It describes the relevant data upon choice of therapy in relation to primary tumor location (Right and Left Sided Colon Cancer)

1. Impact of 1ry Tumor Location on
Treatment Guidelines of mCRC.
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Clinical Oncology Department
Zagazig University Annual Meeting
Dusit Thai Hotel 27/04/2018

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
Speaker Disclosures:

3. 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. 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
1ry Tumor Location
Tumor Immunogenicity
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

6. Is Really Left Better Than Right Sided
Colon Cancer?

7. 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)

8. Right versus Left Colon:
Evidence from Literature
Shen etal. World J Gastroenterol 2015 June 7; 21(21): 6470-6478
56%
67%
60%
71%
0.00%
50.00%
100.00%
1990s 2000s
5-Y OAS
Right Colon
Left Colon
0%
50%
100%
2010 2014.00
5-Y PFS
Right Colon
Left Colon
18
29
0.00
50.00
Right Colon Left Colon
median OAS
median OAS
P < 0.05
P < 0.001
P > 0.05

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

10. Petrelli et al. Jama Oncology. 2017 Vol 3 Number 2
66 RCT = 1437846 Colon Cancer Patients
Location as an Independent Prognostic Factor:

12. Why Left Colon is Better Than Right
Sided disease?

13. Right versus Left Colon:
Why different disease entities?
Different:
• Blood Supply
• LN Drainage
1. Embryologic Origin
2. Blood Supply & Nodal Drainage
3. Microbiome Difference
4. Precancerous Lesions.
6. Histopathology & Natural History
5. Consensus Molecular Subtypes.
Stintzing et al. European Journal of Cancer 84 (2017) 69e80

14. 3. Microbiome Difference:
Right Colon Cancer Left Colon Cancer
Prevotella, Pyramido-bacterium,
Selenomonas and Peptostreptococcus.
Fusobacterium, Escherichia-Shigella
and Leptotrichia
Escherichia coli phylogroup B2. Helicobacter pylori infection
Dense Bacterial Aggregates
1. E-Cadherin
2. IL-6
3. STAT3
Cellular
Proliferation
Invasion of Colonic Mucous Layer
Proinflammatory Genes
Flemer et al. Tumour-associated and non-tumour- associated microbiota in colorectal cancer. Gut 2017;66(4): 633e43.

15. 4. Pre-Neoplastic Lesions:
Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

16. Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017
Molecular Alterations in
CRC:

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

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

19. 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.

20. Parameter Right Colon Left Colon
Gender Female Male
Age Higher Lower
Grade Higher Lower
Mucoid Activity More Prevalent Less Prevalent
Stage Higher Lowe
Spread Peritoneum Liver & Lung
6.Natural History &
Histopathology:
Nitsche et al. Right sided colon cancer as a distinct histopathological subtype with reduced prognosis.
Dig Surg 2016;33(2):157e63.

21. Differential Effects of Adding EGFR
MOA to Chemotherapy?

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

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

24. Right Versus Left Sided Colon
Cancer OAS & Anti-EGFR:
Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

25. Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564
Right Versus Left Sided Colon
Cancer PFS & Anti-EGFR:

27. Do We Have Something New
Regarding EGFR MOA Based on
Sidedness?

28. Arnold D, et al. Ann Oncol. 2017;28(8):1713-1729.

29. Prognostic Analysis: Overall Survival
Arnold D, et al. Ann Oncol. 2017;28(8):1713-1729.
Favors Right FavorsLeft
Heterogeneity: P = .54; I2 = 0%
Hazard Ratio

30. The image part with relationship ID rId3 was not found in the file.
Predictive Analysis: Overall Survival
Favors CT + Anti-EGFR Favors CT
CT, chemoatherapy
Arnold D, et al. Ann Oncol. 2017;28(8):1713-1729.
Hazard Ratio

31. Predictive Analysis: Overall Response Rate
Arnold D, et al. Ann Oncol. 2017;28(8):1713-1729.
Favors CT + Anti-EGFRFavors CT
Odds Ratio

32. Meta-Analysis: Doublet +/- EGFR and
Influence of Side of Primary
PRIME/CRYSTAL
Holch JW, et al. Eur J Cancer. 2017;70:87-98.

33. Differential Effects of Adding VEGF
MOA to Chemotherapy?

34. 994 (78.3) .71 (.62 to .82) <.001
NO16966
Evaluable patients
(n =1268)
CT arm s (n = 827)
CT + bevacizumab arms
(n =441)
664 (80.3)
330 (74.8)
.67 (.57 to .80)
.78 (.61 to .99)
<.001
.04
Loupakis et al. JNCI J Natl Cancer Inst 2015
17.0 (14.7 to 18.5)
20.6 (17.6 to 24.7)
p-value ?
22.0 (20.5 to 23.7)
24.7 (22.2 to 27.6)
p-value ?
Is Bevacizumab Improving OS Over
FOLFOX/XELOX in Left or Right Sided Tumors?
• This question has probably been addressed in this study, but has
not been reported
• We don’t know whether bevacizumab is working in left or right
sided tumors
• It is unlikely that sidedness plays a role for bevacizumab
Left
23.0 (21.5 to 24.4)
Right
18.0 (16.5 to 19.8)
Loupakis F, et al. J Natl Cancer Inst. 2015;107(3).

35. RAS wt or Mut: Doublet vs Triplet
RAS wt or Mut Disease
Unproven / unclear role of bevacizumab
Regimen N RR PFS OS Author
FOLFIRI 122 41% 6.9 16.7 Falcone JCO 2007
+/- Oxaliplatin 122 66% 9.9 23.6
FOLFIRI / Bev 256 53% 9.7 25.8 Falcone NEJM 2015
+/- Oxaliplatin 252 65% 12.2 29.8
FOLFOX / Bev 39 62% Grünberger Ann Oncol 2015
+/- Irinotecan 41 81%
FOLFOX / Bev 121 60% 9.8 n.a. Schmoll ESMO 2016
+/- Irinotecan 121 79% 12 n.a.

36. BRAF Mutant Disease
Cremolini C, et al. Lancet Oncol. 2015;16(13):1306-1315.

37. Cremolini C, et al. Lancet Oncol. 2015;16(13):1306-1315.
Irinotecan + 5-Fu/LV Bevacizumab
Irinotecan + 5-Fu/LV Bevacizumab
Oxaliplatin

38. EGFR OR VEGF MOA According to
Sidedness?

39. 0.0
0.2
0.4
0.6
0.8
1.0
ProbabilityofOS
12 6024 4836
Months
0 72
Median OS (95% CI), months
Cet +
FOLFIRI
Bev +
FOLFIRI HR (95% CI)
Left 306 38.3 28.0
0.63
P=.002
Right 88 18.3 23.0
1.31
P=.28
Median OS (95% CI), months
Cet +
FOLFIRI
Bev +
FOLFIRI HR (95% CI)
Left 325 39.3 32.7
0.77
P=.04
Right 149 13.7 29.2
1.36
P=.10
Anti-EGFR + Doublet vs anti-VEGF
+ Doublet: Influence of Side of
PrimaryFIRE-3 CALGB 80405
Tejpar S, et al. JAMA Oncol. 2016 Oct 10. [Epub ahead of print]. Venook AP, et al. JAMA. 2017;317(23):2392-2401.

40. 18
VOLFI- PH2 TRIAL
mCRC
Unresectable
1st-line
WT RAS**
Age ≥ 18yrs
ECOG PS 0-1
(n=96)
Randomization:
6/2011 - 1/2017
R
Treatment until PD, resectability,
or to maximum 12 cycles
mFOLFOXIRI+
panitumumab 6 mg/kg
Q2W
N=63
Irinotecan 150 mg/m2***, oxaliplatin 85 mg/m2,
2 2
LV 200 mg/m , 5-FU 3000 mg/m CIV;
Planned safety analysis after 10 patients
treated in panitumumab arm
FOLFOXIRI Q2W
N=33
2:1
If resectable:
Surgery, then
protocol treatment to
maximum 12 cycles
If CR/PR/SD after 12 cycles:
re-induction
(same combination)
recommended on PD
Strata:
Cohort 1: histologically confirmed and definitively inoperable or unresectable
Cohort 2: chance of secondary resection with curative intent (*pretreatment liver/tumorbiopsy)
*
*
• 21 active centers in Germany
**amendment in 11/2013 to include all RAS wild-type only
***Trial started with irinotecan 165 mg/m2 (n=2), first amendment to 130 mg/m2
(n=9) and final amendment to 150 mg/m2 (n=52)
1 cycle FOLFOXIRI
prior R wasallowed
Geissler

41. 19
PRIMARY ENDPOINT: OBJECTIVE
RESPONSE RATE
mFOLFOXIRI +
panitumumab
N=63
FOLFOXIRI
N=33
Odds ratio p% 95%-CI % 95%-CI
85.7 74.6 – 93.3 60.6 42.1 – 77.1
3.900
(1.44-10.52)
0.0096
85.7
60.6

42. 20
EVALUATION OF RESPONSE
SIDEDNESS + GENOTYPE
OR4.518
(1.29-15.71)
P=0.0210
OR2.500
(0.37-16.88)
P=0.6372
OR8.750
(0.9-84.80)
P=0.1262
N=60
OR3.364
(0.90-12.54)
P=0.0806
N=16N=78 N=18
90.6
68.0
60.0
37.5
86.0
64.7
71.4
22.2

43. 22
SUMMARY (I)
• VOLFI 1st RCT comparing FOLFOXIRI to FOLFOXIRI + mAb
• Primary endpoint met: improved ORR.
• Panitumumab + FOLFOXIRI high RR in left and right sided as well as BRAFmt
mCRC.
• Increased toxicity
• The high RR are of interest for
• symptomatic patients
• pts.with a chance of secondary resections of initially unresectable metastatic dis

44. Right Left
DC
Tripplet?/
Doublet
+/-VEGF?
Doublet＋
EGFR
CyR Doublet＋
EGFR
Doublet＋
EGFR
Right Left
DC
Doublet+
VEGF
Doublet＋
EGFR
CyR
Triplet+
VEGF
Doublet＋
EGFR
Right Left
DC
Doublet
+VEGF
Doublet＋
EGFR
CyR
Doublet＋
EGFR
Triplet+
VEGF
Doublet＋
EGFR
Different perspective about sidedness from EU and US
Key opinion leaders have changed their
thought
DC, disease control. CyR, cytoreduction
Treatment of RAS wt mCRC

46. 1. Reinforce the use of EGFR antibody therapy in patients
with mCRC and left-sided RAS wt tumors
2. Promote the idea that patients with right-sided RAS wt
tumors might be better treated with chemotherapy alone
or chemotherapy plus bevacizumab, except maybe if the
goal is cytoreduction (?)
3. Emphasize that in the absence of data on specific
treatment sequences, there is no reason that EGFR-antibody
therapy should be avoided in cases of disease progression
or treatment intolerance independent of primary
tumor location
4. Promote the concept of a “continuum of care” and the
sequential use of all therapies, including bevacizumab
where appropriate, in the treatment of patients with mCRC
Conclusions
wt, wildtype
Arnold D, et al. Ann Oncol. 2017;28(8):1713-1729.

47. Thank You