;5OCJ .la te ,mestuC naV .2011;6OMSE .la te ,regnaL .2008
7. Sobrero, et al. ASCO GI 2012;8OCJ .la te ,odamA .2008;9MJEN .la te ,stieparaK .2008
First line Second line Salvage
(single agent)
Adjuvant
1.2
1.0
0.8
0.6
0.4
0.2
0
Study1817
EPIC6
Albert Sobrero , WCGIC 2012

14. First Head-to-Head Comparisons of First-Line
Bevacizumab Versus EGFR Inhibitors in KRAS WT
mCRC
1. Schwartzberg LS, et al. J Clin Oncol. 2014;32(21):2240-2247. 2. Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.
3. Venook A, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA3.
PEAK1
Phase II
Untreated –
Unresectable mCRC
N = 285
Bevacizumab + mFOLFOX6
Panitumumab + mFOLFOX6
FIRE-32
Phase III
Untreated mCRC
N = 592
Bevacizumab + FOLFIRI
Cetuximab + FOLFIRI
CALGB-804053
Phase III
Untreated mCRC
N = 1200
Bevacizumab +
FOLFIRI or FOLFOX
Cetuximab
+ FOLFIRI or FOLFOX
No Hypothesis
OAS
ORR
DP

15. FIRE-3 Trial: FOLFIRI + Either Cetuximab or
Bevacizumab in KRAS WT mCRC
Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.
HR 0.77
P .011
Parameter Chemo + CET Chemo + Bev P
ORR (%) 62 58 .183
PFS (ms) 10 10.3 .547
OAS Dif.
= 8.5 ms

16. CALGB/SWOG 80405: Overall Survival
Arm N (Events)
OS (m)
Median
95% CI
Chemo +
Cetux 578 (375) 29.9 27.0-32.9
Chemo + Bev 559 (371) 29.0 25.7-31.2
P=0.34
HR 0.925 (0.78-1.09)

17. CALGB/SWOG 80405: Progression-Free Survival
(Investigator Determined)
Arm N (Events)
PFS (m)
Median
95% CI
Chemo + Bev 559 (498) 10.8 9.7-11.4
Chemo + Cetux 578 (499) 10.4 9.6-11.3
P=0.55
HR 1.04 (0.91 -1.17)

18. Sequence:

19. Sequence versus Exposure:
Modest et al. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

20. Sequence versus Exposure:
Bevacizumab
47.1%
Cetuximab or
Panitumumab
52.2%
Modest et al. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

21. Sequence versus Exposure:
Modest et al. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
Sequence may be more important than Exposure.

23. Which Treatment Line First?
Better Insight:
Heinemann et al. EJC 67 (2016) 11-20. New Era

24. Which Treatment Line First?
Better Insight:
Heinemann et al. EJC 67 (2016) 11-20.
OASPFS
OARETS

25. Lancet Oncol 2016; 17: 1426–34
Which Treatment Line First?
Better Insight:

26. Lancet Oncol 2016; 17: 1426–34
Which Treatment Line First?
Better Insight:

27. Lancet Oncol 2016; 17: 1426–34
Which Treatment Line First?
Better Insight:

28. Inducing Tumor Shrinkage is
essential

29. Lancet Oncol 2016; 17: 1426–34
Which Treatment Line First?
Better Insight:

30. Correlation between ETS and increased OS has been
consistently observed in 1st line Phase III clinical
trials
• 1. Piessevaux H, et al. J Clin Oncol 2013;31:3764–3775;
2. Stintzing S, et al. ESMO 2014 (Abstract No. LBA11);
3. Douillard JY, et al. Eur J Cancer 2015;51:1231–1242;
4. Cremolini C, et al. Ann Oncol 2015;26:1188–1194;
5. Erbitux SmPC June/2014;
6. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075.
*KRAS exon 2 wt population; Cetuximab is approved in patients with RAS wt mCRC.6 Cetuximab is not indicated for the
treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS tumor status is unknown.5
**FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC
based on investigators’ read.6
†Not including the first four months after randomization.
Trial
Biomarker
status
Treatment regimen
(n)
OS, months ∆OS,
mont
hs
ETS
<20%
ETS ≥20%
CRYST
AL1
KRAS exon
2 wt*
FOLFIRI + cetuximab (n=299) 18.6 30.0 11.4
FOLFIRI (n=332) 18.6 24.1 5.5
FIRE-
3**2 RAS wt
FOLFIRI + cetuximab (n=157) 20.5 38.3 17.8
FOLFIRI + bevacizumab
(n=173)
21.2 31.9 10.7
PRIME
3 RAS wt
FOLFOX4 + panitumumab
(n=219)
12.6 32.5 19.9
FOLFOX4 (n=221) 15.2 26.0 10.8
TRIBE4 Unselected
FOLFOXIRI + bevacizumab/
FOLFIRI + bevacizumab
(n=407)
21.9† 31.9† 10.0

31. Inducing ETS with Cetuximab correlates with
symptoms relief and QoL
1. Griebsch I, et al. ASCO GI 2011 (Abstract No. 3626)

32. 16
14
12
10
8
6
4
2
0
13,2
2,,00
5,1
14
12
10
8
6
4
2
0
KRAS wt –
Liver-limited disease
cohort
CRYSTAL
7,3
3,1
Patients,%
OPUS
Patients,%
KRAS wt-
Liver-limited disease
cohort
16.0
KRAS wt
P = .22 †KRAS wt
P = .027 †
4,3
Van Cutsem E, et al. J Clin Oncol. 2011;29(4S): Abstract 472.
*Fisher’s exact test;
†Cochran-Mantel-Haenszel test
P = .15*
P = .35*
5,6
R0 RESECTIONS IN RANDOMIZED TRIALS WITH CETUXIMAB
FOLFIRI ERBITUX FOLFIRI ERBITUX FOLFOX4 ERBITUX FOLFOX4 ERBITUX
N = 350 + FOLFIRI N = 72 + FOLFIRI N = 97 + FOLFOX4 N = 23 + FOLFOX4
N = 316 N = 68 N = 82 N = 25

33. 1. Folprecht G et al. Lancet Oncol 2010; 11(1): 38-47.
Higher Resection Rates correlates with Prolonged OS and PFS

34. Phase III TAILOR study:
open-label, randomized ,1st line FOLFOX-4 ± Erbitux in
patients with RAS wild-type metastatic colorectal cancer (RAS
wt mCRC)
3
First prospective Phase III analysis to assess the efficacy and safety of Erbitux plus
FOLFOX versus FOLFOX alone as 1st line therapy in RAS wt mCRC
Endpoints
• Primary:
PFS
• Key secondary:
OS, ORR,
safety/tolerability
1st line,
RAS wt
mCRC
R
1:
1
Arm A:
Erbitux +
FOLFOX-4
Arm B:
FOLFOX-4
alone
Treatment
until
progressive
disease or
unacceptable
toxicity*
IRC, independent review committee; HR, hazard ratio; OS, overall survival; ORR, overall response rate
*In the case of non-PD treatment discontinuation, tumor assessment was to be continued
FOLFOX-4:
• Oxaliplatin 85 mg/m2 Day 1, every 2 weeks
• Folinic acid 200 mg/m2 Day 1 and Day 2, every 2 weeks
• 5-FU 400 mg/m2 bolus, then 22h continuous infusion of 600 mg/m2/day Day 1
and Day 2, every 2 weeks
Erbitux:
• 400 mg/m2 Day 1, then 250 mg/m2/week
Qin S, et al. WCGC 2016 (Abstract no. O-025)

35. 35
GORTEC 2007-021
TAILOR
Confirms Erbitux as a Standard of care
for all patients with RAS wt mCRC, with
consistent benefit in combination with
standard CT regimens
PFS: 9.2 vs 7.4 months1
HR: 0.69
p=0.004
• ORR: 61.1% vs 39.5%1
OR: 2.41
p=<0.001
• OS: 20.7 vs 17.8 months1
HR: 0.76
p=0.02
SOC, standard of care; CT, chemotherapy; PFS, progression-free
survival; HR, hazard ratio; OS, overall survival; ORR, overall
response rate
6
31% decrease in the risk
of disease progression1
• 24% reduction in the
risk of death1
• 61% ORR is consistent
with previous studies2,3
1. Qin S, et al. WCGC 2016 (Abstract no. O-025)
2. Van Cutsem E, et al. J Clin Oncol 2015;33:692–700;
3. Bokemeyer C et al. Eur J Cancer 2015;51:1243–1252
Significant benefit with Erbitux + FOLFOX versus FOLFOX alone
across all efficacy endpoints1

36. Tumor location in CRC
ESMO updates

37. 37
FIRE-3
No difference in outcomes
between arms in right-sided
tumors, but conclusions are
limited by small sample size &
imbalances
38.3

38. 38
CRYSTAL
No significant difference in
outcomes between arms in
right-sided tumors, but
conclusions are limited by small
sample size
Numerical
increase in ORR
compared with
CT alone
In RS, patients in the Erbitux
arm had poorer PS, larger
tumors, and more frequent
prior adjuvant therapy,
compared with CT alone
28.7

39. 39
CALGB/SWOG
80405
Longer PFS with
bevacizumab vs Erbitux, but
no difference in OS between
arms, in right-sided tumors;
conclusions limited by small
sample size
Data for patients with right-sided tumors are
inconclusive due to:
• Small patient numbers
• Unreported baseline characteristics,
treatment dose, treatment duration and
subsequent therapies
39.3

40. ~30% of patients
40
Conclusion
~70% of patients
Median OS
>38 months!
• Over 10 months more than bev + CT
(FIRE-3)
• 7 months more than bev + CT (CALGB
80405)
• 7 month more than CT (crystal)
Bad prognosis
regardless of
therapy
Small sample size ,
premature data
LEFT RIGHT

41. Anti-EGFR agents
1. Erbitux SmPC June/2014;
2. Imai K, Takaoka A. Nat Rev Cancer 2006;6:714–727;
3. Vectibix SmPC February/2015.
Human constant
domains
Mouse
variable
domains
Human constant and
variable domains
Cetuximab1,2 Panitumumab2,3
Chimeric monoclonal
IgG1 antibody
Fully human monoclonal
IgG2 antibody
Differences in molecular structure
Potent ADCC Less ADCC

42. Take Home Message:
• Better insight to decide for first line treatment.
• Growing evidence of 1st line Anti-EGFR MCA as SOC in All-
RAS wild type patients (Resection or OAS).
• Availability of 2nd line data from major RCT emphasized the
survival advantage of 1st line Anti-EGFR based combination
therapy.
• Emphasizing ETS as an endpoint to predict Survival,
Resectability and Symptom Relief.
• Data for tumor location needs more validation, with
retrospective data favoring anti-EGFR for left sided tumors.
• Immunogenic response to Cetuximab needs to be
highlighted in the era of immunotherapy.

43. Thank You