COLON CANCER:

WHAT SHOULD WE KNOW IN 2015?

MOHAMED ABDULLA M.D.

PROF. OF CLINICAL ONCOLOGY
KASR AL-AINI SCHOOL OF MEDICINE
CAIRO UNIVERSITY

Pfizer Headquarter Office. Wednesday; 18/02/2015

CRC: Figures & Facts:
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: 5-year OAS > 40%
Median survival of metastatic disease > 30 months.
Improved OAS with exposure to all available drugs.
Unified global ideal treatment algorhytm is still
controversial.
Colon Cancer Mortality:
Why Improving Outcome?
1. Better life style.
Why Improving Outcome?
1. Better life style.
2. Risk groups and Screening utility.
High Risk Factors:
Familial Adenomatous Polyposis
Hereditary Non Poliposis Colon Cancer
Family history of Colo Rectal Carcinoma
Previous Colorectal CA, Ovarian,
Endometrial, Breast CA
Age >50 (3/1000 at the age of 80)
Inflammatory Bowel Disease.
Diet (increased fat, red meat, decreased
fibre)
Smoking
Diabetes mellitus.
HIV.
Radiation therapy for prostate
cancer.
Risk Assessment:
Ask The Following:
1. Have you had colorectal cancer or polyp?
2. Have you had inflammatory bowel disease or
abdominal irradiation during childhood?
3. Have any family members had colorectal cancer or
polyp?
All Answers Any Answer
are NO is YES

Average Increased
Risk Risk
Screening of CRC: Cost
Benefit:
US Data: Screening for CRC (1987 2010):
The incidence of late stage from 118

74/100000.
The incidence of early stage disease from

77 67/100000.
Reduction of 550000 CRC cases over 3
decades.

Cancer 2014;120:2893-2901.
Why Improving Outcome?
1. Better life style.
2. Risk groups and Screening utility.
3. Identification of prognostic groups of patients
More precise adoption of adjuvant therapy
Better DFS & OAS.
 Recurrence Rate Over Time:
% Recurrence
> 80% of Recurrences
Within the 1st 3 Years.
7.64

6.92

5.44

3.68

2.97
2.63
2.07
1.7
1.32 1.23
0.86
0.6
0.14

Sargent DJ, et al. J Clin Oncol. 2009;27(15S): Abstract 4011.

Who Needs Adjuvant Therapy?

60 m 30 m 0 month Stage
% Survival % Survival % Survival
93.2 96.1 100 I
84.7 91.0 100 IIa
72.2
83.4
64.1
LNs = > 80.2
91.4
77.3
100
100
100
IIb
IIIa
IIIb
52.3
43.0 12 67.1
57.3
100
100
IIIc
IIId
26.8 43.1 100 IIIe
8.1 17.3 100 IV

OConnellJB, Maggard MA, Ko CY: Colon Cancer Survival Rates with The New American
Joint Committee on Cancer, Sixth Edition Staging. J Natl Cancer Inst 2004;96:1423.
 Who Should Receive Adjuvant
Therapy?
2. Mesentric Nodules: Contour
Role:
13

T-Stage N-Stage

Stage III Not

1. V1 (micro).
2. V2 (macro)
Isolated Tumor
Cells &
Micrometastase

IV
s
0 0.2 mm (N0)
0.2 2 mm (N1mi)

Cancer 2008;112:504.
Who Should Receive Adjuvant Therapy?
3. Peri-neural Invasion: An Under-Estimated
Variable:

15 25%

JCO.2009.22.4949
 Who Should Receive Adjuvant
Therapy?
3. Peritoneal Minimal Residual
Disease:
15

Surgical
Techniques.
1/5 : Peritoneal Minimal
Residual Disease.
Intraperitoneal & Intraportal
Chemotherapy.
1/7 : Peritoneal
Carcinomatois.
HCE.
Prevention of The
Inflammatory Response.

thelancet.com/oncology Vol 10 January 2009

 Timing of Chemotherapy:
16

Conflicting data.
The most accepted timing is 4 6 weeks.
2 meta-analyses:
One showed no effect.
Other showed significant impact on
mortality and disease relapse.

Des Guetz G, Nicolas P, Perret GY, Morere JF, Uzzan B. Eur J Cancer.
2010;46(6):1049.

Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM JAMA.
2011;305(22):2335.
Which Program & What
Schedule?
Anti-
Anti- Oxaliplatin Angiogen
EGFR
ic

5-Fu
Modulated
Capecitabi
/ Irinotecan
ne
Non-
Modulated

UFT
 Accepted Standards of Care:
Stage III Colon Cancer
18

Stage III
NSABP
Colon Cancer
Co1-6 Patients

5-
IMPAC Fu/Leucovori
T n

NCCTG Mayo Clinic Roswell Park De Gramont

NCIC-CTG 30% Lower Toxicity

Profile & Better
Compliance
Adjuvant FOLFOX4 in Stage II-
III Colon Cancer: MOSAIC Study
Schema
FOLFOX4

Leucovorin 200 mg/m2 IV +

5-FU 400 mg/m2 bolus +
5-FU 600 mg/m2 IV over 22 hrs +
Oxaliplatin 85 mg/m2 IV
Patients with previously (n = 1123)
untreated, completely
resected stage II-III
colon cancer

(N = 2246) LV5FU2

Leucovorin 200 mg/m2 IV +

5-FU 400 mg/m2 bolus +
5-FU 600 mg/m2 IV over 22 hrs
(n = 1123)

de Gramont A, et al. ASCO 2007. Abstract 4007.

 MOSAIC Study: 6-Y OAS; by
Treatment Arm:

J Clin Oncol. 2009,27:3109-3116

 MOSAIC Study: 6-Y OAS; by
Treatment Arm & Stage:

J Clin Oncol. 2009,27:3109-3116

Final MOSAIC Results (contd)

Rate of peripheral sensory neuropathy decreased

over time
At 4 yrs
Grade 1: 12.0%

Grade 2: 2.8%

Grade 3: 0.7%

Neutropenia grade 3 in 41.0% of patients

receiving FOLFOX4 vs 4.7% of patients receiving
LV5FU2
Febrile neutropenia in 1.8% of patients receiving
FOLFOX4

de Gramont A, et al. ASCO 2007. Abstract 4007.

MOSAIC Patients > 70
Years:
NSABP C 07:
2407
Colon
Cancer
Stage 2 &
3

Weekly +
Oxaliplatin
Bolus 5-Fu on wks 1,
and LV 3&5
5-y DFS: 69% vs 64% (HR 0.82)
OAS: 80% vs 78% (HR 0.88)
High toxicity profile
 X-ACT: Xeloda (capecitabine) Adjuvant
Chemotherapy Trial of stage III colon
cancer
R n=1, 004
A
Capecitabine
N 1,250mg/m2 b.i.d.
D days 114 q3w
O
Chemonave stage III M
resection 8 weeks I
S
A
T Bolus 5-FU/LV
I 5-FU 425mg/m2 +
O LV 20mg/m2
N n=983
days 15 q4w

Primary endpoint: non-inferiority in

DFS
Secondary endpoint: OS
Data cut-off: January 2007 Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
b.i.d. = twice daily
X-ACT: 5-year OS
(median follow-up 6.8
years)
Non inferior: p = 0.000116
Trend of Superiority: p = 0.06
Lower toxicity profile except for
hand & foot syndrome.

Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

Role of Irinotecan in Adjuvant
Treatment of Stage III Colon Cancer
PETACC-3 Study:

J Clin Oncol.2009,27:3117-3125
 Role of Irinotecan in Adjuvant
Treatment of Stage III Colon Cancer
PETACC-3 Study:

J Clin Oncol.2009,27:3117-3125
Role of Irinotecan in Adjuvant
Treatment of Stage III Colon Cancer
PETACC-3 Study:

After Exclusion of Cases Developed Second Primary in Both

Arms
J Clin Oncol.2009,27:3117-3125
 XELOXA: Adjuvant CAPOX

R CAPOX Capecitabine 1000 mg/m2

A BID days 1-15 Oxaliplatin 130
N mg/m2 day 1 q3w
D
O
Chemo/radiother M
apy I Duration of therapy: 24 weeks
naive stage III Z
colon cancer A
T
I
O Bolus 5FU/LV Mayo Clinic or
N Roswell Park

Primary endpoint: Disease-free

Haller DG, et al. J Clin Oncol. 2011;29(11):
1465-1471.
survival
Cetuximab in Adjuvant Sitting:
N0147 Trial:
Cetuximab in Adjuvant Sitting:
N0 147 Trial:
 NSABP Protocol C-08:
mFOLFOX Bevacizumab in
Stage II/III CRC
Arm A: mFOLFOX6 Q2W x 26
(n = 1356)
Pts with stage II or III
colon adenocarcinoma
with ECOG PS of 0/11
(N = 2710) Arm B: mFOLFOX6 +
Bevacizumab 5 mg/kg Q2W x 26
(n = 1354)

Pts stratified by number of positive lymph nodes and

randomized between Days 29 and 50 postoperatively
mFOLFOX6 regimen: LV 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-
FU 2400 mg/m2 over 46 hours; oxaliplatin 85 mg/m2 IV
Primary endpoint: DFS

Wolmark N, et al. ASCO 2009. Abstract LBA4.

NSABP Protocol C-08:
3-Yr DFS Results:

100

80
DFS (%)

60

40
Events 3-Yr DFS
20 mFF6 + B 291 77.4 HR: 0.89 (P = .15)
mFF6 312 75.5

0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Yrs
Wolmark N, et al. ASCO 2009. Abstract LBA4.
 Where Do We Go in Adjuvant Therapy of
Colon Cancer?
36

Shorten Duration: Less is More

6 months versus 3 months.
Non inferiority trial design.
Dont lose any curability in adjuvant sitting.
More is Better:
FOLFIRINOX in high risk Stage III.
Toxicity and compliance are of upfront
concern.
 Who Needs Adjuvant
Therapy?
80% Cured by
Surgery only

Stage II 16% will Recur

Regardless
Colon Cancer Treatment

4% will Benefit
of Treatment
Treatment Related
Mortality

Quasar Collaborative G, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with

colorectal cancer: a randomized study. Lancet 2007; 370:2020-9.

Who Needs Adjuvant Therapy?
Stage II:

Uptodate.com 01/06/2014
Who Needs Adjuvant Therapy?
Stage II:

Molecular Markers:
1. ++MSI Poor response to fluoroupyremidine
therapy No Role of Adjuvant Chemotherapy.
2. Chromosomal Instability: Worse outcome.

3. LOH 18q: Worse outcome.

Genetic Expression Profiling:
1. Oncotype DX:
7 Recurrence Genes.
5 Reference Genes +
5 Treatment Benefit Genes.
2. Coloprint.
Stage II Colon Cancer:
Trials of Better Identification:
NSABP
C 01, 02, 04, 06
(1851 Pts)

5 7 6
Reference Recurrence Treatment Benefit
Genes Genes Genes

QUASAR Study
(1436/3239 Pts)

Surgery + 5-
Surgery
Fu/LV

Kerr D, et al. ASCO 2009. Abstract 4000.

 Translational Study on PETACC
41 3: Results:

Parameter, % HR 95% CI P Value

Both stage II and III (N = 1233)
RFS 0.569 0.400-0.811 .0018
OS 0.548 0.357-0.842 .006
Stage II (n = 391)
RFS 0.265 0.107-0.661 .0044
OS 0.159 0.039-0.659 .011
Stage III (n = 842)
RFS 0.693 0.473-1.02 .06
OS 0.699 0.446-1.09 .12

Strong effect in stage II, decreases in stage III disease

Roth AD, et al. ASCO 2009. Abstract 4002.

Why Improving Outcome?
1. Better life style.
2. Risk groups and Screening utility.
3. Identification of prognostic groups of patients
More precise adoption of adjuvant therapy
Better DFS & OAS.
4. Identification of molecular key players of growth
& aggressiveness Better RR, PFS and OAS.
 The Adenoma-Carcinoma
Process:
Normal colonic epithelium
Mutation in APC
Dysplastic aberrant crypt
foci
Initial adenoma develops
Mutation in K-
ras
Intermediate adenoma
Mutation in DCC
Late adenoma
Mutation in p53
Carcinoma
Other
Metastasis alteration?
EGFR & VEGF

Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87.
Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.
 Molecular Key Players:
EGFR
NK
CELLS

PI3- Grb2
K
STAT SOS RAS

AA
AKT
DD
RAF
CC
CC 1
MPA
K MEK

Gene Transcription & Cell Cycle 1. Angiogenesi

Progression s
2. Survival
Carter P. Nat Rev. Cancer 2001.
Heinemann V et al. Cancer Treat Rev. 2009.
3. Proliferation
Molecular Key Players:
Angiogenesis:

Wound Healing
Physiologic Placental
al Implantation
Formation Growth
of New
Blood
Vessels Pre-Eclampsia
Pathologic Diabetic
al Retinopathy
Tumors
Disease Overview:
Angiogenesis:
Hallmark of Malignancy:

+
TK

VEGF +
+
m-TOR

Proliferation Invasion Metastases

Treatment Apoptosis
Failure Resistance
Angiogenesis Process:

Receptor Degradation &

Release of GFs
Activation Proteolytic Enz.

Disruption of Invasion & Tumor

ECM & Wall Migration Proliferation
Angiogenic Factors:
VEGFs

VEGF - VEGF - VEGF - VEGF -

C D PlGF
A B

VEGFR VEGFR VEGFR

NRP - 1 NRP - 2
-1 -2 -3

Tyrosine Kinase
Receptors
Angiogenesis in
Malignancy:

Hypoxia

HIF

VEGF
Gene

VEGFR on Nearby VEGFR on Tumor

VEGF
Vessels Vessels
Resistance to Angiogenesis
Inhibitors Types:
Keep in Mind:

Number of LNs > 12.

Timing: 4-8 wks.
Age.
Molecular Markers.
5-Fu/LV is the Backbone.
Stage II Disease: Better Assessment.
Stage III Disease: MOSAIC & X-ACT.
NO Role for Adjuvant Targeted Therapy.
Metastatic Colon Cancer
Advances in the Treatment of Stage IV CRC:
1980 1985 1990 1995 2000 2005

Best supportive care (BSC)

5FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab
Advances in the Treatment of Stage IV CRC:
1980 1985 1990 1995 2000 2005

Best supportive care (BSC)

5FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab

Median Overall Survival

Management of Met. CRC:
Playing a Strategic Game:

The King Should SURVIVAL

SURVIVE

What You Have to Pharmaceutica

Play? ls

How to Play? 1st, 2nd , 3rd .

Lines

Try to be Creative Research

mCRC patient segmentation:
potentially resectable and long-term disease control

Presentation Upfront resectable Unresectable disease

10% 20% 70%

Treatment goal Curative surgery Potentially resectable Un-resectable

Resection
Most patients remain
unresectable

Required Long-term
Optimising PFS and OS represents majority of patients
outcome DFS

Van Cutsem, WCGIC 2012

 Treatment for mCRC
Comparing Combination Chemotherapy Regimen
The Tournigand Study:
Scheme

FOLFIRI FOLFOX6
Arm A CPT-11 180 mg /m2 IV +
Simplified LV5FU
226 pt
Stage IV
mCRC R Till Progression Till Progression

Arm B

FOLFOX6 FOLFIRI
Oxaliplatin 100 mg/m2
IV+Siplified LV5FU

Tournigand at al. J Clin Oncol 2004; 22: 229-237

 Treatment for mCRC
Comparing Combination Chemotherapy Regimen

The Tournigand Study:

Time to Progression

There is no statistical difference in TTP regardless of sequence or arm.

There is a slight improvement in TTP in 2nd line favoring FOLFOX, but not significant

Tournigand at al. J Clin Oncol 2004; 22: 229-237

 Treatment for mCRC
Comparing Combination Chemotherapy Regimen
The Tournigand Study:
Overall Survival

1.00

0.75
FOLFIRI/FOLFOX6

FOLFOX6/FOLFIRI
Probability

0.50

0.25 Overall Survival

P = .99
FOLFIRI/FOLFOX6 21.6
FOLFOX6/FOLFIR 20.6
0
0 10 20 30 40 50

59
Tournigand at al. J Clin Oncol 2004; 22: 229-237
 Treatment for mCRC
Comparing Combination Chemotherapy Regimen

The Tournigand Study:

Summary of Efficacy results

Endpoint FOLFIRI FOLFOX P value

RR 1st line 54 % 56% 0.26
RR 2nd line 4% 15% 0.05
TTP 1st line 8.5 mo 8.0 0.26
TTP 2nd line 2.5 mo 4.2 mo 0.64
OS 1st line 21.5 mo 20 mo 0.99

Tournigand at al. J Clin Oncol 2004; 22: 229-237

Challenges in The Palliative Treatment of Stage
IV CRC:

How can biologics in combination with conventional

chemotherapy be used to their full potential?
Duration of therapy
Predictive markers
Can a patient population be identified that would
benefit most from one specific treatment strategy?
Anti-VEGF Agents
 Phase III Trial IFL +/-
Bevacizumab in MCRC: Efficacy
IFL+ IFL+
Placebo Bevacizumab
(n = (n = 402) P Value
411)
Median survival, months 15.6 20.3 .00004

Progression-free survival (PFS),

6.2 10.6 <.00001
months
Overall response rate (ORR), %
35 45 .0036
Complete response (CR)
2.2 3.7
Partial response (PR)
32. 41.2
5
Duration of response, months 7.1 10.4 .0014

Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342.

 XELOX vs FOLFOX +/- Bevacizumab
NO16966
Study Design
Recruitment Recruitment
June 2003 May 2004 Feb 2004 Feb 2005

XELOX + placebo XELOX +

XELOX N = 350 bevacizumab
N = 317 N = 350
FOLFOX4 + placebo FOLFOX4 +
FOLFOX4
N = 351 bevacizumab
N = 317 N = 350

Initial 2-arm Protocol amended to 2x2 placebo-

controlled design after bevacizumab
open-label study phase III data1 became available
(N = 634) (N = 1401)
1. Hurwitz H, et al. Proc Am Soc Clin Oncol. 2003;22: Abstract 3646.
Saltz LB, et al. J Clin Oncol. 2008;26(12):2013-2019.
 NO16966 PFS Subgroup Analyses:
On-Treatment Population
1.0
XELOX Group FOLFOX Group
1.0

0.8 0.8
Survival

Survival
0.6 0.6

0.4 0.4

0.2 0.2
7.0 m 9.5 m 8.4 m 10.6 m
0 0
0 100 200 300 500 0 100 200 300 500
400 400
Study Day Study Day

HR = 0.61 [97.5% CI 0.480.78] HR = 0.65 [97.5% CI 0.500.84]

P.0001 P = .0002

FOLFOX4 + FOLFOX-4 +
XELOX + placebo VS XELOX + Bev VS
placebo Bev

Saltz L, et al. Presented at: 2007 Gastrointestinal Cancer Symposium; January 19-21, 2007: Orlando, Florida. Abstract.
 CAIRO-3: Validation of BEV-Containing
Maintenance Therapy (MT)
XELOX-Bx6 CTX-BEV HR
MT CFI
P
MT
PFS1, 0.44
months 8.5 4.1 <.00001
R PD1 PD2
PFS2, 0.81
months 11.8 10.5 .028
CFI
0.67
XELOX-Bx6 CTX-BEV TT2PD 19.8 15.0
<.00001
0.87
OS 21.7 18.2
N = 558 PFS1 .16
MT:
PFS2 LD-Cape (625 mg/m2 BID daily)
+ BEV (7.5 mg/kg every 3 weeks)
TT2PD
PFS2: time from R until PD upon re-introduction of XELOX-B
TT2PD: time from R until PD upon any treatment after PFS1
CFI, observation; OS, overall survival; PFS1, first progression; PFS2, second progression; TT2PD, time to second progression
Koopman M, et al. J Clin Oncol. 2013;31(suppl): Abstract 3502.
ML18147 (TML) Study Design (Phase III)
Standard second-line CT
BEV + standard (oxaliplatin or irinotecan-
first-line CT (either based) until PD
Randomize
oxaliplatin or PD 1:1
irinotecan-based) BEV (2.5 mg/kg/wk) +
(n = 820) CT switch: standard second-line CT
Oxaliplatin Irinotecan (oxali or irino-based) until PD
Irinotecan Oxaliplatin

Primary endpoint OS from randomization

Secondary endpoints PFS
included Best ORR
Safety
Stratification factors First-line CT (oxaliplatin-based, irinotecan-based)
First-line PFS (9 months, >9 months)
Time from last BEV dose (42 days, >42 days)
ECOG PS at baseline (0/1, 2)
Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.
 OS: ITT Population PFS:\ITT Population

1.0 CT (n = 410)
1.0 CT (n=410)
BEV + CT (n = 409) BEV + CT (n=409)
OS Estimate

0.8 0.8
Unstratifieda HR: 0.81 (95% CI: 0.690.94)

PFS Estimate
P = .0062 (log-rank test) Unstratifieda HR: 0.68 (95% CI: (0.590.78)
0.6 0.6 P<.0001 (log-rank test)
Stratifiedb HR: 0.83 (95% CI: 0.710.97)
P = .0211 (log-rank test) Stratifiedb HR: 0.67 (95% CI: 0.580.78)
0.4 0.4 P<.0001 (log-rank test)

0.2 0.2

9.8 mo 11.2 mo 4.1 mo 5.7 mo

0 0
0 6 12 18 24 30 36 42 0 6 12 18 24 36
No. at risk Time , Months Time, Months

No. at risk

CT 410 293 162 51 24 7 3 2 CT 119 20 6 4 0

410
BEV + CT409 328 188 64 29 13 4 1 BEV + CT409 189 45 5 2
12

Median follow-up: CT, 9.6 months (range 045.5); BEV + CT, 11.1 months (range 0.3
44.0)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (9 months, >9 months), time from last dose
of BEV (42 days, >42 days), ECOG performance status at baseline (0, 1)

Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.

 Adverse Events (AEs) of Special Interest
to BEV: Safety Population
Chemotherapy BEV + Chemo
n = 409 n = 401
Patients, % All Grades Grade All Grades Grade
AEs of special interest to BEV
35 35
Hypertension 21
7 6
1 41 12 12 2
Proteinuria 1 5 <1
Bleeding/hemorrhage 9 <1 26 2
Abscesses and fistulae 1 <1
GI perforation <1 <1 3 2
Congestive heart failure <1 <1 <1
VTE 4 3 6 5
ATE 1 <1 <1 <1

Wound-healing <1 <1 1 <1

complications

RPLS
ATE, arterial thromboembolic events; GI, gastrointestinal; RPLS, reverse posterior leukoencephalopathy
syndrome; VTE, venous thromboembolic events
Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.
 21

EFC10262: VELOUR
Phase III Trial Second-Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Aflibercept 4 mg/kg
600 pts IV
+ FOLFIRI q 2
mCRC after weeks
failure of an
oxaliplatin R 1:1

based regimen
600 pts Placebo + FOLFIRI
Stratification factors: q 2 weeks
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
30% of patients had prior BEV
Principle investigators: Allegra, Van Cutsem
 VELOUR Study
OS PFS

HR 0.82 HR 0.76

Time, Months Time, Months

Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.

Aflibercept: VELOUR Phase III: OS and
PFS Stratified by Prior Bevacizumab
Overall Survival Interaction
Strata (as per UVRS) N HR (95.34% CI) HR P
All patients 1226 0.82 (0.713-
0.937)
Prior .5668
BEV 853 0.79 (0.669-
373 0.927)
No 0 1 2 3
Ye 0.86 (0.673-
1.104) Favors aflibercept Favors placebo
s

Progression-Free Survival Interaction

Strata (as per UVRS) N HR (95% CI) HR P
All patients 1226 0.76 (0.661-
0.869)
Prior .1958
BEV 853 0.80 (0.679-
373 0.936)
No 0 1 2 3
Ye 0.66 (0.512-
0.852) Favors aflibercept Favors placebo
s
Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.
Conclusion Anti-VEGF Therapy
Duration of VEGF-inhibition matters
Treatment to progression
Maintenance strategies
Treatment beyond progression

Clinical synergism between FP +

bevacizumab
Positive distinguishing factors for aflibercept
vs BEV in second-line Tx not clear
Head-to-head comparison warranted
(Efficacy? Toxicity?)
BEV combinable with FOLFOXIRI
(TRIBE)
EGFR Monoclonal Antibodies
 NCIC CTG CO.17:
Randomized Phase III Trial in mCRC
Cetuximab vs BSC (No Cross-Over)
KRAS Mut KRAS Wildtype All Patients
BSC BSC Cetux BSC Cetux
Cetux n= n= n= n=
n = 83 n = 81 113 117 285 287
RR 0% 1.2% 0% 12.8% 0% 6.6%

PFS,
1.8 1.8 1.9 3.8 1.8 1.9
months
<.0001 <.0001

OS,
4.6 4.5 4.8 9.5 4.6 6.1
months <.0001 .0046

Karapetis CS, et al. N Engl J Med. 2008;359(17):1757-1765.

 CRYSTAL: FOLFIRI +/- Cetuximab
PFS in Patients With KRAS Wildtype Tumors
FOLFIRI FOLFIRI + Cetuximab
1.0
(n = 350) (n = 316)
0.9 No of events 189 146
Median PFS 8.4 months 9.9 months
0.8 [95% CI] [7.49.2] [9.011.3]
Probability of PFS

0.7 HR [95% 0.70 [0.558

Cl] 0.867]
0.6 P value .0012
0.5

0.4

0.3

0.2
FOLFIRI
0.1 FOLFIRI + cetuximab

0.0
0 4 8 12 16 20
Number of patients Time, Months
FOLFIRI 237 111 22 4 0
227 128 40 8 1
350
Van Cutsem
FOLFIRI E, et316
+ cetuximab al. J Clin Oncol. 2011;29(15):2011-
2019.
 PRIME (FOLFOX +/- Panitumumab)
PFS by KRAS Mutation Status
Final Analysis
WT KRAS MT KRAS
100 100
% %
90 90
% %
Proportion Event-Free

80 80

Proportion Event-Free
% %
70 70
% %
60 60
% %
50 50
% %
40 40
% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 36 38 40 42 % 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 36 38 40 42
34 44 34 44
30 30
% Months % Months
20 Median, months 20
% % Median, months
(95% CI) (95% CI)
10 10
% Panitumumab + 10.0 (9.3 11.4) % Panitumumab 7.4 (6.9 8.1)
0 FOLFOX4 0 + FOLFOX4
% 8.6 (7.5 9.5) %
FOLFOX4 FOLFOX4 9.2 (8.1 9.9)

HR = 0.80 (95% CI: 0.67 0.95) HR = 1.27 (95% CI: 1.04 1.55)
Log-rank P value = .01 Log-rank P value = .02
Douillard J, et al. J Clin Oncol. 2011;29(Suppl): Abstract 3510.
 FIRE-3 Phase III Study Design
FOLFIRI +
Cetuximab
Cetuximab: 400 mg/m IV 120 min initial dose
2

mCRC 250 mg/m 2 IV 60 min q1w

first-line therapy Randomize 1:1

KRAS wildtype
N = 592 FOLFIRI + Bevacizumab
Bevaciizumab: 5 mg/kg iIV.v.3300-9-900miin q
2ww
FOLFIRI: 5FU: 400 mg/m2 (IV bolus); folinic acid: 400 mg/m2
irinotecan: 180 mg/m2
5FU: 2400 mg/m2 (IV 46h)

Primary objective: ORR (investigator assessed)

Designed to detect a difference of 12% in ORR induced
by FOLFIRI + cetuximab (62%) as compared to FOLFIRI +
bevacizumab (50%)
284 evaluable patients per arm needed to achieve 80%
power for an one-sided Fishers exact test at an alpha level
of 2.5%
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
 FIRE-3 ORR
Primary Endpoint

FOLFIRI + Cetuximab FOLFIRI + Bevacizumab

Odd P
s
ORR % 95%-CI % 95%-CI ratio
ITT
52.1
population 62.0 56.2 67.5 58.0 63.7
1.18 .183
(N = 592) 0.85-1.64

Assessable
1.52
for response 72.2 66.2 77.6 63.1 57.1 68.9 .017
1.05-2.19
(N = 526)

P = Fishers exact test (one-

sided)

Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

 FIRE-3 PFS: Events Median 95% CI
1.0 n/N (%) (months
FOLFIRI + Cetuximab 250/297 )
8.8 10.8
(84.2%) 10.0
FOLFIRI + Bevacizumab 242/295 9.8
0.75 10.3
(82.0%)
Probability of Survival

11.3
HR 1.06 (95% CI 0.88 1.26)
0.50 Log-rank P = .
547

0.25

0.0
12 60 72
24 36 48
Months
Number 297 100 19 Since Start
10 of Treatment
5 3

at risk 295 99 15 6 4

Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

 FIRE-3 OS: Events Median 95% CI
1.0 n/N (%) (months
158/297 )
FOLFIRI + 24.0 36.6
Cetuximab (53.2%) 28.7
0.75 FOLFIRI + 185/295 25.0 22.7 27.6
Probability of Survival

Bevacizumab (62.7%)
HR 0.77 (95% CI: 0.62 0.96)
0.50 PFS Log-rank P = .
017

0.25

Split of
0.0
curves
12 24 60 72
36 48
Months Since Start of
218 Treatment
111 60 29 9
Number 297
214 111 47 18 2
at risk 295

Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

 FIRE-3 OS:
1.0 Who are these patients?
FOLFIRI + Analysis of
Cetuximab
RAS, PIK3CA,
0.75
FOLFIRI + Bevacizumab BRAF,
Probability of Survival

PTEN, EGFR ligands

0.50

0.25

0.0
12 60 72
24 36 48
Months Since Start of Treatment
Number 297 218 111 60 29 9

at risk 295 214 111 47 18 2

Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
 Progression-Free Survival By
Arm (All RAS Wildtype
100 Patients)
Percent Event Free

80 Arm N Median HR (95% CI) P

(Events) (95% CI)

Chemo 256 11.3 1.1 .31

60 + Bev
(221) (10.3-12.6) (0.9-1.3)
270 11.4
Chemo (241) (9.6-12.9)
40 + Cetux

20

0
0 12 24 36 48 60 72

No at Risk
Months From Study Entry
256 112 49 23 13 6
270 126 49 18 5 2 1
Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.
 Overall Survival By Arm
(All RAS Wildtype Patients)
Arm N Median HR (95% CI) P
100 (Events) (95% CI)

Chemo 256 31.2 0.9 .40

Percent Event Free

(178) (26.9-34.3) (0.7-1.1)

80 + Bev
270 32.0
Chemo (177) (27.6-38.5)
+ Cetux
60

40

20

0 0 12 24 36 48 60 72 84 96
No at Risk Months From Study Entry
256 199 147 77 35 16 5 2
270 205 164 88 41 24 7 1 1
Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.
 Conclusions EGFR mAbs (2)

All-RAS wildtype CRC = 40% to 45% of CRC

Further molecular refinements in future

(PTEN, EGFR ligands, PIK3CA) could cut
the patient population suitable for EGFR
mAbs down to 30% to 35%

This refined patient population could sustain

a marked benefit from use of first-line EGFR
mAbs!
Outcomes by Chemotherapy
Backbone
All RAS Wildtype FOLFOX Patients
Progression-Free Survival Overall Survival
N Median HR N Median HR
P P
(Events) (95% CI) (95% CI) (Events) (95% CI) (95% CI)

Chemo 192 11.0 192 29.0

+ Bev (163) (9.5-13.1) (137) (24.0-32.8)
1.1 0.86
.3 .2
Chemo (0.9-1.4) (0.6-1.1)
198 11.3 198 32.5
+ Cetux (177) (9.4-13.1) (129) (26.1-40.4)

All RAS Wildtype FOLFIRI Patients

Progression-Free Survival Overall Survival
N Median HR N Median HR
P P
(Events) (95% CI) (95% CI) (Events) (95% CI) (95% CI)
Chemo 64 11.9 64 35.2
+ Bev (58) (10.3-14.8) (41) (28.3-41.3)
1.1 1.1
Chemo .7 .7
72 12.7 (0.7-1.5) 72 32.0 (0.7-1.6)
+ Cetux (64) (8.9-14.1) (48) (25.6-42.9)

Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.

Bevacizumab +
oxaliplatin-based
regimens:
Bevacizumab + irinotecan-
based regimens
First-line efficacy of EGFR
inhibitors
in KRAS WT populations

1. Van Cutsem et al. ASCO GI 2010; 2. Maughan, et al. ASCO 2010; 3.

Tvelt, et al. ESMO 2010; 4. Doulliard, et al. JCO 2010
Irinotecan vs Oxaliplatin for
Cetuximab??
Take Home Message:
Exposure to all available agents is mandatory to optimize
OAS.
Unified global treatment algorhytm is still controversial.
Careful interpretation of available clinical trials to establish
guidelines of management.
FIRE3 trial should not be used as a practice changing
guideline although it might point to a better selection of
patients for anti-EGFR therapy.
Cost-effective studies should be kept in mind especially in
developing regions of the world.
Thank You