Download A Report from ASCO GI 2008

A Report from ASCO GI 2008
Up-to-Date Review of the Treatment
of Metastatic Colorectal Cancer
Edward Chu, MD
Professor of Internal Medicine and Pharmacology
Chief, Section of Medical Oncology
Yale Cancer Center
Yale University School of Medicine
New Haven, CT
Outline
• Cytotoxic chemotherapy
• FOLFOX and neurotoxicity
• FOLFOX versus XELOX
• Integration of biologics with cytotoxic chemotherapy
• Bevacizumab
• Bevacizumab plus panitumumab
• Biomarker development for anti-EGFR antibodies
Abstract 280
Effect of Intravenous Calcium and
Magnesium vs Placebo on Response to
FOLFOX+bevacizumab in the
CONcePT Trial
Hochster HS, Grothey A, Shpilsky A, Childs BH
CONcePT : Schema
1° Endpoint:
TTF for continuous vs.
intermittent oxaliplatin
Exclusion Criteria:
• Prior exposure to bev
and/or oxaliplatin
• Peripheral neuropathy
grade >1
R
A
N
D
O
M
I
Z
E
mFOLFOX7/bev + placebo
mFOLFOX7/bev + Ca2+/Mg2+
mFOLFOX7/bev + placebo
mFOLFOX7/bev + Ca2+/Mg2+
Continuous
Oxaliplatin
Intermittent
Oxaliplatin
mFOLFOX7/bev: oxaliplatin 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr, 5-FU 2400 mg/m2 over 46 hours,
bevacizumab 5 mg/kg over 30-90 minutes, Day 1 biweekly
Ca2+/Mg2+: 1 g calcium gluconate/1 g magnesium sulfate over 30 min before and after oxaliplatin
Intermittent: alternating between 8 cycles with oxaliplatin and 8 cycles with 5-FU/LV only
CONcePT : Schema
R
mFOLFOX7/bev + placebo
A
TTF for continuous vs.
N
intermittent oxaliplatin
mFOLFOX7/bev + Ca2+/Mg2+
D
Study closed early due to negative
Exclusion Criteria:
O of Ca2+/Mg2+ on efficacy of
impact
mFOLFOX7/bev + placebo
M
• Prior exposure to bev
mFOLFOX7/bev
(int and cont)
and/or oxaliplatin
• Peripheral neuropathy
foundI by IDMC during unplanned
Z interim
grade >1
mFOLFOX7/bev + Ca2+/Mg2+
analysis
E
1° Endpoint:
Continuous
Oxaliplatin
Intermittent
Oxaliplatin
mFOLFOX7/bev: oxaliplatin 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr, 5-FU 2400 mg/m2 over 46 hours,
bevacizumab 5 mg/kg over 30-90 minutes, Day 1 biweekly
Ca2+/Mg2+: 1 g calcium gluconate/1 g magnesium sulfate over 30 min before and after oxaliplatin
Intermittent: alternating between 8 cycles with oxaliplatin and 8 cycles with 5-FU/LV only
CONcePT : Clinical Efficacy
Cont
Placebo
(N = 34)
Cont
Ca2+Mg2+
(N = 35)
Int
Placebo
(N = 36)
Int
Ca2+Mg2+
(N = 35)
15.1
17.1
28.1
18.1
21
36
45
43
Adverse Event
16
13
8
12
Progression
9
5
8
8
Physician/Pt Decision
8
14
10
11
Other
1
2
10
4
Median Duration
of Treatment
ORR (evaluable), %
Discontinuation of Treatment, N
CONcePT: Conclusions
• Two-factor logistic regression exploratory model of
response data revealed no significant relationship
between use of Ca2+/Mg2+ and response
• Future reports of neuroprophylaxis await pending
data
Abstract 347
Diabetes Mellitus and the Incidence and Time
to Onset of Oxaliplatin-Induced Peripheral
Sensory Neuropathy (PSN) in Patients with
Colorectal Cancer: A Pooled Analysis of
Three Randomized Studies
Ramanathan RK, André T, Rothenberg ML, de Gramont A,
Tournigand C, Goldberg RM, Gupta S
Pooled Analysis
• Conducted pooled analysis of data from randomized clinical trials
including FOLFOX4 treatment arm
– EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant
therapy in CRC
– EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or
oxaliplatin alone as second-line therapy of metastatic CRC
– EFC2962: Phase II/III study of LV5–FU2 + oxaliplatin
• PSN data from the overall study population with or without diabetes
were analyzed for:
– Incidence and time to onset of PSN (Kaplan-Meier)
– Trends indicating clinically relevant differences in the incidence and
severity of PSN (Kaplan-Meier)
Ramanathan et al, ASCO GI 2008, abstract 347.
Incidence and Severity of PSN
All Patients
DM Patients
(N = 1585)
(N = 135)
Grade 1
45.2
46.7
Grade 2
28.4
26.7
Grade 3
13.0
12.6
PSN
Ramanathan et al, ASCO GI 2008, abstract 347.
Conclusions
• Patients with diabetes mellitus do not have an
increased risk of developing cumulative neurotoxicity
Abstract 341
XELOX vs. FOLFOX-4: Update of Efficacy
Results from XELOX-1/NO16966, a
Randomized Phase III Trial of First-Line
Treatment for Patients with Metastatic
Colorectal Cancer (MCRC)
Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, A. Figer A,
Wong R, Koski S, Sirzen F, Gilberg F, Saltz L
Phase III NO16966 Trial
Schema
Recruitment
June 2003 – May 2004
Recruitment
Feb 2004 – Feb 2005
XELOX
XELOX + Placebo
(N = 317)
(N = 350)
FOLFOX4
FOLFOX4 + Placebo
(N = 317)
(N = 351)
Initial 2-arm
open-label study
(N = 634)
XELOX +
Bevacizumab
(N = 350)
FOLFOX4 +
Bevacizumab
(N = 349)
Protocol amended to 2x2 placebocontrolled design after bevacizumab
phase III data became available
(N = 1400)
Cassidy et al, ASCO GI 2008, Abstract 341.
XELOX-1/NO16966 Trial
Adverse Events
FOLFOX-4 + Placebo
(N = 649)
XELOX + Placebo
(N = 655)
Diarrhea
<12
20
Nausea
5
5
Stomatitis
2
1
Peripheral Neuropathy
4
4
Peripheral Sensory Neuropathy
3
3
Hand-foot syndrome
1
6
Fatigue
<9
<6
Paresthesia
4
5
Neutropenia
43
<7
Febrile neutropenia
5
<2
Thrombocytopenia
<4
7
Grade 3/4 Adverse Events, %
Cassidy et al, ASCO GI 2008, Abstract 341.
XELOX-1/NO16966 Trial
Efficacy Results
XELOX
(N = 1,017)
FOLFOX-4
(N = 1,017)
Hazard Ratio
(97.5% CI)
Median PFS
(All Patients)
8.0 months
(886 events)
8.5 months
(919 events)
1.01 (0.91-1.12)
Median OS
(All patients)
19.8 months
(692 events)
19.6 months
(695 events)
0.99 (0.88-1.12)
Cassidy et al, ASCO GI 2008, Abstract 341.
Abstract 340
Efficacy of Capecitabine vs. 5-FU in
Colorectal and Gastric Cancer:
Meta-analysis of Survival in 6 Clinical Trials
Cassidy J, Rothenberg M, Saltz L, Twelves C, Van Cutsem E,
Hoff P, Kang Y-K, Sirzen F, Gilberg F, Cunningham D
Meta-Analysis: Capecitabine vs 5-FU
• Included individual patient data from 6 phase III trials
comparing the efficacy of capecitabine and 5-FU in
metastatic colorectal and gastric cancers
• Main endpoint was overall survival
• Assessment completed with unstratified and stratified (by
study) data
• Included 6,171 patients (3,074 received 5-FU-based
regimens and 3,097 received capecitabine-based
regimens)
• Unstratified data found a median OS of 23.1 and 22.4
months for patients who received capecitabine and 5-FU,
respectively (HR = 0.96)
Cassidy J et al, ASCO GI 2008, abstract 340.
Meta-Analysis: Stratified OS Analysis
Study
1.
2.
3.
4.
5.
6.
N
HR
Range
SO146951
605
1.01
0.86 - 1.19
SO147962
602
0.89
0.76 - 1.05
M660013
1,987
0.86
0.74 - 1.01
ML170324
316
0.89
0.69 - 1.15
NO169665
2,034
0.99
0.89 - 1.10
NO169676
627
1.02
0.86 - 1.21
Unstratified
6,171
0.96
0.90 - 1.02
Hoff PM et al. JCO 2001; 19:2282-92.
Van Cutsem E, et al. JCO 2001; 19:4097-106.
Twelves C, et al. N Eng J Med 2005; 352:2696-704.
Kang YK, et al, ESMO 2006 (abstract 1072O).
Cassidy J, et al. ASCO 2007 (abstract 4030).
Rothenberg ML, et al. ASCO 2007 (abstract 4031).
Cassidy J et al, ASCO GI 2008, abstract 340.
Conclusions
• Findings of meta-analysis suggest:
– Equivalency of capecitabine and 5-FU in the treatment
of adjuvant and metastatic colorectal cancer
– Equivalency of capecitabine and 5-FU in the treatment
of metastatic gastric cancer
• Equivalency of capecitabine and 5-FU is supported by
updated results of the NO16966 trial comparing
capecitabine and 5-FU as treatment for metastatic
colorectal cancer
Abstract 342
Capecitabine and Oxaliplatin as First-Line
Treatment in Patients with MCRC:
A Meta-analysis of Randomized
Phase II-III Trials
Arkenau H-T, Arnold D, Diaz-Rubio E, Douillard J-Y, Martoni A,
Grothey A, Hinke A, Schmiegel W, Schmoll H-J, Porschen R
Meta-Analysis: Comparing PFS of Capecitabineand 5-FU-Containing Regimens
N
HR
(fixed)
Range
1,335
1.02
0.91 - 1.15
474
1.17
0.96 - 1.43
342
1.18
0.94 - 1.49
306
1.05
0.82 - 1.35
118
0.66
0.44 - 0.99
2,575
1.05
0.97 - 1.14
Study
NO16966 Phase III1
XELOX vs. FOLFOX4
German AIO Phase III2
CAPOX vs. FUFOX
Spanish TTD Phase III3
XELOX vs. FUOX
French Phase III4
XELOX vs. FOLFOX6
Italian GOAM Phase II5
XELOX vs. PVIFOX
All
1. Cassidy J, et al. ASCO 2007 (abstract 4030).
2. Porschen R, et al. J Clin Oncol 2007:4217-4223.
3. Díaz-Rubio E, et al. J Clin Oncol 2007:4224-4230.
4. Ducreux M, et al. ASCO 2007 (abstract 4029).
5. Martoni A, et al. Eur J Cancer 2006: 3161-3168.
Arkenau HT, et al, ASCO GI 2008, abstract 342.
Conclusions
• Findings of meta-analysis suggest non-inferiority of
capecitabine/oxaliplatin compared to 5-FU/oxaliplatin,
based on PFS analysis and combination regimens.
Abstract 350
Preliminary Efficacy of Bevacizumab with
First-Line FOLFOX, XELOX, FOLFIRI and
Fluoropyrimidines for MCRC: First BEAT
Berry S, Cunningham D, Michael M, Kretzschmar A,
Rivera F, DiBartolomeo M, Mazier M, Van Cutsem E,
on behalf of the First BEAT investigators
First BEAT: Study Schema
First-line
metastatic
CRC
(1,965)
Bevacizumab +
standard
chemotherapy
PD
• Bevacizumab: 5 mg/kg Q2W or 7.5 mg/kg Q3W
• Endpoints: safety and efficacy
• Median follow-up 22.9 months
Berry et al, ASCO GI 2008, abstract 350.
Serious BEV-Related Adverse Events
Event (%)
Any AE or SAE
(N = 1,914)
CTC grade 3–5 or SAE*
(N = 1,914)
Hypertension
29.9
5.3
Proteinuria
10.4
1.1
Bleeding
31.0
3.4
Wound-healing complications
4.0
1.1
Arterial thromboembolic events
1.5
1.5
GI perforation
1.9
1.8
Berry et al, ASCO GI 2008, abstract 350.
First BEAT: Clinical Efficacy (PFS)
Overall (N = 1914)
Median PFS
10.9
FOLFIRI (N = 503)
11.6
FOLFOX (N = 552)
11.2
XELOX (N = 346)
11.0
5-FU/Capecitabine (N = 300)
8.6
Berry et al, ASCO GI 2008, abstract 350.
Abstract 363
First-line Irinotecan, Oxaliplatin and Infusional
5FU/LV (FOLFOXIRI) in Combination with
Bevacizumab (BV) in MCRC Patients (pts):
A Phase II Study by the GONO Group
Masi G, Loupakis F, Baldi G, Fornaro L, Di Leo A,
Ciarlo A, Amoroso D, Granetto C, Di Donato S, Falcone A
Study Design
• Phase II trial evaluating first-line therapy with
FOLFOXIRI plus Bev in patients with initially
unresectable mCRC
• Primary endpoint: PFS rate at 10 months
Masi et al, ASCO GI 2008, abstract 363.
First-Line Bev/FOLFOXIRI: Safety
Toxicity (N = 38)
G1
G2
G3
G4
Nausea
42
18
5
0
Vomiting
24
21
0
0
Diarrhea
24
24
8
0
Stomatitis
42
13
3
0
Neutropenia
18
13
21
13
Thrombocytopenia
26
0
0
0
Anemia
42
24
5
0
Neurotoxicity
34
24
3
0
Hypertension
18
3
8
0
Deep venous thrombosis
0
0
5
0
Bleeding
32
0
0
0
Cardiac ischemia
0
0
5
0
Masi et al, ASCO GI 2008, abstract 363.
Bev/FOLFOXIRI: Clinical Efficacy
Efficacy, N (%)
Complete Response (CR)
N = 29
2 (7)
Partial Response (PR)
20 (69)
Stable Disease (SD)
7 (24)
Progressive Disease
0
Disease Control Rate
(CR + PR + SD)
29 (100)
Resection Rates
R0
4 (14)
R1
1 (3)
Masi et al, ASCO GI 2008, abstract 363.
Bev/FOLFOXIRI: Conclusions
• First-line therapy with bevacizumab/FOLFOXIRI
associated with high response rates (76%) and 100%
tumor control, in patients with MCRC
• High response rates coincided with high R0 resection rate
in initially unresectable patients
• Grade 3/4 toxicities included nausea, diarrhea, stomatitis,
neutropenia, anemia, neurotoxicity, hypertension, deep
vein thrombosis, and cardiac ischemia
Abstract 273
An Updated Analysis of Safety and Efficacy of
Oxaliplatin (Ox)/bevacizumab (bev) +/Panitumumab (pmab) for First-line Treatment
(tx) of MCRC from a Randomized, Controlled
Trial (PACCE)
Hecht J. R., Mitchell E, Chidiac T, Scroggin C, Hagenstad C,
Spigel D, Marshall J, Cohn A, Shahin S, Griffin T
PACCE Phase III Trial
S
C
R
E
E
N
I
N
G
Ox-based CT
(e.g.,
FOLFOX)
N = 800
Inv choice
Iri-basedCT
(e.g.,
FOLFIRI)
N = 200
Inv choice
R
A
N
D
O
M
I
Z
E
1:1
Panitumumab
+
Bevacizumab
Bevacizumab
Panitumumab
+
Bevacizumab
1:1
Bevacizumab
Stratification Factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs
Tumor assessments: Q12W until disease progression or intolerability
FOLFOX Chemotherapy: Efficacy
Pmab + Bev-Ox
(N = 413)
Bev - Ox
(N = 410)
CR
0
<1
PR
45
46
SD
29
34
PD
7
4
mPFS, mos
9.6
11.1
mOS, mos
19.4
NR
Hecht et al, ASCO GI 2008, abstract 273.
PACCE Trial: Grade 3/4 Toxicity
Skin toxicity
Diarrhea
Dehydration
Hypokalemia
Hypomagnesemia
Neutropenia
Neuropathy
Nausea
Infections
DVT
Pulmonary embolism
Pmab + Bev
Bev
(N = 401), %
(N = 392), %
Gr 3
33
21
14
8
3
12
9
10
16
6
0
Gr 3
1
12
4
3
0
17
10
4
7
7
0
Gr 4
<1
2
2
2
1
10
<1
0
2
0
6
Gr 4
0
1
1
1
0
7
<1
<1
2
0
4
Hecht et al, ASCO GI 2008, abstract 273.
Abstract 279
Interim Results from PACCE: Irinotecan
(Iri)/bevacizumab (bev) + Panitumumab (pmab)
as First-line Treatment (tx) for MCRC
Hecht J. R., Mitchell E, Chidiac T, Scroggin C, Hagenstad C,
Spigel D, Marshall J, Cohn A, Suzuki S, Griffin T
FOLFIRI Chemotherapy: Efficacy
Pmab+ Bev-Iri
(N = 115)
Bev-Iri
(N = 115)
CR
0
0
PR
43
39
mut KRAS
(N = 46)
30
38
WT KRAS
(N = 57)
54
47
SD
27
38
PD
13
3
mPFS, mos
10.1
11.7
mOS, mos
20.7
20.5
Hecht et al, ASCO GI 2008, abstract 279.
PACCE FOLFIRI Chemotherapy:
Discontinuation of Treatment
Reason for Discontinuation,
N(%)
Pmab+ Bev-Iri
(N = 115)
Bev-Iri
(N = 115)
Discontinued First-line
102 (89)
99 (86)
Disease Progression
36 (35)
27 (27)
6 (6)
2 (2)
17 (17)
6 (6)
3 (3)
5 (5)
15 (15)
33 (33)
Death
Adverse Events
Protocol Violation
Consent Withdrawn
Hecht et al, ASCO GI 2008, abstract 279.
PACCE: Safety Analysis of FOLFIRI Arms
Pmab+ Bev/Iri (N = 111)
Adverse Event, %
Bev/Iri (N = 113)
Grade 3
Grade 4
Grade 3
Grade 4
Skin Toxicity
37
0
0
0
Diarrhea
27
1
9
0
Neutropenia
14
3
17
4
Dehydration
14
0
6
0
Infections
12
2
9
0
Nausea
10
2
6
0
Hypokalemia
9
2
4
0
Vomiting
8
2
7
0
Paronychia
4
0
0
0
Hypomagnesemia
3
2
0
1
Hypertension
2
0
3
0
Deep Vein Thrombosis
13
0
6
0
Pulmonary Embolism
0
11
0
5
Hecht et al, ASCO GI 2008, abstract 279.
PACCE Trial: Conclusions
• Addition of panitumumab to oxaliplatin-containing
chemotherapy+bevacizumab worsened PFS and increased
toxicity
• Panitumumab added to irinotecan modestly increased
response, although PFS and OS were similar for both treatment
arms
• Toxicity of panitumumab/bev-iri was considerable, additionally
causing 2% grade 5 infections and gastrointestinal perforation,
and 1% grade 5 pulmonary embolism
• Most patients discontinued treatment for non-progressive
events
• Panitumumab/bev-iri improved response rates (54% vs. 47%)
in patients with wild type KRAS tumor status
• Evaluation of toxicity is ongoing
Role of K-RAS Mutations as
Predictive Biomarker
• K-RAS: Downstream signalling molecule in EGFR signalling
pathway1
• Lower response to erlotinib and gefitinib in NSCLC2,3
– erlotinib: 8% responders in patients with mutations
vs 26% in wild-type K-RAS
– gefitinib: 24% refractory tumors with K-RAS mutations
vs 0% in drug-sensitive tumours (P = 0.02)
• Lower response to cetuximab in CRC4
– 0% responders in patients with mutations vs 49%
in non-mutated patients (P < 0.001)
1Calvo
& Baselga, J Clin Oncol 2006; 14: 2158.
et al, J Clin Oncol 2005; 23: 5900.
3Pao et al, PLoS Med 2005; 2: e17.
4Lièvre et al, AACR Annual Meeting 2007; Abstract 5671.
2Eberhard
Abstract 278
Panitumumab Efficacy and Patient-Reported
Outcomes in MCRC Patients with
Wild-Type KRAS Tumor Status
Amado R, Wolf M, Freeman D, Peeters M, Van Cutsem E,
Siena S, Suggs S, Devercelli G, Woolley M, and Chang D
KRAS Analysis of a Phase III Trial of
Panitumumab as Salvage Therapy for MCRC
R
A
N
D
O
M
I
Z
E
Panitumumab
6.0 mg/kg Q2W + BSC
PD
BSC
PD
Optional
Crossover
Stratification
• ECOG score (0-1 vs. 2)
• Geographic region (Western EU vs. Central
& Eastern EU vs. Rest of World)
Van Cutsem E et al. J Clin Oncol 25:1658–1664, 2007.
Molecular Composition of Treatment Arms
Screened
N = 1,040
Tumors screened for
KRAS mutation status
using DxS, LTD kit
Randomized
N = 463
Randomized to
panitumumab + BSC
N = 231
Randomized to
BSC alone
N = 232
Excluded from KRAS analyses
(missing or unevaluable)
N = 36
KRAS mutant
N = 84
WT KRAS
N = 124
KRAS mutant
N = 100
Received
P’mab in
X-over protocol
N = 77
BSC = Best supportive care; WT = wild-type
WT KRAS
N = 119
Received
P’mab in
X-over protocol
N = 90
Amado 2008 ASCO GI
abstract #278
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
Mutant
PR (0%)
SD (12%)
PD (70%)
PR (0%)
SD (8%)
PD (60%)
% Change
BSC
Alone
% Change
Patient
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
Wild-Type
PR (17%)
SD (34%)
PD (36%)
% Change
Pmab
+ BSC
% Change
Percent Decrease of Target Lesions
in KRAS Evaluable Patients
Patient
BSC = Best supportive care; Pmab = panitumumab
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
Patient
PR (0%)
SD (12%)
PD (75%)
Patient
Amado et al, ASCO GI 2008, abstract 278.
KRAS Mutation Status and Efficacy
of Single Agent Panitumumab
BSC
Pmab
HR
Median PFS, weeks
mut KRAS
wt KRAS
7.3 (N = 100)
7.4 (N = 84)
7.3 (N = 119) 12.3 (N = 124)
0.99
0.45
(P < .0001)
Median OS, months
mut KRAS
4.4 (N = 100)
4.9 (N = 84)
NR
wt KRAS
7.6 (N = 119)
8.1 (N = 124)
NR
BSC, basic supportive care; NR, not reported
Amado et al, ASCO GI 2008, abstract 278.
Conclusions
• Salvage single agent panitumumab significantly (P < .0001)
improved PFS in patients with KRAS wild type tumors with no
benefit in those having mutant KRAS tumors
• Only patients with wild type KRAS benefited from single agent
panitumumab in the salvage setting
• Long-term outcome of patients was primarily dictated by
KRAS mutation status
• Future studies will focus on prospective analysis of the
efficacy of panitumumab-containing combination therapy in
patients with wild type and mutant KRAS tumors
Abstract 343
Panitumumab Efficacy in Patients with MCRC
with Low or Undetectable Levels of
Epidermal Growth Factor Receptor:
Final Efficacy and KRAS Analysis
Hecht JR, Mitchell EP, Baranda J, Richards D, Reiner M, Stout S, Amado RG
Trial Design
• Phase II single-arm, open-label study
• Patients received panitumumab 6 mg/kg (Q2W) until disease
progression or unacceptable toxicity
• Previous analyses indicated that panitumumab efficacy is
independent of tumor EGFR expression levels (Mitchell, ASCO
2007 abstract 4082, Hecht, ASCO GI 2007 abstract 350)
• Exploratory analysis of KRAS mutation status
– Total of 203 pts enrolled
– EGFR expression levels available for 195 pts
– KRAS mutation status available for 171 pts (55%
wild type, 45% mutant)
Hecht et al, ASCO GI 2008, abstract 343.
Panitumumab in Low EGFR Expressors:
KRAS and Efficacy
EGFR Expression
KRAS Status
<1%
1%-9%
Wild type
Mutant
(N = 81)
(N = 111)
(N = 94)
(N = 77)
Objective Response
—
—
12%
0
Stable Disease
—
—
47%
14%
Median PFS, mos
8.1
8.1
15.0
7.1
Median OS, mos
41.6
37.4
54.0
29.1
Efficacy Measure
Hecht et al, ASCO GI 2008, abstract 343.
Conclusions
• Patients received panitumumab 6 mg/kg (Q2W) until
disease progression or unacceptable toxicity
• EGFR expression levels, by immunohistochemistry, do not
correlate with clinical benefit in treated patients
• Response to panitumumab in treated patients correlates
with wild-type KRAS status
• Progression-free survival is doubled, and overall survival
nearly doubled, when comparing clinical benefit in patients
with wild type and mutant KRAS
Hecht et al, ASCO GI 2008, abstract 343.
Abstract 411
High Amphiregulin and Epiregulin Expression in
KRAS Wild Type Colorectal Primaries Predicts
Response and Survival Benefit After Treatment with
Cetuximab and Irinotecan for Metastatic Disease
Tejpar S, De Roock W, Biesmans B, De Schutter J, Piessevaux H,
Humblet Y, Peeters M, Celik I, Van Cutsem E
Study Design
• Primary tumor specimens from patients treated on
clinical trials with cetuximab and irinotecan for
metastatic colorectal carcinoma
• 152 patients with irinotecan-refractory disease were
identified who had been treated with cetuximab
• Tumors were analyzed for KRAS mutation status and
amphiregulin and epiregulin mRNA levels
Tejpar et al, ASCO GI 2008, abstract 411.
Findings
• mRNA levels of epiregulin and amphiregulin were
significantly correlated (P < .0001)
• KRAS was mutated in 43% (64/149) patients
• Wild type KRAS and high EGFR ligand levels significantly
correlated (P = .03 for amphiregulin and P = .02 for
epiregulin) with each other
• Response correlated with mutation status: ORR was 39.7%
for patients with wild type KRAS and < 1% for those with
mutant KRAS
• Patients who achieved objective response were
approximately 4 times more likely to have tumors with high
(above median) levels of amphiregulin and epiregulin
Tejpar et al, ASCO GI 2008, abstract 411.
Findings
KRAS Status
All
Wild-type
Mutant
Epiregulin Exp.
Median PFS
mos
Median OS
mos
< 0.5233
12
26
> 0.5233
30
45.86
Overall
18
36
< 0.5233
12
31.57
> 0.5233
36
65.4
Overall
24.14
44.29
< 0.5233
12
22.86
> 0.5233
12
29.14
Overall
12
24.3
P < .001
P < .001
Tejpar et al, ASCO GI 2008, abstract 411.
Conclusions
• Patients with irinotecan-refractory disease who have mutant
KRAS status received no benefit from cetuximab treatment
in terms of response
• Patients with tumors expressing above-median levels of
epiregulin and amphiregulin, excluding those with mutant
KRAS, have significantly longer progression-free and overall
survival than those with below-median levels
• This study supports the notion that response to cetuximab
therapy depends upon KRAS status, and further suggests
that patients with high expression of epiregulin and
amphiregulin benefit the most from cetuximab therapy
Tejpar et al, ASCO GI 2008, abstract 411.
A Report from ASCO GI 2008
Up-to-Date Review of the Treatment
of Metastatic Colorectal Cancer
Thank You!