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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
Colon Cancer Mortality:
Why Improving Outcome?
1. Better life style.
colon cancer synopsis 2015
Why Improving Outcome?
1. Better life style.
2. Risk groups and Screening utility.
High Risk Factors:
 FamilialAdenomatous 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
are NO
Average Risk
Any Answer is
YES
Increased
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:
0.14
2.63
7.64
6.92
5.44
3.68
2.97
2.07
1.7
1.32 1.23
0.86
0.6
0 1 2 3 4 5 6
Years
% RECURRENCE
> 80% of Recurrences
Within the 1st 3 Years.
Sargent DJ, et al. J Clin Oncol. 2009;27(15S): Abstract 4011.
Who Needs Adjuvant
Therapy?
60 m30 m0 monthStage
% Survival% Survival% Survival
93.296.1100I
84.791.0100IIa
72.280.2100IIb
83.491.4100IIIa
64.177.3100IIIb
52.367.1100IIIc
43.057.3100IIId
26.843.1100IIIe
8.117.3100IV
O’ConnellJB, 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.
LNs = > 12
Who Should Receive Adjuvant
Therapy?
2. Mesentric Nodules: Contour Role:
T-Stage N-Stage
1. V1 (micro).
2. V2 (macro)
Isolated Tumor Cells
&
Micrometastases
0 – 0.2 mm (N0)
0.2 – 2 mm (N1mi)
Stage III Not IV
Cancer 2008;112:50–4.
13
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:
• 1/5 : Peritoneal Minimal
Residual Disease.
• 1/7 : Peritoneal Carcinomatois.
 Surgical Techniques.
 Intraperitoneal & Intraportal
Chemotherapy.
 HCE.
 Prevention of The Inflammatory
Response.
thelancet.com/oncology Vol 10 January 2009
15
 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.
Timing of Chemotherapy:
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.
16
Which Program & What
Schedule?
5-Fu
Modulated/
Non-
Modulated
Oxaliplatin
Irinotecan
UFT
Capecitabin
e
Anti-EGFR
Anti-
Angiogeni
c
Accepted Standards of Care:
Stage III Colon Cancer
Stage III Colon
Cancer Patients
5-
Fu/Leucovorin
Mayo Clinic Roswell Park De Gramont
Lower Toxicity Profile
& Better Compliance
NSABP
Co1-6
IMPACT
NCCTG
NCIC-CTG 30%
18
Adjuvant FOLFOX4 in Stage II-III
Colon Cancer: MOSAIC Study
Schema
de Gramont A, et al. ASCO 2007. Abstract 4007.
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
(n = 1123)
LV5FU2
Leucovorin 200 mg/m2 IV +
5-FU 400 mg/m2 bolus +
5-FU 600 mg/m2 IV over 22 hrs
(n = 1123)
Patients with previously
untreated, completely resected
stage II-III
colon cancer
(N = 2246)
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 (cont’d)
 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
Bolus 5-Fu
and LV
+
Oxaliplatin
on wks 1, 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
 Primary endpoint: non-inferiority in DFS
 Secondary endpoint: OS
Bolus 5-FU/LV
5-FU 425mg/m2
+
LV 20mg/m2
days 1–5 q4w
Capecitabine
1,250mg/m2
b.i.d.
days 1–14 q3w
Chemonaïve stage III
resection 8 weeks
n=1,004
n=983
R
A
N
D
O
M
I
S
A
T
I
O
N
Data cut-off: January 2007
b.i.d. = twice daily
Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
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:
J Clin Oncol.2009,27:3117-3125
After Exclusion of Cases Developed Second Primary in Both Arms
XELOXA: Adjuvant CAPOX
Chemo/radiotherapy
naive stage III
colon cancer
R
A
N
D
O
M
I
Z
A
T
I
O
N
CAPOX Capecitabine 1000 mg/m2 BID
days 1-15 Oxaliplatin 130 mg/m2 day 1
q3w
Bolus 5FU/LV Mayo Clinic or Roswell
Park
Duration of therapy: 24 weeks
Primary endpoint: Disease-free survival
Haller DG, et al. J Clin Oncol. 2011;29(11):
1465-1471.
colon cancer synopsis 2015
Cetuximab in Adjuvant Sitting:
N0147 Trial:
Cetuximab in Adjuvant Sitting:
N0 147 Trial:
NSABP Protocol C-08: mFOLFOX
± Bevacizumab in Stage II/III CRC
Wolmark N, et al. ASCO 2009. Abstract LBA4.
Arm A: mFOLFOX6 Q2W x 26
(n = 1356)
Arm B: mFOLFOX6 +
Bevacizumab 5 mg/kg Q2W x 26
(n = 1354)
Pts with stage II or III
colon adenocarcinoma
with ECOG PS of 0/11
(N = 2710)
 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
NSABP Protocol C-08:
3-Yr DFS Results:
Wolmark N, et al. ASCO 2009. Abstract LBA4.
DFS(%)
Yrs
0
20
40
60
80
100
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
HR: 0.89 (P = .15)mFF6 + B
mFF6
Events
291
312
3-Yr DFS
77.4
75.5
Where Do We Go in Adjuvant
Therapy of Colon Cancer?
 Shorten Duration: “Less is More”
 6 months versus 3 months.
 Non inferiority trial design.
 Don’t lose any curability in adjuvant sitting.
 More is Better:
 FOLFIRINOX in high risk Stage III.
 Toxicity and compliance are of upfront concern.
36
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.
Stage II
Colon Cancer
80% Cured by
Surgery only
16% will Recur
Regardless
Treatment
4% will Benefit of
Treatment
Who Needs Adjuvant Therapy?
Treatment Related Mortality
Who Needs Adjuvant
Therapy?
Stage II:
Uptodate.com 01/06/2014
 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.
Who Needs Adjuvant
Therapy?
Stage II:
Stage II Colon Cancer:
Trials of Better Identification:
NSABP
C 01, 02, 04, 06
(1851 Pts)
5
Reference
Genes
7
Recurrence
Genes
6
Treatment Benefit
Genes
QUASAR Study
(1436/3239 Pts)
Surgery
Surgery + 5-
Fu/LV
Kerr D, et al. ASCO 2009. Abstract 4000.
Translational Study on PETACC 3:
Results:
Strong effect in stage II, decreases in stage III disease
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
Roth AD, et al. ASCO 2009. Abstract 4002.
41
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:
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.
Normal colonic epithelium
Dysplastic aberrant crypt foci
Initial adenoma develops
Intermediate adenoma
Late adenoma
Carcinoma
Metastasis
Mutation in APC
Mutation in K-ras
Mutation in DCC
Mutation in p53
Other alteration?
EGFR & VEGF
PI3-K
STAT
AKT
Grb2
SOS RAS
RAF1
MEK
MPA
K
Gene Transcription & Cell Cycle
Progression
1. Angiogenesis
2. Survival
3. Proliferation
4. Progression
Molecular Key Players: EGFR
Carter P. Nat Rev. Cancer 2001.
Heinemann V et al. Cancer Treat Rev. 2009.
NK
CELLS
Formation of
New Blood
Vessels
Physiological
Wound Healing
Placental
Implantation
Growth
Pathological
Pre-Eclampsia
Diabetic
Retinopathy
Tumors
Molecular Key Players:
Angiogenesis:
Disease Overview:
Angiogenesis:
Hallmark of Malignancy:
Proliferation Invasion Metastases
Treatment Failure
Apoptosis
Resistance
VEGF +
+
TK
+
m-TOR
Angiogenesis Process:
Release of GFs
Receptor
Activation
Degradation &
Proteolytic Enz.
Disruption of
ECM & Wall
Invasion &
Migration
Tumor
Proliferation
Angiogenic Factors:
Tyrosine Kinase
Receptors
VEGFR -
1
VEGFR -
2
VEGFR -
3
NRP - 1 NRP - 2
VEGFs
VEGF -
A
VEGF -
B
VEGF -
C
VEGF -
D PlGF
Angiogenesis in Malignancy:
Hypoxia
HIF
VEGF
Gene
VEGF
VEGFR on Nearby
Vessels
VEGFR on Tumor
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
SURVIVE
SURVIVA
L
What You Have to Play? Pharmaceuticals
How to Play? 1st, 2nd , 3rd …seniL .
Try to be Creative Research
mCRC patient segmentation:
potentially resectable and long-term disease control
Resection
Optimising PFS and OS –represents majority of patients
Treatment goal
Required
outcome
Long-term
DFS
10% 20% 70%
Curative surgery
Presentation Unresectable diseaseUpfront resectable
Un-resectablePotentially resectable
Most patients remain
unresectable
Van Cutsem, WCGIC 2012
Treatment for mCRC
Comparing Combination Chemotherapy Regimen
The Tournigand Study:
Scheme
FOLFIRI
Tournigand at al. J Clin Oncol 2004; 22: 229-237
R
FOLFOX6
FOLFOX6
FOLFIRI
Till Progression Till Progression
Arm A
Arm B
226 pt
Stage IV
mCRC
CPT-11 180 mg /m2 IV +
Simplified LV5FU
Oxaliplatin 100 mg/m2
IV+Siplified LV5FU
Treatment for mCRC
Comparing Combination Chemotherapy Regimen
The Tournigand Study:
Time to Progression
Tournigand at al. J Clin Oncol 2004; 22: 229-237
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
59
Treatment for mCRC
Comparing Combination Chemotherapy Regimen
Tournigand at al. J Clin Oncol 2004; 22: 229-237
The Tournigand Study:
Overall Survival
1.00
0.75
0.50
0.25
0
Probability
0 10 20 30 40 50
FOLFIRI/FOLFOX6
FOLFOX6/FOLFIRI
Overall Survival
P = .99
FOLFIRI/FOLFOX6 21.6
FOLFOX6/FOLFIR 20.6
Treatment for mCRC
Comparing Combination Chemotherapy Regimen
The Tournigand Study:
Summary of Efficacy results
Tournigand at al. J Clin Oncol 2004; 22: 229-237
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
• 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?
Challenges in The Palliative Treatment of Stage
IV CRC:
Anti-VEGF Agents
Phase III Trial IFL +/-
Bevacizumab in MCRC: Efficacy
IFL+
Placebo
(n = 411)
Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342.
IFL+
Bevacizumab
(n = 402) P Value
Median survival, months 15.6 20.3 .00004
Progression-free survival (PFS),
months
6.2 10.6 <.00001
Overall response rate (ORR), %
Complete response (CR)
Partial response (PR)
35
2.2
32.5
45
3.7
41.2
.0036
Duration of response, months 7.1 10.4 .0014
XELOX
N = 317
FOLFOX4
N = 317
Initial 2-arm
open-label study
(N = 634)
Protocol amended to 2x2 placebo-
controlled design after bevacizumab
phase III data1 became available
(N = 1401)
Recruitment
June 2003 – May 2004
Recruitment
Feb 2004 – Feb 2005
XELOX vs FOLFOX +/- Bevacizumab
NO16966
Study Design
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.
XELOX + placebo
N = 350
XELOX +
bevacizumab
N = 350
FOLFOX4 + placebo
N = 351
FOLFOX4 +
bevacizumab
N = 350
NO16966 PFS Subgroup Analyses:
On-Treatment Population
HR = 0.61 [97.5% CI 0.48–0.78]
P≤.0001
HR = 0.65 [97.5% CI 0.50–0.84]
P = .0002
XELOX + placebo
FOLFOX4 +
placeboXELOX + Bev
FOLFOX-4 +
BevVS VS
XELOX Group FOLFOX Group
Survival
1.0
0.8
0.6
0.4
0.2
0
0 100 200 300 400 500
Study Day
1.0
0.8
0.6
0.4
0.2
0
0 100 200 300 400 500
Survival
Study Day
10.6 m
Saltz L, et al. Presented at: 2007 Gastrointestinal Cancer Symposium; January 19-21, 2007: Orlando, Florida. Abstract.
8.4 m9.5 m7.0 m
CAIRO-3: Validation of BEV-Containing
Maintenance Therapy (MT)
XELOX-Bx6 CTX-BEV
XELOX-Bx6 CTX-BEV
R PD1 PD2
PFS1
TT2PD
MT CFI
8.5 4.1
11.8 10.5
HR
P
PFS1,
months
0.44
<.00001
PFS2,
months
0.81
.028
TT2PD 19.8 15.0
0.67
<.00001
OS 21.7 18.2
0.87
.16
MT:
LD-Cape (625 mg/m2 BID daily)
+ BEV (7.5 mg/kg every 3 weeks)
MT
CFI
N = 558
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.
PFS2
BEV + standard
first-line CT (either
oxaliplatin or
irinotecan-based)
(n = 820)
BEV (2.5 mg/kg/wk) +
standard second-line CT
(oxali or irino-based) until PD
PD
Randomize
1:1
CT switch:
Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.
Standard second-line CT
(oxaliplatin or irinotecan-
based) until PD
ML18147 (TML) Study Design (Phase III)
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
Primary endpoint
Secondary endpoints
included
• OS from randomization
• PFS
• Best ORR
• Safety
• 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)
Stratification factors
OS: ITT Population
OSEstimate
0.4
0.2
0
0 6
11.2 mo
12 18 24 30 36 42
9.8 mo
P = .0211 (log-rank test)
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)
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
1.0
0.8
0.6
CT (n = 410)
BEV + CT (n = 409)
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
P = .0062 (log-rank test)
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
PFSEstimate
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 36
CT (n=410)
BEV + CT (n=409)
4.1 mo 5.7 mo
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78)
P<.0001 (log-rank test)
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
P<.0001 (log-rank test)
PFS:ITT Population
Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.
No. at risk Time , Months Time, Months
No. at risk
CT 410 293 162 51 24 7 3 2 CT 410 119 20 6 4 0
BEV + CT409 328 188 64 29 13 4 1 BEV + CT409 189 45 12 5 2
Adverse Events (AEs) of Special Interest
to BEV: Safety Population
Patients, %
Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.
Chemotherapy
n = 409
All Grades Grade 3–5
21 6
BEV + Chemo
n = 401
All Grades Grade 3–5
41 12AEs of special interest to BEV
ATE, arterial thromboembolic events; GI, gastrointestinal; RPLS, reverse posterior leukoencephalopathy
syndrome; VTE, venous thromboembolic events
Hypertension 7 1 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
complications
RPLS
<1
–
<1
–
1
–
<1
–
EFC10262: VELOUR
Phase III Trial Second-Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Stratification factors:
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
1:1
mCRC after
failure of an
oxaliplatin
based regimen
R
600 pts
Aflibercept 4 mg/kg
IV
+ FOLFIRI q 2 weeks
600 pts Placebo + FOLFIRI
q 2 weeks
Principle investigators: Allegra, Van Cutsem
21
30% of patients had prior BEV
VELOUR Study
OS
HR 0.82
PFS
HR 0.76
Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.
Time, Months Time, Months
Overall Survival
Strata (as per UVRS) N HR (95.34% CI) HR
Interaction
P
All patients
Prior BEV
No
Yes
1226 0.82 (0.713-0.937)
853
373
0.79 (0.669-0.927)
0.86 (0.673-1.104)
.5668
0
Favors aflibercept
1 2
Favors placebo
3
Progression-Free Survival
Strata (as per UVRS) N HR (95% CI) HR
Interaction
P
All patients
Prior BEV
No
Yes
1226 0.76 (0.661-0.869)
853
373
0.80 (0.679-0.936)
0.66 (0.512-0.852)
.1958
0
Favors aflibercept
1 2
Favors placebo
3
Aflibercept: VELOUR Phase III: OS and
PFS Stratified by Prior Bevacizumab
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)
BSC Cetux
n = 83 n = 81
BSC
n = 113
Cetux
n = 117
BSC
n = 285
Cetux
n = 287
RR 0% 1.2% 0% 12.8% 0% 6.6%
PFS,
months
1.8 1.8 1.9 3.8 1.8 1.9
OS,
months
4.6 4.5 4.8 9.5 4.6 6.1
<.0001 <.0001
Karapetis CS, et al. N Engl J Med. 2008;359(17):1757-1765.
KRAS Mut KRAS Wildtype All Patients
<.0001 .0046
CRYSTAL: FOLFIRI +/- Cetuximab
PFS in Patients With KRAS Wildtype Tumors
Number of patients
FOLFIRI 350
FOLFIRI + cetuximab 316
237
227
111
128
22
40
4
8
0
1
FOLFIRI
(n = 350)
FOLFIRI + Cetuximab
(n = 316)
No of events 189
8.4 months
[7.4‒9.2]
146
9.9 months
[9.0‒11.3]
Median PFS
[95% CI]
HR [95% Cl]
P value
0.70 [0.558‒0.867]
.0012
ProbabilityofPFS
Time, Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
120 4 8 16 20
FOLFIRI
FOLFIRI + cetuximab
Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019.
PRIME (FOLFOX +/- Panitumumab)
PFS by KRAS Mutation Status
“Final Analysis”
Median, months
(95% CI)
Panitumumab +
FOLFOX4
FOLFOX4
10.0 (9.3 – 11.4)
8.6 (7.5 – 9.5)
HR = 0.80 (95% CI: 0.67 – 0.95)
Log-rank P value = .01
Median, months
(95% CI)
Panitumumab
+ FOLFOX4
FOLFOX4
7.4 (6.9 – 8.1)
9.2 (8.1 – 9.9)
HR = 1.27 (95% CI: 1.04 – 1.55)
Log-rank P value = .02
WT KRAS MT KRAS
ProportionEvent-Free
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Months
36 38 40 42 44
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ProportionEvent-Free
Douillard J, et al. J Clin Oncol. 2011;29(Suppl): Abstract 3510.
18 20 22 24 26 28 30 32 34
Months
0 2 4 6 8 10 12 14 16 36 38 40 42 44
FOLFIRI + Bevacizumab
Bevaciizumab: 5 mg/kg iIV.v.3300-9-900miin q 2ww
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
FIRE-3 Phase III Study Design
FOLFIRI + Cetuximab
mCRC
first-line therapy
KRAS wildtype
N = 592
Randomize 1:1
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 Fisher‘s exact test at an alpha level of 2.5%
Cetuximab: 400 mg/m2 IV 120 min initial dose
250 mg/m2 IV 60 min q 1 w
FIRE-3 ORR
Primary Endpoint
FOLFIRI + Cetuximab FOLFIRI + Bevacizumab
Odds
ratio
P
Assessable
for response
(N = 526)
72.2 66.2 – 77.6 63.1 57.1 – 68.9
1.52
1.05-2.19
.017
1.18
0.85-1.64
.183
P = Fisher´s exact test (one-sided)
ORR % 95%-CI % 95%-CI
ITT
population
(N = 592)
62.0 56.2 – 67.5 58.0
52.1 –
63.7
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
0.75
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
1.0
0.50
0.25
ProbabilityofSurvival
Events
n/N (%)
Median
(months)
10.0
95% CI
8.8 – 10.8
HR 1.06 (95% CI 0.88 – 1.26)
10.3 9.8 – 11.3
Log-rank P = .547
0.0
12 24 36 48
Months Since Start of Treatment
60 72
—FOLFIRI + Cetuximab 250/297
(84.2%)
— FOLFIRI + Bevacizumab 242/295
(82.0%)
Number 297 100 19 10 5 3
at risk 295 99 15 6 4
FIRE-3 PFS:
Events
n/N (%)
Median
(months)
28.7
95% CI
— FOLFIRI + Cetuximab 158/297
(53.2%)
185/295
(62.7%)
24.0 – 36.6
— FOLFIRI + Bevacizumab
HR 0.77 (95% CI: 0.62 – 0.96)
25.0 22.7 – 27.6
Log-rank P = .017
0.75
1.0
0.50
0.25
ProbabilityofSurvival
0.0
12 24 36 48 60 72
Months Since Start of Treatment
Number 297
at risk 295
218
214
111
111
60
47
29
18
9
2
PFS
Split of
curves
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
FIRE-3 OS:
— FOLFIRI + Cetuximab
ProbabilityofSurvival
— FOLFIRI + Bevacizumab
PTEN, EGFR ligands
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
0.75
1.0
0.50
0.25
0.0
12 24 36 48
Months Since Start of Treatment
60 72
Who are these patients?
Analysis of
RAS, PIK3CA, BRAF,
Number 297 218 111 60 29 9
at risk 295 214 111 47 18 2
FIRE-3 OS:
Progression-Free Survival By
Arm (All RAS Wildtype
Patients)100 –
80 –
60 –
40 –
20 –
0 –
0 12
PercentEventFree
24 36 48
Months From Study Entry
60 72
No at Risk
Arm
Chemo +
Bev
Chemo +
Cetux
Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.
256 112 49 23 13 6
270 126 49 18 5 2 1
N
(Events)
Median
(95% CI)
HR (95% CI) P
256
(221)
270
(241)
11.3
(10.3-12.6)
11.4
(9.6-12.9)
1.1
(0.9-1.3)
.31
Overall Survival By Arm
(All RAS Wildtype Patients)
100 –
80 –
60 –
40 –
20 –
0 –
0 12 24 36 48 60 72 84 96
PercentEventFree
Arm
Chemo +
Bev
Chemo +
Cetux
Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.
N
(Events)
Median
(95% CI)
HR (95% CI) P
256
(178)
270
(177)
31.2
(26.9-34.3)
32.0
(27.6-38.5)
0.9
(0.7-1.1)
.40
No at Risk Months From Study Entry
256 199 147 77 35 16 5 2
270 205 164 88 41 24 7 1 1
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!
Progression-Free Survival Overall Survival
N
(Events)
Median
(95% CI)
HR
(95% CI)
P
N
(Events)
Median
(95% CI)
HR
(95% CI)
P
Chemo
+ Bev
Chemo
+ Cetux
192
(163)
11.0
(9.5-13.1)
1.1
(0.9-1.4)
.3
192
(137)
29.0
(24.0-32.8)
0.86
(0.6-1.1)
.2
198
(177)
11.3
(9.4-13.1)
198
(129)
32.5
(26.1-40.4)
All RAS Wildtype FOLFOX Patients
Progression-Free Survival
Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.
Overall Survival
N
(Events)
Median
(95% CI)
HR
(95% CI)
P
N
(Events)
Median
(95% CI)
HR
(95% CI)
P
Chemo
+ Bev
Chemo
+ Cetux
64
(58)
11.9
(10.3-14.8)
1.1
(0.7-1.5)
.7
64
(41)
35.2
(28.3-41.3)
1.1
(0.7-1.6)
.7
72
(64)
12.7
(8.9-14.1)
72
(48)
32.0
(25.6-42.9)
All RAS Wildtype FOLFIRI Patients
Outcomes by Chemotherapy
Backbone
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

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colon cancer synopsis 2015

  • 1. 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
  • 2. 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
  • 4. Why Improving Outcome? 1. Better life style.
  • 6. Why Improving Outcome? 1. Better life style. 2. Risk groups and Screening utility.
  • 7. High Risk Factors:  FamilialAdenomatous 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.
  • 8. 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 are NO Average Risk Any Answer is YES Increased Risk
  • 9. 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.
  • 10. 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.
  • 11. Recurrence Rate Over Time: 0.14 2.63 7.64 6.92 5.44 3.68 2.97 2.07 1.7 1.32 1.23 0.86 0.6 0 1 2 3 4 5 6 Years % RECURRENCE > 80% of Recurrences Within the 1st 3 Years. Sargent DJ, et al. J Clin Oncol. 2009;27(15S): Abstract 4011.
  • 12. Who Needs Adjuvant Therapy? 60 m30 m0 monthStage % Survival% Survival% Survival 93.296.1100I 84.791.0100IIa 72.280.2100IIb 83.491.4100IIIa 64.177.3100IIIb 52.367.1100IIIc 43.057.3100IIId 26.843.1100IIIe 8.117.3100IV O’ConnellJB, 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. LNs = > 12
  • 13. Who Should Receive Adjuvant Therapy? 2. Mesentric Nodules: Contour Role: T-Stage N-Stage 1. V1 (micro). 2. V2 (macro) Isolated Tumor Cells & Micrometastases 0 – 0.2 mm (N0) 0.2 – 2 mm (N1mi) Stage III Not IV Cancer 2008;112:50–4. 13
  • 14. Who Should Receive Adjuvant Therapy? 3. Peri-neural Invasion: An Under-Estimated Variable: 15 – 25% JCO.2009.22.4949
  • 15. Who Should Receive Adjuvant Therapy? 3. Peritoneal Minimal Residual Disease: • 1/5 : Peritoneal Minimal Residual Disease. • 1/7 : Peritoneal Carcinomatois.  Surgical Techniques.  Intraperitoneal & Intraportal Chemotherapy.  HCE.  Prevention of The Inflammatory Response. thelancet.com/oncology Vol 10 January 2009 15
  • 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. Timing of Chemotherapy: 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. 16
  • 17. Which Program & What Schedule? 5-Fu Modulated/ Non- Modulated Oxaliplatin Irinotecan UFT Capecitabin e Anti-EGFR Anti- Angiogeni c
  • 18. Accepted Standards of Care: Stage III Colon Cancer Stage III Colon Cancer Patients 5- Fu/Leucovorin Mayo Clinic Roswell Park De Gramont Lower Toxicity Profile & Better Compliance NSABP Co1-6 IMPACT NCCTG NCIC-CTG 30% 18
  • 19. Adjuvant FOLFOX4 in Stage II-III Colon Cancer: MOSAIC Study Schema de Gramont A, et al. ASCO 2007. Abstract 4007. 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 (n = 1123) LV5FU2 Leucovorin 200 mg/m2 IV + 5-FU 400 mg/m2 bolus + 5-FU 600 mg/m2 IV over 22 hrs (n = 1123) Patients with previously untreated, completely resected stage II-III colon cancer (N = 2246)
  • 20. MOSAIC Study: 6-Y OAS; by Treatment Arm: J Clin Oncol. 2009,27:3109-3116
  • 21. MOSAIC Study: 6-Y OAS; by Treatment Arm & Stage: J Clin Oncol. 2009,27:3109-3116
  • 22. Final MOSAIC Results (cont’d)  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.
  • 23. MOSAIC Patients > 70 Years:
  • 24. NSABP C – 07: 2407 Colon Cancer Stage 2 & 3 Weekly Bolus 5-Fu and LV + Oxaliplatin on wks 1, 3 & 5 • 5-y DFS: 69% vs 64% (HR 0.82) • OAS: 80% vs 78% (HR 0.88) • High toxicity profile
  • 25. X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer  Primary endpoint: non-inferiority in DFS  Secondary endpoint: OS Bolus 5-FU/LV 5-FU 425mg/m2 + LV 20mg/m2 days 1–5 q4w Capecitabine 1,250mg/m2 b.i.d. days 1–14 q3w Chemonaïve stage III resection 8 weeks n=1,004 n=983 R A N D O M I S A T I O N Data cut-off: January 2007 b.i.d. = twice daily Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
  • 26. 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)
  • 27. Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study: J Clin Oncol.2009,27:3117-3125
  • 28. Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study: J Clin Oncol.2009,27:3117-3125
  • 29. Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study: J Clin Oncol.2009,27:3117-3125 After Exclusion of Cases Developed Second Primary in Both Arms
  • 30. XELOXA: Adjuvant CAPOX Chemo/radiotherapy naive stage III colon cancer R A N D O M I Z A T I O N CAPOX Capecitabine 1000 mg/m2 BID days 1-15 Oxaliplatin 130 mg/m2 day 1 q3w Bolus 5FU/LV Mayo Clinic or Roswell Park Duration of therapy: 24 weeks Primary endpoint: Disease-free survival Haller DG, et al. J Clin Oncol. 2011;29(11): 1465-1471.
  • 32. Cetuximab in Adjuvant Sitting: N0147 Trial:
  • 33. Cetuximab in Adjuvant Sitting: N0 147 Trial:
  • 34. NSABP Protocol C-08: mFOLFOX ± Bevacizumab in Stage II/III CRC Wolmark N, et al. ASCO 2009. Abstract LBA4. Arm A: mFOLFOX6 Q2W x 26 (n = 1356) Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg Q2W x 26 (n = 1354) Pts with stage II or III colon adenocarcinoma with ECOG PS of 0/11 (N = 2710)  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
  • 35. NSABP Protocol C-08: 3-Yr DFS Results: Wolmark N, et al. ASCO 2009. Abstract LBA4. DFS(%) Yrs 0 20 40 60 80 100 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 HR: 0.89 (P = .15)mFF6 + B mFF6 Events 291 312 3-Yr DFS 77.4 75.5
  • 36. Where Do We Go in Adjuvant Therapy of Colon Cancer?  Shorten Duration: “Less is More”  6 months versus 3 months.  Non inferiority trial design.  Don’t lose any curability in adjuvant sitting.  More is Better:  FOLFIRINOX in high risk Stage III.  Toxicity and compliance are of upfront concern. 36
  • 37. 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. Stage II Colon Cancer 80% Cured by Surgery only 16% will Recur Regardless Treatment 4% will Benefit of Treatment Who Needs Adjuvant Therapy? Treatment Related Mortality
  • 38. Who Needs Adjuvant Therapy? Stage II: Uptodate.com 01/06/2014
  • 39.  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. Who Needs Adjuvant Therapy? Stage II:
  • 40. Stage II Colon Cancer: Trials of Better Identification: NSABP C 01, 02, 04, 06 (1851 Pts) 5 Reference Genes 7 Recurrence Genes 6 Treatment Benefit Genes QUASAR Study (1436/3239 Pts) Surgery Surgery + 5- Fu/LV Kerr D, et al. ASCO 2009. Abstract 4000.
  • 41. Translational Study on PETACC 3: Results: Strong effect in stage II, decreases in stage III disease 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 Roth AD, et al. ASCO 2009. Abstract 4002. 41
  • 42. 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.
  • 43. The Adenoma-Carcinoma Process: 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. Normal colonic epithelium Dysplastic aberrant crypt foci Initial adenoma develops Intermediate adenoma Late adenoma Carcinoma Metastasis Mutation in APC Mutation in K-ras Mutation in DCC Mutation in p53 Other alteration? EGFR & VEGF
  • 44. PI3-K STAT AKT Grb2 SOS RAS RAF1 MEK MPA K Gene Transcription & Cell Cycle Progression 1. Angiogenesis 2. Survival 3. Proliferation 4. Progression Molecular Key Players: EGFR Carter P. Nat Rev. Cancer 2001. Heinemann V et al. Cancer Treat Rev. 2009. NK CELLS
  • 45. Formation of New Blood Vessels Physiological Wound Healing Placental Implantation Growth Pathological Pre-Eclampsia Diabetic Retinopathy Tumors Molecular Key Players: Angiogenesis:
  • 46. Disease Overview: Angiogenesis: Hallmark of Malignancy: Proliferation Invasion Metastases Treatment Failure Apoptosis Resistance VEGF + + TK + m-TOR
  • 47. Angiogenesis Process: Release of GFs Receptor Activation Degradation & Proteolytic Enz. Disruption of ECM & Wall Invasion & Migration Tumor Proliferation
  • 48. Angiogenic Factors: Tyrosine Kinase Receptors VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2 VEGFs VEGF - A VEGF - B VEGF - C VEGF - D PlGF
  • 49. Angiogenesis in Malignancy: Hypoxia HIF VEGF Gene VEGF VEGFR on Nearby Vessels VEGFR on Tumor Vessels
  • 51. 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.
  • 53. 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
  • 54. 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
  • 55. Management of Met. CRC: Playing a Strategic Game: The King Should SURVIVE SURVIVA L What You Have to Play? Pharmaceuticals How to Play? 1st, 2nd , 3rd …seniL . Try to be Creative Research
  • 56. mCRC patient segmentation: potentially resectable and long-term disease control Resection Optimising PFS and OS –represents majority of patients Treatment goal Required outcome Long-term DFS 10% 20% 70% Curative surgery Presentation Unresectable diseaseUpfront resectable Un-resectablePotentially resectable Most patients remain unresectable Van Cutsem, WCGIC 2012
  • 57. Treatment for mCRC Comparing Combination Chemotherapy Regimen The Tournigand Study: Scheme FOLFIRI Tournigand at al. J Clin Oncol 2004; 22: 229-237 R FOLFOX6 FOLFOX6 FOLFIRI Till Progression Till Progression Arm A Arm B 226 pt Stage IV mCRC CPT-11 180 mg /m2 IV + Simplified LV5FU Oxaliplatin 100 mg/m2 IV+Siplified LV5FU
  • 58. Treatment for mCRC Comparing Combination Chemotherapy Regimen The Tournigand Study: Time to Progression Tournigand at al. J Clin Oncol 2004; 22: 229-237 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
  • 59. 59 Treatment for mCRC Comparing Combination Chemotherapy Regimen Tournigand at al. J Clin Oncol 2004; 22: 229-237 The Tournigand Study: Overall Survival 1.00 0.75 0.50 0.25 0 Probability 0 10 20 30 40 50 FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI Overall Survival P = .99 FOLFIRI/FOLFOX6 21.6 FOLFOX6/FOLFIR 20.6
  • 60. Treatment for mCRC Comparing Combination Chemotherapy Regimen The Tournigand Study: Summary of Efficacy results Tournigand at al. J Clin Oncol 2004; 22: 229-237 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
  • 61. • 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? Challenges in The Palliative Treatment of Stage IV CRC:
  • 63. Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy IFL+ Placebo (n = 411) Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342. IFL+ Bevacizumab (n = 402) P Value Median survival, months 15.6 20.3 .00004 Progression-free survival (PFS), months 6.2 10.6 <.00001 Overall response rate (ORR), % Complete response (CR) Partial response (PR) 35 2.2 32.5 45 3.7 41.2 .0036 Duration of response, months 7.1 10.4 .0014
  • 64. XELOX N = 317 FOLFOX4 N = 317 Initial 2-arm open-label study (N = 634) Protocol amended to 2x2 placebo- controlled design after bevacizumab phase III data1 became available (N = 1401) Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 XELOX vs FOLFOX +/- Bevacizumab NO16966 Study Design 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. XELOX + placebo N = 350 XELOX + bevacizumab N = 350 FOLFOX4 + placebo N = 351 FOLFOX4 + bevacizumab N = 350
  • 65. NO16966 PFS Subgroup Analyses: On-Treatment Population HR = 0.61 [97.5% CI 0.48–0.78] P≤.0001 HR = 0.65 [97.5% CI 0.50–0.84] P = .0002 XELOX + placebo FOLFOX4 + placeboXELOX + Bev FOLFOX-4 + BevVS VS XELOX Group FOLFOX Group Survival 1.0 0.8 0.6 0.4 0.2 0 0 100 200 300 400 500 Study Day 1.0 0.8 0.6 0.4 0.2 0 0 100 200 300 400 500 Survival Study Day 10.6 m Saltz L, et al. Presented at: 2007 Gastrointestinal Cancer Symposium; January 19-21, 2007: Orlando, Florida. Abstract. 8.4 m9.5 m7.0 m
  • 66. CAIRO-3: Validation of BEV-Containing Maintenance Therapy (MT) XELOX-Bx6 CTX-BEV XELOX-Bx6 CTX-BEV R PD1 PD2 PFS1 TT2PD MT CFI 8.5 4.1 11.8 10.5 HR P PFS1, months 0.44 <.00001 PFS2, months 0.81 .028 TT2PD 19.8 15.0 0.67 <.00001 OS 21.7 18.2 0.87 .16 MT: LD-Cape (625 mg/m2 BID daily) + BEV (7.5 mg/kg every 3 weeks) MT CFI N = 558 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. PFS2
  • 67. BEV + standard first-line CT (either oxaliplatin or irinotecan-based) (n = 820) BEV (2.5 mg/kg/wk) + standard second-line CT (oxali or irino-based) until PD PD Randomize 1:1 CT switch: Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37. Standard second-line CT (oxaliplatin or irinotecan- based) until PD ML18147 (TML) Study Design (Phase III) Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin Primary endpoint Secondary endpoints included • OS from randomization • PFS • Best ORR • Safety • 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) Stratification factors
  • 68. OS: ITT Population OSEstimate 0.4 0.2 0 0 6 11.2 mo 12 18 24 30 36 42 9.8 mo P = .0211 (log-rank test) 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) Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0) 1.0 0.8 0.6 CT (n = 410) BEV + CT (n = 409) Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) P = .0062 (log-rank test) Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) PFSEstimate 1.0 0.8 0.6 0.4 0.2 0 0 6 12 18 24 36 CT (n=410) BEV + CT (n=409) 4.1 mo 5.7 mo Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) P<.0001 (log-rank test) Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) P<.0001 (log-rank test) PFS:ITT Population Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37. No. at risk Time , Months Time, Months No. at risk CT 410 293 162 51 24 7 3 2 CT 410 119 20 6 4 0 BEV + CT409 328 188 64 29 13 4 1 BEV + CT409 189 45 12 5 2
  • 69. Adverse Events (AEs) of Special Interest to BEV: Safety Population Patients, % Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37. Chemotherapy n = 409 All Grades Grade 3–5 21 6 BEV + Chemo n = 401 All Grades Grade 3–5 41 12AEs of special interest to BEV ATE, arterial thromboembolic events; GI, gastrointestinal; RPLS, reverse posterior leukoencephalopathy syndrome; VTE, venous thromboembolic events Hypertension 7 1 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 complications RPLS <1 – <1 – 1 – <1 –
  • 70. EFC10262: VELOUR Phase III Trial Second-Line FOLFIRI +/- VEGF-TRAP (Aflibercept) Stratification factors: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) 1:1 mCRC after failure of an oxaliplatin based regimen R 600 pts Aflibercept 4 mg/kg IV + FOLFIRI q 2 weeks 600 pts Placebo + FOLFIRI q 2 weeks Principle investigators: Allegra, Van Cutsem 21 30% of patients had prior BEV
  • 71. VELOUR Study OS HR 0.82 PFS HR 0.76 Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506. Time, Months Time, Months
  • 72. Overall Survival Strata (as per UVRS) N HR (95.34% CI) HR Interaction P All patients Prior BEV No Yes 1226 0.82 (0.713-0.937) 853 373 0.79 (0.669-0.927) 0.86 (0.673-1.104) .5668 0 Favors aflibercept 1 2 Favors placebo 3 Progression-Free Survival Strata (as per UVRS) N HR (95% CI) HR Interaction P All patients Prior BEV No Yes 1226 0.76 (0.661-0.869) 853 373 0.80 (0.679-0.936) 0.66 (0.512-0.852) .1958 0 Favors aflibercept 1 2 Favors placebo 3 Aflibercept: VELOUR Phase III: OS and PFS Stratified by Prior Bevacizumab Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.
  • 73. 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)
  • 75. NCIC CTG CO.17: Randomized Phase III Trial in mCRC Cetuximab vs BSC (No Cross-Over) BSC Cetux n = 83 n = 81 BSC n = 113 Cetux n = 117 BSC n = 285 Cetux n = 287 RR 0% 1.2% 0% 12.8% 0% 6.6% PFS, months 1.8 1.8 1.9 3.8 1.8 1.9 OS, months 4.6 4.5 4.8 9.5 4.6 6.1 <.0001 <.0001 Karapetis CS, et al. N Engl J Med. 2008;359(17):1757-1765. KRAS Mut KRAS Wildtype All Patients <.0001 .0046
  • 76. CRYSTAL: FOLFIRI +/- Cetuximab PFS in Patients With KRAS Wildtype Tumors Number of patients FOLFIRI 350 FOLFIRI + cetuximab 316 237 227 111 128 22 40 4 8 0 1 FOLFIRI (n = 350) FOLFIRI + Cetuximab (n = 316) No of events 189 8.4 months [7.4‒9.2] 146 9.9 months [9.0‒11.3] Median PFS [95% CI] HR [95% Cl] P value 0.70 [0.558‒0.867] .0012 ProbabilityofPFS Time, Months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 120 4 8 16 20 FOLFIRI FOLFIRI + cetuximab Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019.
  • 77. PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status “Final Analysis” Median, months (95% CI) Panitumumab + FOLFOX4 FOLFOX4 10.0 (9.3 – 11.4) 8.6 (7.5 – 9.5) HR = 0.80 (95% CI: 0.67 – 0.95) Log-rank P value = .01 Median, months (95% CI) Panitumumab + FOLFOX4 FOLFOX4 7.4 (6.9 – 8.1) 9.2 (8.1 – 9.9) HR = 1.27 (95% CI: 1.04 – 1.55) Log-rank P value = .02 WT KRAS MT KRAS ProportionEvent-Free 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Months 36 38 40 42 44 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ProportionEvent-Free Douillard J, et al. J Clin Oncol. 2011;29(Suppl): Abstract 3510. 18 20 22 24 26 28 30 32 34 Months 0 2 4 6 8 10 12 14 16 36 38 40 42 44
  • 78. FOLFIRI + Bevacizumab Bevaciizumab: 5 mg/kg iIV.v.3300-9-900miin q 2ww Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506. FIRE-3 Phase III Study Design FOLFIRI + Cetuximab mCRC first-line therapy KRAS wildtype N = 592 Randomize 1:1 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 Fisher‘s exact test at an alpha level of 2.5% Cetuximab: 400 mg/m2 IV 120 min initial dose 250 mg/m2 IV 60 min q 1 w
  • 79. FIRE-3 ORR Primary Endpoint FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Odds ratio P Assessable for response (N = 526) 72.2 66.2 – 77.6 63.1 57.1 – 68.9 1.52 1.05-2.19 .017 1.18 0.85-1.64 .183 P = Fisher´s exact test (one-sided) ORR % 95%-CI % 95%-CI ITT population (N = 592) 62.0 56.2 – 67.5 58.0 52.1 – 63.7 Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
  • 80. 0.75 Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506. 1.0 0.50 0.25 ProbabilityofSurvival Events n/N (%) Median (months) 10.0 95% CI 8.8 – 10.8 HR 1.06 (95% CI 0.88 – 1.26) 10.3 9.8 – 11.3 Log-rank P = .547 0.0 12 24 36 48 Months Since Start of Treatment 60 72 —FOLFIRI + Cetuximab 250/297 (84.2%) — FOLFIRI + Bevacizumab 242/295 (82.0%) Number 297 100 19 10 5 3 at risk 295 99 15 6 4 FIRE-3 PFS:
  • 81. Events n/N (%) Median (months) 28.7 95% CI — FOLFIRI + Cetuximab 158/297 (53.2%) 185/295 (62.7%) 24.0 – 36.6 — FOLFIRI + Bevacizumab HR 0.77 (95% CI: 0.62 – 0.96) 25.0 22.7 – 27.6 Log-rank P = .017 0.75 1.0 0.50 0.25 ProbabilityofSurvival 0.0 12 24 36 48 60 72 Months Since Start of Treatment Number 297 at risk 295 218 214 111 111 60 47 29 18 9 2 PFS Split of curves Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506. FIRE-3 OS:
  • 82. — FOLFIRI + Cetuximab ProbabilityofSurvival — FOLFIRI + Bevacizumab PTEN, EGFR ligands Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506. 0.75 1.0 0.50 0.25 0.0 12 24 36 48 Months Since Start of Treatment 60 72 Who are these patients? Analysis of RAS, PIK3CA, BRAF, Number 297 218 111 60 29 9 at risk 295 214 111 47 18 2 FIRE-3 OS:
  • 83. Progression-Free Survival By Arm (All RAS Wildtype Patients)100 – 80 – 60 – 40 – 20 – 0 – 0 12 PercentEventFree 24 36 48 Months From Study Entry 60 72 No at Risk Arm Chemo + Bev Chemo + Cetux Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010. 256 112 49 23 13 6 270 126 49 18 5 2 1 N (Events) Median (95% CI) HR (95% CI) P 256 (221) 270 (241) 11.3 (10.3-12.6) 11.4 (9.6-12.9) 1.1 (0.9-1.3) .31
  • 84. Overall Survival By Arm (All RAS Wildtype Patients) 100 – 80 – 60 – 40 – 20 – 0 – 0 12 24 36 48 60 72 84 96 PercentEventFree Arm Chemo + Bev Chemo + Cetux Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010. N (Events) Median (95% CI) HR (95% CI) P 256 (178) 270 (177) 31.2 (26.9-34.3) 32.0 (27.6-38.5) 0.9 (0.7-1.1) .40 No at Risk Months From Study Entry 256 199 147 77 35 16 5 2 270 205 164 88 41 24 7 1 1
  • 85. 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!
  • 86. Progression-Free Survival Overall Survival N (Events) Median (95% CI) HR (95% CI) P N (Events) Median (95% CI) HR (95% CI) P Chemo + Bev Chemo + Cetux 192 (163) 11.0 (9.5-13.1) 1.1 (0.9-1.4) .3 192 (137) 29.0 (24.0-32.8) 0.86 (0.6-1.1) .2 198 (177) 11.3 (9.4-13.1) 198 (129) 32.5 (26.1-40.4) All RAS Wildtype FOLFOX Patients Progression-Free Survival Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010. Overall Survival N (Events) Median (95% CI) HR (95% CI) P N (Events) Median (95% CI) HR (95% CI) P Chemo + Bev Chemo + Cetux 64 (58) 11.9 (10.3-14.8) 1.1 (0.7-1.5) .7 64 (41) 35.2 (28.3-41.3) 1.1 (0.7-1.6) .7 72 (64) 12.7 (8.9-14.1) 72 (48) 32.0 (25.6-42.9) All RAS Wildtype FOLFIRI Patients Outcomes by Chemotherapy Backbone
  • 89. 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
  • 90. Irinotecan vs Oxaliplatin for Cetuximab??
  • 91. 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.