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
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)
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.
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.
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
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
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
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
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
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.