New view of therapy selection in different therapeutic scenarios and treatment sequencing

1. 1st Line Treatment of mCRC:
“The Benefit of Strategic Thinking”
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University

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

3. Management of Met. CRC:
Playing a Strategic Game:
The King Should SURVIVE SURVIVAL
What You Have to Play?
Surgery, Pharmaceuticals,
Interventional Radiology,
…
How to Play?
Sequence and Treatment
Lines
Try to be Creative Research

4. mCRC Outcomes Have Improved With the
Evolution of Treatment Options
Median survival shifted, on average, from 1 year to >2.5 years
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. Cunningham D, et al. N Engl J Med. 2004;351(4):337-345. 5. Van Cutsem E, et al. N Engl J Med. 2009;360(14):1408-1417. 6. Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-
2342. 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. 10. Tabernero J, et al. Lancet Oncol. 2015;16(5):499-508. 11. Mayer RJ, et al. N Engl J Med. 2015;372(20):1909-1919. 12. Le DT, et al. J Clin Oncol. 2016;34(Suppl): Abstract
103. 13. Le DT, et al. N Engl J Med. 2015;372(26):2509-2520. 14. Overman MJ, et al. Lancet Oncol. 2017;18(9):1182-1191.

5. 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
Khattak et al. Clinical Colorectal Cancer, Vol. 14, No. 2, 81-90 a 2015
Survival Advantage is Modest in 2nd & 3
Lines
Don’t Lose The Most Active Agent out of
1st Line
Parameter 1st Line 2nd Line 3rd Line
OOR (%) 38 - 69 10 - 41 1 - 22
PFS (ms) 9 - 13 4 - 9 2 - 4

6. mCRC: The Expanding Landscape
mOAS
> 30 months
Efficacy of 1st L
“Biomarker”
Resection/Ablation of
Organ Limited Disease
More Subsequent
Treatment Options
Treatment Holidays (QoL)
Maintenance Therapy
Re-challenge Beyond Progression
Treatment Intensification
MDT Approach - Intention
1ry Tumor Location
Tumor Immunogenicity
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

8. Questions to Be Answered Before
Decision for 1st Line Treatment:
1. Therapeutic Goal?
2. Why MDT is a Mandatory Practice?
3. Chemotherapy Backbone?
4. Molecular Background & Predictive Marker?
5. Which Biologic?
6. How to Continue Beyond Progression?
7. Maintenance Treatment?
8. Tumor Location?

9. 1. Therapeutic Goal? General Consensus
mCRC
Oligometastatic
(Cytoreduction)
Symptomatic Asymptomatic
Progressive Metastatic
(Disease Control)
Cure 1. Decrease Tumor Burden
2. Extension of OAS & QoL
1. R.R.
2. Shrinkage
Predictive Markers
Intensive +/- Biologic
Effective
Toxicity
Well Tolerated
All Lines
King GT et al. THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY. VOL. 12, NO. 10. OCTOBER 2016
FIT UNFIT

10. Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60
Treatment Goals
“Maintain QoL Across Treatment Journey”
1st & 2nd
Subsequent Therapies
OAS ORR Shrinkage
3rd Line
PFS
1. Therapeutic Goal?
Different Across Treatment Lines:

11. 1. Therapeutic Goal?
Be Realistic:

12. 2. MDT: A Mandatory Practice?
Munro et al. BMC Cancer (2015) 15:686

13. FOLFIRI → FOLFOX
FOLFOX → FOLFIRI
R
1st-Line
FOLFIRI
2nd-Line
FOLFOX
1st-Line
FOLFOX
2nd-Line
FOLFIRI
ORR 56% 15% 54% 4%
PFS 8.5 months 4.2 months 8.0 months 2.5 months
OS 21.5 months 20.6 months
ORR, overall response rate; OS, overall survival; PFS, progression-free survival
Tournigand C, et al. J Clin Oncol. 2004;22(2):229-237.
OS
0 10 20 30 40 50
Months
0
0.25
0.50
0.75
1.00
FOLFIRI/FOLFOX6
FOLFOX6/FOLFIRI
Probability
3. Chemotherapy Backbone?
Oxaliplatin versus Irinotecan?

14. 3. Chemotherapy Backbone?
Triplet versus Doublet?
Marques et al. Critical Reviews in Oncology / Hematology 118 (2017) 54–62

15. 4. Molecular Background & Predictive
Biomarkers?
BETTER
OUTCOME
WORSE OUTCOME
KRAS
NRAS
Anti-EGFR
BRAF
Triplet + Beva
MSI/MMR
I/O
NGS
Guinney et al. Nature Medicine. 21,1350-1356 (2015)
Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017.

16. 5. Which Biologic? Bevacizumab:
First-Line Chemotherapy ± Bevacizumab inmCRC
Randomized Controlled Trials
1. Saltz LB, et al. J Clin Oncol. 2008;26(12):2013-2019. 2. Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342. 3. Kabbinavar, et al. J Clin Oncol.
2005;23(16):3697-3705. 4. Tebbutt NC, et al. J Clin Oncol. 2010;28(19):3191-3198. 5. Cunningham D, et al. Lancet Oncol. 2013;14(11):1077-1085.
Treatment Regimen n
Median PFS
(Months)
Median OS
(Months)
Response Rate
(%)
FOLFOX/CAPOX ± bevacizumab1 1,400 9.4 vs 8
HR = 0.83
21.3 vs 19.8
HR = 0.89
38 vs 38
IFL ± bevacizumab2 813 10.6 vs 6.2
HR = 0.54
20.3 vs 15.6
HR = 0.66
45 vs 35
5-FU/LV ± bevacizumab3
(pooled analysis)
241 8.8 vs 5.6
HR = 0.63
17.9 vs 14.6
HR = 0.74
34 vs 24
Capecitabine ± bevacizumab4 313 8.7 vs 5.7
HR = 0.63
18.9 vs 18.9
HR = 0.88
56 vs 43
Capecitabine ± bevacizumab5
*Patients ≥70 years old
280* 9.1 vs 5.1
HR = 0.53
20.7 vs 16.8
HR = 0.79
19 vs 10
PFS: YES
OAS: +/-
R.R.: Query
PFS Disease Stabilization
 Subsequent Treatment
Lines

17. Influence of KRAS and NRAS Mutational Status onSurvival Randomized Trials
of EGFR Antibodies
1st Line Infusional 5-FURegimens
Trial Therapy OS (mo) KRAS
wt
OS (mo) NRAS
wt
OS (mo) RAS
mut
CTx + EGFR CTx + EGFR CTX + EGFR
CRYSTAL
(n=666)
FOLFIRI
+/- cetux*
20.0 23.5 20.2 28.4 17.7 16.4
PRIME
(n=656)
FOLFOX
+/- pani*
19,4 23.8 20.2 26.0 19.2 15.6
OPUS
(n=197)
FOLFOX
+/- cetux*
18,5 (22.8) 17.8 19.8 17.8 13.5
Chinese
(n=138)
Chemo
+/- cetux
21.0 30.9 - - - -
TAILOR
(n=354)
FOLFOX
+/- cetux
17.8 20.7
Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019. Ye LC, et al. J Clin Oncol. 2013;31(16):1931-1938. Douillard
JY, et al. J Clin Oncol. 2010;28(31):4697-4705. Bokemeyer C, et al. Ann Oncol. 2011;22(7):1535-1546.
5. Which Biologic? Anti-EGFR:
OAS: YES Early Treatment Line

18. 58%
60%
57%
54%
47%
62%
65% 66%
69%
66%
40%
30%
50%
60%
70%
80% Chemo+Bev Chemo+Cet
P Value：
FIRE-3
KRAS-wt*
.016
FIRE-3
RAS-wt*
.003
CALGB80405
KRAS-wt
.02
CALGB80405
RAS-wt
<.01
ORR
2014 Yang YH
KRAS-wt#
.037
Trial：
Anti-EGFR-based Regimen Increases Overall Response Rate Compared to
Bevacizumab-based Regimen in KRAS/RAS wt mCRC
# Bevacizumab group also includes KRAS mutation patients
Heineman V, et al. Lancet Oncol. 2014;15(10):1065-1075. Lenz HJ, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 501O. Yang YH, et al. J Cancer Res Clin Oncol.
2014;140(11):1927-1936.
5. Which Biologic? R.R. :
When you Need an Early Impressive Response Rate, Where to go?

19. Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075. Venook AP, et al. JAMA. 2017;317(23):2392-2401.
HR 0·70, 95% CI 0·53–0·92
P=.011
FIRE-3: OS RAS wt CALGB: OS in expanded RAS
analysis
5. Which Biologic? CET/PAN or Beva?

20. 5. Which Biologic? CET/PAN or Beva?
Bevacizumab
47.1%
Cetuximab or
Panitumumab
52.2%
Modest et al. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
Maintained Survival Benefit  Confirming the 1st L Survival Advantage
seen in FIRE-3 Trial

21. Sequence:

22. 45 42 38 35 29 26 20 14 10 5 1 0 0 0
117 111 99 85 67 54 36 20 13 8 3 2 0 0
119 111 106 85 58 47 40 27 13 7 1 0 0 0
16 14 10 8 7 4 3 3 0 0 0 0 0 0
12 8 5 4 3 2 1 0 0 0 0 0 0 0
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
TRIBE: FOLFOXIRI + Bevacizumab in BRAF-Mutant
mCRC
mOS, median overall survival; mPFS, medial progression-free survival. Cremolini C, et al. Lancet Oncol. 2015;16(13):1306-1315.
0 6 12 18 24 30 36 42 48 54 60 66 72 78
48 46 43 40 32 29 26 17 8 5 3 0 0 0
RAS- and BRAF-wildtype FOLFOXIRI plus bevacizumab
RAS- and BRAF-wildtype FOLFIRI plus bevacizumab
RAS-mutant FOLFOXIRI plus bevacizumab
RAS-mutant FOLFIRI plus bevacizumab
BRAF-mutant FOLFOXIRI plus bevacizumab
BRAF-mutant FOLFIRI plus bevacizumab
OverallSurvival,%
Number at Risk
RAS- and BRAF-wildtype FOLFOXIRI
plusbevacizumab
RAS- and BRAF-wildtype FOLFIRIplus
bevacizumab
RAS-mutant FOLFOXIRIplus
bevacizumab
RAS-mutant FOLFIRI plusbevacizumab
BRAF-mutant FOLFOXIRIplus
bevacizumab
BRAF-mutant FOLFIRIplus
bevacizumab
FOLFOXIRI plus bevacizumab
in patients who are BRAF+:
• mOS: 19 months
• mPFS: 7.5 months
• ORR: 56%

23. 6. How to Continue Beyond Progression?
Bevacizumab Beyond Progression After 1st Line
Containing Bevacizumab (ML 18147)
Bennouna et al. Lancet Oncol 2013; 14: 29–37
Outcome Beva + Cth Cth
mOAS 2nd Line 11.2 m 9.8 m
mOAS 1st Line 23.9 m 22.5
mPFS 5.7 m 4.1 m

24. 6. How to Continue Beyond Progression?
Bevacizumab Beyond Progression After 1st Line
Containing Bevacizumab (BEBYP) FINAL RESULTS
Masi et al. Annals of Oncology 26: 724–730, 2015

25. 7. Maintenance Treatment?
Hegewisch-Becker et al. Lancet Oncol 2015; 16: 1355–69

26. 7. Maintenance Treatment?
Hegewisch-Becker et al. Lancet Oncol 2015; 16: 1355–69

27. 80405: (KRAS WT) Overall Survival by Sidedness
Presented by:ASCO ANNUAL MEETING ‘16
Side N (Events)
Median
(95% CI)
HR
(95% CI)
p
Left 732 (550)
33.3
(31.4-35.7) 1.55
(1.32-1.82)
< 0.0001
Right 293 (242)
19.4
(16.7-23.6)

28. Right versus Left Colon:
Evidence from Literature
Outcome Right Sided Colon Left Sided Colon P
5-Y OAS 1990s 56.3% 59.7% < 0.01
5-Y OAS 2000s 67% 71% < 0.01
5-Y PFS 2010 73% 74% > 0.05
5-Y PFS 2014 88.6% 89.4% > 0.05
Median OAS 18.2 ms 29.4 ms < 0.001
Shen etal. World J Gastroenterol 2015 June 7; 21(21): 6470-6478

29. Right versus Left Colon:
Evidence from Literature
King et al. AJHO. 2016;12(10):4-11

30. Molecular Alterations in CRC:
Stintzing et al. European Journal of Cancer 84 (2017) 69e80

31. 5. Consensus Molecular Subtypes
(CMS):
RIGHTCOLONLEFTCOLON
BETTER
OUTCOME
WORSE OUTCOME
Guinney et al. Nature Medicine. 21,1350-1356 (2015)
Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15
Number 3. March 2017.

32. TEJPAR et al. JAMA Oncology February 2017 Volume 3, Number 2

33. TEJPAR et al. JAMA Oncology February 2017 Volume 3, Number 2

35. Responses to Pembrolizumab in
Mismatch Repair-Deficient (dMMR) mCRC
RECIST, Response Evaluation Criteria in Solid Tumors
Le DT, et al. N Engl J Med. 2015;372(26):2509-2520.