Colorectal cancer management

1. Colorectal Cancer

2. Cancers of the Colon and Rectum
International Statistics
Colorectal cancer is the 3rd most
common cancer in
men and the 2nd in women.
Incidence
Mortality
1.2 Million
609,000
Worldwide
Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014

3. Colorectal Carcinogenesis
Shiff S J , Rigas B J Exp Med 1999;190:445-450

4. CRC Risk Factors
• Intrinsic
• Age
• Personal history of colorectal
polyps or cancer
• Inflammatory bowel disease
• Race/ethnicity
• CRC family history
• Inherited syndromes
• FAP
• HNPCC
• Extrinsic
• Diet
• Red meat, processed meat
• Cooking methods
• Physical inactivity
• Obesity
• Smoking
• Alcohol
• Type II diabetes
American Cancer Society http://www.cancer.org/docroot/CRI/content/CRI_2_4_2X_What_are_the_risk_factors_for_colon_and_rectum_cancer.asp

5. Risk of Colorectal Cancer
0 20 40 60 80 100
General population
Personal history of
colorectal neoplasia
Inflammatory
bowel disease
HNPCC mutation
FAP
5%
15%–20%
15%–40%
70%–80%
>95%
Lifetime risk (%)
Aarnio M et al. Int J Cancer 64:430, 1995 , Houlston RS et al. Br Med J 301:366, 1990 , St John DJ et al. Ann Intern Med 118:785, 1993

6. Familial Risks
Approximate
lifetime
CRC risk
(%)
Affected family members
0
20
40
60
80
100
None One 1° One 1°
and two
2°
One 1°
age
<45
Two 1° HNPCC
mutation
2%
6% 8% 10%
17%
70%
Aarnio M et al. Int J Cancer 64:430, 1995 , Houlston RS et al. Br Med J 301:366, 1990 , St John DJ et al. Ann Intern Med 118:785, 1993

7. Clinical Presentation

8. CRC by Site

9. Stage at Diagnosis
Localized
(confined
to primary
site)
39%
Regional
(spread to
regional
lymphnod
es)
37%
Distant
(cancer has
metastasiz
ed)
19%
Unknown
(unstaged)
5%
Adapted from NCI Cancer Facts and Figures 2010

10. Staging Workup
• Endoscopy with biopsy
• CT Scan
• CXR
• ?PET Scan
• CEA

11. TNM Staging (AJCC-7)

12. Surgery: Considerations
• High Risk Features
• Grade 3 or 4
• Lymphovascular invasion
• Bowel obstruction
• <12 lymph nodes examined
• T4 lesion
• Tumor perforation
• Inadequate or close surgical margins
• Tumor Subsite Location*
• For Rectal Cancer- Total Mesorectal Excision
*Wray, C, Hinojosa, MW, Ziogas, A, Le, H, Stamos, MJ, and Zell, JA. Tumor subsite location within the colon is prognostic for survival after colon cancer diagnosis. Dis Colon Rectum, 2009
Aug;52(8):1359-66.

13. Colorectal Cancer:
Chemotherapeutic & Biologic Agents
• Chemotherapy
• 5-Fluorouracil (5FU) + leucovorin
• Capecitabine
• Oxaliplatin
• Irinotecan (CPT-11)
• Biologic Agents
• Bevacizumab
• US FDA approved 2/26/04
• Cetuximab
• US FDA approved 2/12/04
• Panitumumab
• US FDA approved 9/27/06
• Ziv-aflibercept
• US FDA approved 8/3/12
• Regorafenib
• US FDA approved 9/27/12

14. “Personalized Medicine”
(Molecular Diagnostics)
• Patient-Specific Tests
• UGT-1A1 polymorphism
• Dihydropyrimidine dehydrogenase (DPD)
deficiency
• Tumor-Specific Tests
• Microsatellite Instability (MSI)
• KRAS mutation analysis
 Codons 12, 13, 61
• Extended RAS testing
 KRAS, NRAS
• BRAF V600E mutation
• Gene Signature Profiling
• Circulating Tumor Cells
 FDA approved in 2007

15. NCCN Guidelines for Treatment of Colon Cancer
Clinical Workup Findings Surgery
Presentation
Resectable
colon
cancer
(M0)
•Pathology
review
•Colonoscopy
•CBC,
chemistry
profile, CEA
•CT-C/A/P
•PET-CT not
routinely
indicated
Resectable:
non-
obstructing
Resectable:
obstructing
(unprepped)
Locally
unresectable
or medically
inoperable
Colectomy + en bloc removal
of regional lymph nodes
Colectomy + en bloc
removal of regional
lymph nodes
or
Resection + diversion
or
Stent
or
Diversion
Systemic Chemotherapy
www.nccn.org v.2.2016
Clinical T4b
Consider Neoadjuvant Therapy

16. NCCN Guidelines for Treatment of Colon Cancer
www.nccn.org v.2.2016
Pathologic Stage Adjuvant Therapy
Tis, T1N0M0,
T2N0M0
None
SURVEILLANCE
T3N0M0, no high-
risk features
Capecitabine or
5FU/LV or Clinical
Trial or Observation
T3N0M0 w/ high-
risk features: grade
3-4, lymphovascular
invasion, bowel
obstruction, <12
lymph nodes
examined, perforation,
close/indet./+margins
FOLFOX or
Capecitabine or
5FU/LV or CAPOX
or Clinical Trial or
Observation
TanyN1-3M0
FOLFOX, CAPOX,
Capecitabine or
5FU/LV or Clinical Trial

17. Stage 0 or Stage I
Colon Cancer
• Surgery
• Colonoscopy Surveillance

18. Approaches To Surgical Resection Of Colon Cancer
• Colonoscopic Resection of Polyps
• Anatomic Resection
• Total Abdominal Colectomy
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

19. Colonoscopic Resection of Polyps
• Lesions of the colon are first detected during endoscopic procedures
• Pathologic examination of the tissue
• Only definitive way to make a diagnosis of malignancy
• Goal of a colonoscopic biopsy or resection
• Remove the lesion in its entirety and preserve a tissue architecture
• Various techniques can be employed for the removal of lesions in the colon
depending on their size and location
• Two most commonly employed instruments used during a colonoscopy
• Biopsy forceps and snares
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

20. Anatomic Resection
• For invasive carcinomas of the colon, stages I through III
• Surgical approach will be dictated by the size and location of lesions in the colon
• Location will determine what region of bowel is removed
• Extent of its resection is dictated by its vascular and lymphatic supply
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

21. Anatomic Resection
Surgical resection for a cecal or ascending
colon cancer
Surgical resection for a cancer at the
hepatic flexure
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

22. Anatomic Resection
Surgical resection for a descending
colon cancer
Preferred surgical procedure for cancer of the middle
and proximal sigmoid colon. In poor-risk patients, the
inferior mesenteric artery and the left colic artery may
be preserved.
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

23. Anatomic Resection
Surgical resection for cancer of the rectosigmoid A more radical surgical resection for cancer of the
rectosigmoid.
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

24. Total Abdominal Colectomy (TAC)
• TAC may be required for patients with
• Ulcerative colitis
• Familial polyposis syndrome who
• Either have evidence of invasive carcinoma
• Or are at significant risk for the development of invasive carcinoma
Ligation of the ileocolic, right colic, middle colic, left colic, and sigmoid branches will allow for removal
of the colon down to the peritoneal reflection.
Mobilization of the right colon, transverse colon along the omentum, taking the omentum as part of the
resection, the hepatic and splenic flexures, as well as the complete mobilization of the descending colon
down to the peritoneal reflection
Procedure
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology, 10th edition

25. Stage II Colon Cancer
“Adjuvant Chemotherapy for Stage II Colon Cancer:
Are We Closer to Finding the Patients Who
Benefit?”
Vergo, M, et al., ASCO 2010 Education Book, pp
123-9.
*Kerr, D, et al. J Clin Oncol, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition); 27(15S) (May 20 Suppl), 2009: 4000
Surgical Resection, Stage
II Colon Cancer
MSI-H
No chemotherapy
after discussion
with patient
MSI-Low/MSS
High-Risk Clinical &
Pathological
Features
Molecular Risk
Profile*
Consider chemotherapy
after discussion with patient
Moderate (>=5%) or
small (3-4%) absolute
benefit from
chemotherapy
Very small (<3%)
absolute benefit
from chemotherapy
Consider chemotherapy
after d/w patient
No chemotherapy after
d/w patient

26. Stage II Colon Cancer
MSI Status is Prognostic
Ribic, CM et al, New England J Medicine 349 (3):247-257, 2003
MSI-H
MSS/MSI-L

27. MSI and Adjuvant
5FU-based
Chemotherapy
Ribic, CM et al, New England J Medicine 349 (3):247-257, 2003
MSS/MSI-L
MSI-H

28. Stage III Colon Cancer
• Adjuvant chemotherapy:
• 5FU, leucovorin, oxaliplatin (FOLFOX)
• Mosaic Trial1
• NSABP C-072
• Capecitabine, oxaliplatin3 (CAPOX)
• Biological Agents?
1
Andre, T., et al, N Engl J Med 2004; 350:2343-2351 2
Kuebler, JP et al, J Clin Oncol 2007 25, 2198-2204. 3Haller, DG, et al, J Clin Oncol. 2011 Apr 10;29(11):1465-71.

29. Stage III Colon Cancer (cont’d):
• Adjuvant chemotherapy:
• Duration of treatment? 6 months
• CALGB 80702 (6 months vs. 3 months FOLFOX)
• Calcium/Magnesium Salts  No benefit1
1Loprinzi, C, et al, J Clin Oncol 31, 2013 (suppl; abstr 3501)

30. Stage IV Colorectal Cancer

31. NCCN Guidelines 2016: Rectal Cancer

32. Colorectal Cancer Clinical Management Decisions
• Goal: cure or palliation
• Address primary
• Yes or no
• Now or later
• Chemotherapy
• FOLFOX/FOLFIRI/FOLFOXIRI/capecitabine
• Biologic upfront: bevacizumab or EGFR Ab
• Treatment holiday: yes or no
• Maintenance therapy: yes or no

33. Neoadjuvant Chemotherapy:
Risks/Benefits
• Risks
• Early progression precludes surgery
• Chemotherapy-associated liver damage
• Benefits
• Patients progressing on initial therapy have unfavorable tumor biology and resection is
likely not to be curative
• Renders borderline lesions resectable

34. Phase III study:
patients with CRC and
resectable liver
metastases;
WHO/ECOG
performance
status 0-2
(N = 364)
FOLFOX4
for 6 cycles (12 wks)
(n = 182)
Surgery
(n = 182)
Surgery
FOLFOX4
for 6 cycles (12 wks)
EORTC 40983: FOLFOX4 in mCRC With Resectable Liver Metastases
Primary endpoint: PFS
Secondary endpoints: OS, complete resection
Nordlinger B, et al. Lancet. 2008;371:1007-1016.

35. Yrs
0 1 2 3 4 5 6
HR: 0.77 (95.66% CI:
0.60-1.00; P = .041)
Periop CT
28.1%
36.2%
+8.1% at 3 yrs
0
20
40
60
80
100
Surgery only
PFS(%)
EORTC: Resectable Liver Metastases PFS
• 5-yr OS rate was not significantly different between FOLFOX or surgery alone
(51.2% vs 47.8%; P = .34)
Nordlinger B, et al. Lancet. 2008;371:1007-1016. Nordlinger B, et al. Lancet Oncol. 2013;14:1208-1215.

36. Key First-line Chemotherapy Trials in mCRC: Efficacy
Comparative Regimens Median PFS, Mos Median OS, Mos
IFL vs FOLFOX vs IROX[1] 6.9 vs 8.7 vs 6.5 15.0 vs 19.5 vs 17.4
FOLFIRI vs FOLFOX4[2] 7.0 vs 7.0 14.0 vs 15.0
XELOX (CapeOx) vs FOLFOX4[3,4] 7.3 vs 7.7 19.0 vs 18.9
FOLFIRI vs mIFL vs CapeIRI[5] 7.6 vs 5.9 vs 5.8 23.1 vs 17.6 vs 18.9
1. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et al. J Clin Oncol. 2005;23:4866-4875. 3. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012. 4. Cassidy J, et al. Br J Cancer.
2011;105:58-64. 5. Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.

37. Phase III Trials of FOLFOXIRI vs FOLFIRI as First-line Therapy for Advanced
CRC
Trial RR, % Median TTP/PFS, Mos Median OS, Mos
Souglakos
(n = 283)
43.0 vs 33.6 8.4 vs 6.9 21.5 vs 19.5
Falcone
(n = 244)
60 vs 34* 9.8 vs 6.9* 22.6 vs 16.7*
Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
*Statistically significant difference.

38. VEGF-A[2,3]
VEGF-R1[1,2]
(Flt-1)
Migration
Invasion
Survival
VEGF-R3
(Flt-4)
Lymphangiogenesis
VEGF-R2[1]
(KDR/Flk-1)
Proliferation
Survival
Permeability
PlGF[3]
VEGF-B
VEGF-C,
VEGF-D[2]
Functions
Bevacizumab
Ramucirumab
Ziv-aflibercept
(VEGF Trap)[1]
1. Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398. 2. Roy H, et al. FASEB J. 2006;20:2159-2161. 3. Ghosh D, et al. Mol Hum Reprod. 2000;6:935-941.
Large Molecule VEGF Inhibitors

39. First-line Chemotherapy + Bevacizumab in mCRC: Efficacy
Comparative Regimens, Mos PFS OS
IFL/Bev vs IFL[1] 10.6 vs 6.2 20.3 vs 15.6
FOLFOX4/XELOX/Bev vs
FOLFOX4/XELOX[2] 9.4 vs 8.0 21.3 vs 19.9
1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019.

40. 1. Bevacizumab [package insert]. 2. Nalluri SR, et al. JAMA. 2008;300:2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.
Adverse Event Incidence With Bev
Across Indications,[1] %
Comments
Grade ≥ 3 ATE 2.6  Risk of ATE increased in pts 65 yrs of age or older
or with ATE history
Grade 3/4 HTN 5-18*  Pts should receive otherwise standard CV
prophylaxis and have BP monitored and managed
GI perforations 0.3-2.4
Grade ≥ 3
hemorrhagic event
1.2-4.6†  Bev not recommended for pts with serious
hemorrhage or recent hemoptysis
 Risk of major bleeding does not appear to be
increased in pts receiving full-dose anticoagulation
tx without other risk factors
Wound
complications
15‡  Discontinue 4-8 wks before surgery; resume
6-8 wks postsurgery
 Potential for increased VTE risk controversial; increased risk noted in 1 study but not
in others[2,3]
*Predominantly grade 3. †May apply more to NSCLC. ‡When surgery conducted during Bev therapy.
Bevacizumab-Associated Toxicity

41. Extracellular
Intracellular
Ligand
EGFR
PI3K
Akt
Ras
Raf
MEK
MAPK
Cell motility
Metastasis
Proliferation
Cell survival
DNA
PTEN
EGFR in CRC
 KRAS mutant
 Resistant to EGFR Abs
Ras
Angiogenesis

42. NCCN Guideline 2016: Colon Cancer

43. Trial Comparative Regimens Median PFS, Mos Median OS, Mos
CRYSTAL[1] FOLFIRI/Cetux vs FOLFIRI 9.9 vs 8.4 23.5 vs 20.0
PRIME[2-4]
FOLFOX4/Pmab vs FOLFOX4 9.6 vs 8.0 23.8 vs 19.4
FOLFOX4/Pmab vs FOLFOX4
(KRAS/NRAS WT)
10.1 vs 7.9 26.0 vs 20.2
COIN[5] FOLFOX/XELOX/Cetux vs
FOLFOX/XELOX
8.6 vs 8.6 17.0 vs 17.9
EGFR-Targeted Agents as First-line Therapy in KRAS WT mCRC: Efficacy
• Worse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease[3]
1. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. 3. Douillard JY, et al. ASCO 2013. Abstract 3620. 4. Douillard JY, et al. N Engl J
Med. 2013;369:1023-1034. 5. Maughan TS, et al. Lancet. 2011;377:2103-2114.

44. What Is a Biomarker?
• “Any measurable diagnostic indicator that is used to assess the risk or presence of disease”
• Includes tests for:
• Future risk
• Screening
• Diagnosis
• Prognosis
• Staging
• Monitoring response
• Optimizing treatment outcomes
Gutman S, et al. Nat Rev Cancer. 2006;6:565-571.

45. Molecular Biomarker Profiling for Colon Cancer
• Current NCCN guideline recommendations[1]
• KRAS/NRAS mutation
• BRAF mutation
• Consider only if KRAS mutation is negative
• Further genetic characterization of CRC is continuing[2]
• CRC as many diseases?
• Potential for more biomarkers for personalizing therapy
1. NCCN. Clinical Practice Guidelines In Oncology (NCCN Guidelines) for Colon Cancer. V.3.2014. 2. Moorcraft SY, et al. Therap Adv Gastroenterol. 2013;6:381-395.

46. BRAF Mutations in CRC
• BRAF is primary effector of KRAS
signaling[1]
• BRAF mutations:
• Occur most frequently in exon 15
(V600E)[1]
• Found in 4% to 14% of pts with CRC[1]
• Mutually exclusive with KRAS
mutations[1,2] Raf
MEK
Erk
Tumor cell
proliferation
and survival
EGF
Tumor cell
RasP P
P P
1. Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712. 2. Artale S, et al. J Clin Oncol. 2008;26:4217-4219.

47. CRYSTAL Trial
KRAS WT/BRAF WT
(n = 566)
KRAS WT/BRAF MT
(n = 59)
FOLFIRI
(n = 289)
Cetuximab +
FOLFIRI
(n = 277)
FOLFIRI
(n = 33)
Cetuximab +
FOLFIRI
(n = 26)
Median OS, mos
(95% CI)
21.6
(20.0-24.9)
25.1
(22.5-28.7)
10.3
(8.4-14.9)
14.1
(8.5-18.5)
HR (95% CI)
P value*
0.830 (0.687-1.004)
.0547
0.908 (0.507-1.624)
.7440
Median PFS, mos
(95% CI)
8.8
(7.6-9.4)
10.9
(9.4-11.8)
5.6
(3.5-8.1)
8.0
(3.6-9.1)
HR (95% CI)
P value*
0.673 (0.528-0.858)
.0013
0.934 (0.425-2.056)
0.8656
OR rate, %
(95% CI)
42.6
(36.8-48.5)
61.0
(55.0-66.8)
15.2
(5.1-31.9)
19.2
(6.6-39.4)
P value† < .0001 .9136
Clinical Efficacy in KRAS Wild-Type Tumors by BRAF Mutation Status
*Stratified log-rank test. †Cochran-Mantel-Haenszel test.
Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019.

48. Mutations in KRAS, NRAS, and BRAF Distribution and Prognostic
Significance
BRAF mutation All patients
Any mutation
KRAS mutation
KRAS WT
All WT
Mutation Status
0
6
12
MedianPFS
(Mos)
Arm A Arm B
0
6
12
18
MedianOS
(Mos)
57
340
268
815
367
289
45
366
297
815
362
292
0
10
20
30
40
2-YrOS(%)
Prognostic Effect of Mutational Status
“All WT”
n = 581
(44%)
KRAS MT
n = 565
(43%)
NRAS MT
n = 50 (4%)
BRAF MT
n = 102 (8%)
Total
N = 1316 (81%)
554
11
39
10
2
Population n (%) Arm A Arm B
ITT 1630 815 815
Assessed for mutations 1316 648 668
 KRAS mutation
 NRAS mutation
 BRAF mutation
565 (43)
50 (4)
102 (8)
268
18
57
297
32
45
KRAS WT 729 (55) 367 362
KRAS/NRAS/BRAF WT
“All WT”
581 (44) 289 292
Maughan TS, et al. ASCO 2010. Abstract 3502.

49. FOLFIRI + Cetuximab
Cetuximab: 400 mg/m2 IV 120 min initial dose
250 mg/m2 IV 60 min q1w
FOLFIRI + Bevacizumab
Bevacizumab: 5 mg/kg IV 30-90 min q2w
mCRC first-line
therapy
KRAS wild-type
(N = 592)
Randomize
1:1
FOLFIRI q2w: 5-FU: 400 mg/m2 (IV bolus)
folinic acid: 400mg/m2
irinotecan: 180 mg/m2
5-FU: 2400 mg/m2 (IV 46 hrs)
Phase III FIRE-3 Trial: First-line FOLFIRI + Either Cetux or Bev in KRAS WT
mCRC
• Primary endpoint: ORR (mRECIST 1.0)
• Amendment in October 2008 to include only KRAS WT (ex 12/13) pts
• 150 active centers in Germany and Austria
Heinemann V, et al. ASCO 2013. Abstract LBA3506.

50. Heinemann V, et al. ASCO 2013. Abstract LBA3506.
Cetuximab + CT Bevacizumab + CT P Value
ORR, %
(primary endpoint not met)
62 58 .183
PFS, mos 10.0 10.3 .547
Mos Since Start of Treatment
Cetuximab + CT (FOLFIRI)
Bevacizumab + CT (FOLFIRI)
OSEstimate
HR: 0.77
P = .017
28.7
mos
25.0
mos
0.75
1.00
0.50
0.25
0
12 24 36 48 60 72
Δ = 3.7 mos
FIRE-3 Trial of First-line FOLFIRI + Either Cetux or Bev in KRAS WT mCRC:
OS
0

51. Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC
• Primary endpoint: OS
• Secondary endpoints: ORR, PFS, TTF, duration of response
Patients with mCRC
and KRAS WT (codons
12, 13),
ECOG PS 0/1
(N = 1137)
FOLFOX or FOLFIRI +
Bevacizumab q2w
(n = 559)
ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..
FOLFOX or FOLFIRI +
Cetuximab q1w
(N = 578)
A third arm with CT + bevacizumab + cetuximab was
closed to accrual in September 2009

52. CALGB/SWOG 80405: OS in the ITT Population
mOS (95% CI), mos
CT + Cetux 29.9 (27.0-32.9)
CT + Bev 29.0 (25.7-31.2)
HR 0.925 (0.78-1.09)
P = 0.34
Venook AP, et al. ASCO 2014. Abstract LBA3.
0
12 24 36 48 60 72
Mos
80
100
60
40
0
OS(%)
20
84

53. 80405: OS in Patients Rendered Disease Free With Systemic Therapy +
Surgery
N (Events) mOS, Mos (95% CI)
124 (34) 66.3 (59.8-NA)
Venook AP, et al. ASCO 2014. Abstract LBA3.
0
12 24 36 48 60 72
80
100
60
40
0
OS(%)
20
84
Mos

54. EORTC Global QoL
Venook AP, et al. ASCO 2014. Abstract LBA3.
CALGB/SWOG 80405: QoL and Symptoms
• Hypotheses: cetuximab will reduce satisfaction with appearance and diminish overall quality of life
100
80
70
60
50
40
30
20
10
0
90
Score(0-100Scale,Higher
ScoresRepresentBetterQoL)
Baseline Wk 6 Mo 3 Mo 6 Mo 9
P = .0546
Chemo/Bev Chemo/Cet
DSQL Skin Satisfaction
Baseline Wk 6 Mo 3 Mo 6 Mo 9
P < .0001

55. Analysis of KRAS/NRAS Mutations: FOLFOX ± Panitumumab
Douillard JY, et al. N Engl J Med. 2013;369:1023-1034.
PFS
Subgroup n HR for Progression or Death (95% CI)
Primary analysis
Nonmutated KRAS exon 2 656 0.80 (0.66-0.97)
Mutated KRAS exon 2 440 1.29 (1.04-1.62)
Prospective-retrospective analysis
Nonmutated RAS 512 0.72 (0.58-0.90)
Mutated RAS 548 1.31 (1.07-1.60)
Nonmutated KRAS exon 2, mutated other RAS 108 1.28 (0.79-2.07)
0.40 0.63 1.00 1.58 2.51
Panitumumab-FOLFOX4 Better FOLFOX4 Alone Better
OS
Subgroup n HR for Progression or Death (95% CI)
Primary analysis
Nonmutated KRAS exon 2 656 0.83 (0.67-1.02)
Mutated KRAS exon 2 440 1.24 (0.98-1.57)
Prospective-retrospective analysis
Nonmutated RAS 512 0.78 (0.62-0.99)
Mutated RAS 548 1.25 (1.02-1.55)
Nonmutated KRAS exon 2, mutated other RAS 108 1.29 (0.79-2.10)
0.40 0.63 1.00 1.58 2.51
Panitumumab-FOLFOX4 Better FOLFOX4 Alone Better

56. Events,
n/N (%)
Median,
Mos
95% CI
― FOLFIRI + cetuximab 91/171
(53.2)
33.1 24.5-
39.4
― FOLFIRI + bevacizumab 110/171
(64.3)
25.6 22.7-
28.6
HR: 0.70 (95% CI: 0.53-0.92; log-rank P = .011)
171
171
Pts at
Risk, n
128
127
71
68
39
26
20
9
6
1
Δ = 7.5 mos
*KRAS and NRAS exon 2, 3, and 4 wild type.
0
12 24 36 48 60 72
Mos Since Start of Treatment
0.75
1.0
0.50
0.25
0
ProbabilityofSurvival
FIRE-3: OS According to RAS* Wild Type
Stintzing S, et al. ECC 2013. Abstract LBA17.

57. Where Are We Now? 80405 and FIRE-3
• 70% FOLFOX (and some of other 30% failed FOLFOX adjuvant)
• Does chemotherapy backbone matter?
• Does all WT RAS status refine populations?
• Await expanded RAS analysis from 80405 for comparison
• Other data from 80405 forthcoming
• Complete molecular analyses
• Special subsets
–Meanwhile: PATIENTS AND DOCTORS HAVE CHOICES

58. NCCN Guideline 2016: Colon Cancer

59. NCCN Guideline 2016: Colon Cancer

60. NCCN Guideline 2016: Colon Cancer

61. Management Following Progression on Initial Therapy
for Metastatic Colorectal Cancer

62. Targeting Angiogenesis at Progression in mCRC

63. VEGF-A[2,3]
VEGF-R1[1,2]
(Flt-1)
Migration
Invasion
Survival
VEGF-R3
(Flt-4)
Lymphangiogenes
is
VEGF-R2[1]
(KDR/Flk-1)
Proliferation
Survival
Permeability
PlGF[3]
VEGF-B
VEGF-C,
VEGF-D[2]
Functions
Bevacizumab
Ramucirumab
Ziv-aflibercept
(VEGF Trap)[1]
1. Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398. 2. Roy H, et al. FASEB J. 2006;20:2159-2161. 3. Ghosh D, et al. Mol Hum Reprod. 2000;6:935-941.
Large Molecule VEGF Inhibitors

64. ML18147 (TML): Continuing Bevacizumab Beyond Progression
Standard second-line CT (oxaliplatin or
irinotecan based) until PD
(n = 411)
Bev 2.5 mg/kg/wk +
standard second-line CT (oxaliplatin or
irinotecan-based) until PD
(n = 409)
Progressive mCRC after Bev
+ standard first-line CT
(either oxaliplatin or
irinotecan based)
(n = 820)
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
Stratified by first-line CT (oxaliplatin or irinotecan based),
first-line PFS (≤ 9 or > 9 mos), time
from last Bev dose (≤ 42 or > 42 days),
ECOG PS at baseline (0/1 or 2)
Primary endpoint: OS
Secondary endpoints: PFS, BORR, safety
CT switch
Oxal → Iri
Iri → Oxal

65. ML18147 (TML): Continuing Bevacizumab Beyond Progression Increases
OS (ITT)
OS(%)
Mos
CT (n = 410)
Bev + CT (n = 409)
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
9.8 mos 11.2 mos
Unstratified* HR: 0.81 (95% CI: 0.69-
0.94; log-rank P = .0062)
Stratified† HR: 0.83 (95% CI: 0.71-
0.97; log-rank P = .0211)
*Primary analysis method. †Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS
(≤ 9 mos, > 9 mos), time from last dose of Bev (≤ 42 days, > 42 days), ECOG PS at baseline (0/1 vs 2).
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
100
80
60
40
20
0
PFS(%)
0 6 12 18 24 30 36 42
Mos
Unstratified* HR: 0.68 (95% CI: 0.59-
0.78; log-rank P < .0001)
Stratified† HR: 0.67 (95% CI: 0.58-0.78;
log-rank P < .0001)
4.1mos
5.7 mos

66. Phase III VELOUR Study: FOLFIRI ± ziv-Aflibercept as Second-line Therapy in
mCRC
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, safety, immunogenicity
Patients with mCRC
progressing on first-line
oxaliplatin-based
chemotherapy*
(N = 1226)
FOLFIRI + ziv-Aflibercept 4 mg/kg q2w
(n = 612)
FOLFIRI + Placebo q2w
(n = 614)
*30% had previous bevacizumab
Stratified by previous bevacizumab (yes vs no),
ECOG PS (0 vs 1 vs 2)
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalTrials.gov. NCT00561470.

67. Strata (as per IVRS) N HR (95.34% CI) HR
Interaction
P Value
All patients 1226 0.82 (0.713-0.937)
Previous Bev
No
Yes
853
373
0.79 (0.669-0.927)
0.86 (0.673-1.104)
.5668
0 1 2 3
Favors PlaceboFavors Aflibercept
Strata (as per IVRS) N HR (95% CI) HR
Interaction
P Value
All patients 1226 0.76 (0.661-0.869)
Previous Bev
No
Yes
853
373
0.80 (0.679-0.936)
0.66 (0.512-0.852)
.1958
0 1 2 3
Favors PlaceboFavors Aflibercept
OS
PFS
VELOUR: OS and PFS Stratified by Previous Bevacizumab
Adapted from Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.

68. VELOUR Safety Analysis: Most Frequent AEs*
Safety Population, % of Patients
Placebo (n = 605) Aflibercept (n = 611)
All Grades Grade 3/4 All Grades Grade 3/4
Diarrhea 56.5 7.8 69.2 19.3
Neutropenia
 Complicated neutropenia
56.3 29.5
2.9
67.8 36.7
5.7
Asthenic conditions (HLT) 50.2 10.6 60.4 16.8
Stomatitis and ulceration (HLT) 34.9 5.0 54.8 13.8
AEs leading to treatment discontinuation:
AFL: 26.8%
PL: 12.1%
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.
*≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events.

69. Ramucirumab versus placebo in combination with second line
FOLFIRI in patients with metastatic colorectal carcinoma
that progressed during or after first-line therapy with
bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE):
a randomised, double-blind, multicentre, phase 3 study
Tabernerro, 2015, www.thelancet.com/oncology, http://dx.doi.org/10.1016/S1470-2045(15)70127-0

70. Overall survival and Progression-free survival
Kaplan-Meier survival estimates in the intention-to-treat population
The median OS was 13.3 months in the ramucirumab group compared with 11.7 months in
the placebo group (hazard ratio, HR 0.84, p=0.0219)
The PFS HR was 0.79 (p = 0.0005). Median PFS with ramucirumab was 5.7 months and 4.5
months for placebo
The ORR was 13.4% in the ramucirumab arm and 12.5% in the placebo arm (p = 0.6336)
Tabernerro, 2015, www.thelancet.com/oncology, http://dx.doi.org/10.1016/S1470-2045(15)70127-0

71. Overall survival and Progression-free survival: Subgroup analysis
Subgroup results were consistent with the OS and PFS results.
Tabernerro, 2015, www.thelancet.com/oncology, http://dx.doi.org/10.1016/S1470-2045(15)70127-0

72. Regorafenib: An Oral Multikinase Inhibitor Targeting Multiple Tumor
Pathways
• Inhibition of proliferation
• KIT, PDGFR, RET
• Inhibition of tumor microenvironment
signaling
• PDGFR-β, FGFR
• Inhibition of neoangiogenesis
• VEGFR1-3, TIE2
Biochemical
Activity
Regorafenib IC50
Mean ± SD nmol/l (n)
VEGFR1 13 ± 0.4 (2)
Murine VEGFR2 4.2 ± 1.6 (10)
Murine VEGFR3 46 ± 10 (4)
TIE2 311 ± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202 ± 18 (6)
KIT 7 ± 2 (4)
RET 1.5 ± 0.7 (2)
RAF-1 2.5 ± 0.6 (4)
B-RAF 28 ± 10 (6)
B-RAFV600E 19 ± 6 (6)
1.Wilhelm SM, et al. Int J Cancer, 2011;129:245-255. 2. Mross K, et al. Clin Cancer Res. 2012;18:2658-2667. 3. Strumberg D, et al. Expert Opin Invest Drugs. 2012;21:879-899.

73. CORRECT: Regorafenib After Progression on All Available Std Therapies in
mCRC
• Primary endpoint: OS
• ~ 50% of patients with ≥ 4 systemic therapies
• All patients had received bevacizumab
Patients with
progression after all
available standard
therapies
(N = 760)
Arm A: Regorafenib 160 mg PO QD + BSC
3 wks on, 1 wk off
(n = 505)
Arm B: Placebo + BSC
3 wks on, 1 wk off
(n = 255)
2:1
Grothey A, et al. Lancet. 2013;381:303-312.

74. Primary endpoint met prespecified stopping criteria at second interim analysis
(1-sided P ≤ .009279 at ~ 74% of events required for final analysis)
100
50
25
0
75
Mos From Randomization
OS(%)
HR: 0.77 (95% CI: 0.64-0.94;
P = .0052)
Regorafenib Placebo
Median OS, mos 6.4 5.0
IQR 3.6-11.8 2.8-10.4
Placebo (n = 255)
Regorafenib (n = 505)
Grothey A, et al. Lancet. 2013;381:303-312.
0 2 4 6 8 10 12 14
Regorafenib Placebo
Median PFS, mos 1.9 1.7
IQR 1.6-3.9 1.4-1.9
0 2 4 6 8 10 12
Mos From Randomization
100
50
25
0
75
PFS(%)
Placebo (n = 255)
Regorafenib (n = 505)
HR: 0.49 (95% CI: 0.42-0.58;
P < .0001)
CORRECT: Regorafenib After Progression on All Available Std Therapies in
mCRC

75. Adverse Event Regorafenib (n = 500) Placebo (n = 253)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
Hand–foot skin reaction 47 17 0 8 < 1 0
Fatigue 47 9 < 1 28 5 < 1
Hypertension 28 7 0 6 1 0
Diarrhea 34 7 < 1 8 1 0
Rash/desquamation 26 6 0 4 0 0
Anorexia 30 3 0 15 3 0
Oral mucositis 27 3 0 4 0 0
Thrombocytopenia 13 3 < 1 2 < 1 0
Fever 10 1 0 3 0 0
Nausea 14 < 1 0 11 0 0
CORRECT: Adverse Events Occurring in ≥ 10% of Patients
Dose modification due to adverse event in 67% of patients receiving regorafenib vs 23% of patients receiving
placebo
Grothey A, et al. Lancet. 2013;381:303-312.

76. Management of Hand–Foot Skin Reactions With Regorafenib
• Occurs as early as 2-3 wks
• Painful blistering plaques or rash
• Tender thickened plaques may develop on
fingertips
• Management of the HFSR:
• Minimize friction and trauma with comfortable
well-fitting shoes and protective gloves
• Topical corticosteroids to minimize inflammation
on the hands and feet
• Keratolytic creams such as urea or lactic acid to
minimize inflammation and thickened
hyperkeratotic plaques
• Dose reduction, interruption, or discontinuation
of regorafenib depending on the grade of toxicity
1. Urban C, et al. J Gastrointest Oncol. 2013;4:319-327. 2. Lacouture ME. ASCO Post. 2012;3:85

77. Targeting EGFR at
Progression in mCRC

78. Second-line Therapy With EGFR-Targeted mAbs in KRAS WT mCRC
Trial Comparative Regimens PFS, Mos OS, Mos
EPIC[1] Irinotecan/Cetux vs Irinotecan 4.0 vs 2.6* 10.7 vs 10.0
181[2] FOLFIRI/Pmab vs FOLFIRI 5.9 vs 3.9* 14.5 vs 12.5
SPIRITT[3] FOLFIRI/Pmab vs FOLFIRI/Bev 7.7 vs 9.2 18.0 vs 21.4
PICCOLO[4] Irinotecan/Pmab vs Irinotecan HR: 0.78† 10.9 vs 10.4
1. Sobrero AF, et al. J Clin Oncol. 2008;26:2311-2319. 2. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713. 3. Hecht JR, et al. ASCO 2013. Abstract 335. 4. Seymour MT, et al. Lancet Oncol.
2013;14:749-759.
*Statistically significant difference. Retrospective KRAS analysis(< 25% of pts enrolled).
†P = .015

79. Panitumumab vs BSC in Chemo-Refractory mCRC: Median PFS
Amando RG, et al. J Clin Oncol. 2008;26:1626-1634.
KRAS MT
KRAS WT
Proportion
EventFree(%)
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52Pts at Risk, n
Panit + BSC
BSC alone
Treatment Group
Panit + BSC
BSC alone
Events
76
95
N
84
100
%
90
95
Median, Wks
7.4
7.3
HR: 0.99 (95% CI: 0.73-1.36)
84
100
78
91
76
77
72
61
26
37
10
22
8
19
6
10
5
9
5
8
5
6
5
5
4
5
4
4
4
4
4
4
2
4
2
4
2
4
2
3
2
3
2
3
2
2
1
2
1
2
1
2
Proportion
EventFree(%)
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52Pts at Risk, n
Panit + BSC
BSC alone
Treatment Group
Panit + BSC
BSC alone
Events
115
114
N
124
119
%
93
96
Median, Wks
12.3
7.3
HR: 0.45 (95% CI: 0.34-0.59; stratified log-rank P < .0001)
124
119
119
109
112
91
106
81
80
38
69
20
63
15
58
15
50
14
45
11
44
10
44
9
33
9
25
6
21
6
20
6
17
6
13
5
13
4
13
3
10
3
7
2
7
2
6
2
5
2
5
1

80. Cetuximab vs BSC in Chemo-Refractory mCRC: Median OS
KRAS MT KRAS WT
Karapetis CS, et al. N Engl J Med. 2008;359:1757-1765.
OS(%)
100
80
60
40
20
0
0 2 4 6 8 10 12 14
Mos After Randomization
75
76
67
64
45
39
26
26
15
19
10
12
7
10
4
7
BSC alone
P = 0.89
OS(%)
100
80
60
40
20
0
0 2 4 6 8 10 12 14
Mos After Randomization
Pts at Risk, n
Cetuximab +
BSC
BSC alone
110
105
101
88
88
65
75
34
48
23
31
17
19
12
8
5
P < .001
Cetuximab + BSC
BSC alone
Cetuximab + BSC
Pts at Risk, n
Cetuximab +
BSC
BSC alone

81. Phase 3 ASPECCT trial
pts with WT KRASexon 2 mCRC who received prior bev-containing regimens may have
derived greater benefit with pmab versus cmab monotherapy
J Clin Oncol 34, 2016 (suppl 4S; abstr 519)

82. What Is the Optimal Treatment of Second-line mCRC

83. NCCN Guideline 2016: Colon Cancer

84. NCCN Guideline 2016: Colon Cancer

85. NCCN Guideline 2016: Colon Cancer

86. Treatment Standards Following Progression(1/2)
• “Continuum-of-care” approach to individualized patient care in the management
of mCRC
• Second-line chemotherapy
• Switch regimen based on first-line chemotherapy
• Biologics play an important role in the treatment of mCRC to optimize outcome

87. Treatment Standards Following Progression(2/2)
• Continuation of VEGF inhibition beyond progression improves outcome
• ziv-aflibercept vs bevacizumab for second-line therapy after first-line bevacizumab
treatment?
• Differences in toxicity between bevacizumab and ziv-aflibercept
• EGFR antibodies maintain efficacy in later lines of therapy
• In the era of expanded RAS mutational analysis, where do anti-EGFR antibodies fit?
• Identification of patient population benefiting from one specific sequence of
intervention is emerging (BRAF, RAS . . . )

88. Thank You