Transcript Diapositive 1

A Report from ASCO 2007
First-Line Metastatic Colorectal Cancer
Edward Chu, MD
Professor, Medicine & Pharmacology
Chief, Section of Medical Oncology
Deputy Director, Yale Cancer Center
Yale Cancer Center
Yale University School of Medicine
New Haven, CT
CRC Treatment Review
• Chemotherapy for advanced disease
– Oral vs. IV 5-FU
– Sequential vs. combination
– Continuous vs. intermittent
• Targeted therapies
– Anti-angiogenesis inhibitors
• Bevacizumab
– EGFR inhibitors
• Cetuximab
Chemotherapy for Advanced Disease
Abstract 4029
Efficacy and Safety from a Phase III,
Randomized Study of Capecitabine plus
Oxaliplatin (XELOX) vs. Infusional 5-FU/LV
plus Oxaliplatin (FOLFOX6) as First-Line
Treatment for Metastatic Colorectal Cancer
M. Ducreux, J. Bennouna, M. Hebbar, M. Ychou, G. Lledo,
T. Conroy, A. Adenis, R. Faroux, C. Rebischung, J. Douillard
Phase III Study of XELOX vs. FOLFOX6
as First-Line Treatment of mCRC
Metastatic/advanced
colorectal cancer,
previously untreated
by chemotherapy
(N = 306)
R
A
N
D
O
M
I
Z
E
XELOX
8 cycles
(N = 156)
FOLFOX6
12 cycles
(N = 150)
• Primary Endpoint: Non-inferiority of XELOX to FOLFOX on best RR
• Secondary Endpoints: PFS; OS; Safety; QoL; Pharmacoeconomics
Ducreux M, et al. ASCO 2007. Abstract #4029.
Phase III Study of XELOX vs. FOLFOX6
as First-Line Treatment of mCRC
Grade 3/4 Hematologic Toxicity
Ducreux M, et al. ASCO 2007. Abstract #4029.
Phase III Study of XELOX vs. FOLFOX6
as First-Line Treatment of mCRC
Clinical Activity
Response (%)
XELOX
(N = 156)
FOLFOX6
(N = 150)
ORR (independent review)
42
46
ORR (investigator)
44
44
PFS
8.8 mos.
9.3 mos.
OS
19.9 mos.
20.5 mos.
Ducreux M, et al. ASCO 2007. Abstract #4029.
Abstracts 4028 and 4030
Bevacizumab in Combination with XELOX or
FOLFOX4: Updated Efficacy Results from
XELOX-1/NO16966, a Randomized Phase III
Trial in First-Line Metastatic Colorectal Cancer
Abstract 4028: L. Saltz et al.
Abstract 4030: J. Cassidy et al.
Phase III NO16966 Trial: XELOX ±
Bevacizumab vs. FOLFOX4 ± Bevacizumab
Recruitment
June 2003 – May 2004
Recruitment
Feb 2004 – Feb 2005
XELOX
(N = 317)
XELOX + Placebo
(N = 350)
XELOX +
Bevacizumab
(N = 350)
FOLFOX4
(N = 317)
FOLFOX4 + Placebo
(N = 351)
FOLFOX4 +
Bevacizumab
(N = 350)
Initial 2-arm
open-label study
(N = 634)
Protocol amended to 2x2 placebocontrolled design after bevacizumab
phase III data became available
(N = 1,401)
Phase III NO16966 Trial: XELOX ±
Bevacizumab vs. FOLFOX4 ± Bevacizumab
Study Objectives
•
Main endpoint: progression-free survival (PFS)
•
Two primary objectives
–
–
XELOX is non-inferior to FOLFOX
Bevacizumab + chemotherapy is superior to placebo +
chemotherapy
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
XELOX vs. FOLFOX: PFS
2-Arm Study Only (ITT)
1.0
HR = 0.96 [97.5% CI: 0.80–1.16] (ITT)
HR = 0.98 [97.5% CI: 0.81–1.18] (EPP)
Survival
0.8
0.6
0.4
FOLFOX
XELOX
N = 317; 294 events
N = 317; 285 events
0.2
7.3
0
0
5
7.7
10
15
20
25
30
Months
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
XELOX/BV vs. FOLFOX/BV: PFS
(ITT)
1.0
HR = 1.01 [97.5% CI: 0.83–1.23] (ITT)
HR = 1.04 [97.5% CI: 0.84–1.27] (EPP)
PFS Estimate
0.8
0.6
0.4
0.2
9.3
0
0
5
9.4
10
15
20
25
Months
FOLFOX + bevacizumab N = 349; 255 events
XELOX + bevacizumab
N = 350; 258 events
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
FOLFOX vs. XELOX: Safety Profile
FOLFOX
XELOX
(N = 649)
(N = 655)
Grade 3/4 AEs
78.3%
71.5%
Diarrhea grade 3/4
11.2%
20.2%
Neutropenia grade 3/4
43.8%
7.0%
Febrile neutropenia grade 3/4
4.8%
0.9%
Hand-foot syndrome grade 3
1.2%
6.1%
16.5%
17.4%
Venous thromboembolic events grade 3/4
6.3%
3.8%
Cardiac disorders grade 3/4
1.4%
0.9%
Discontinuations due to AE
24.8%
26.0%
All-cause 60-day mortality
2.3%
3.4%
Treatment-related mortality up to 28 days after last
dose
1.7%
2.1%
Neurosensory toxicity grade 3/4
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
XELOX vs. FOLFOX: Conclusions
• XELOX and FOLFOX are equivalent in terms of clinical
efficacy (RR, PFS, and OS)
• Safety profiles of XELOX and FOLFOX are similar
– Increased grade 3/4 myelosuppression and neutropenic fever
with FOLFOX
– Increased incidence of hand-foot syndrome with XELOX
• XELOX should be considered a standard treatment
option in first-line setting
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
Capecitabine-Based Regimens
Issues to Consider
• What is the optimal dose of capecitabine when used in
combination with oxaliplatin?
– 1,000 mg/m2 bid 2 weeks on / 1 week off
– Lower doses, 750-850 mg/m2 bid
– Fixed dose
• What is the optimal schedule for capecitabine-based
regimens?
– 2 weeks on / 1 week off (every 3 weeks)
– 1 week on / 1 week off (every 2 weeks)
Capecitabine Dosing
U.S. vs Europe
• European trials
– Capecitabine 1,000-1,250 mg/m2 bid (d1-14, q3w)
• United States trials
– Capecitabine 1,250 mg/m2 bid dose too toxic (d1-14, q3w)
– 1,000 mg/m2 bid more tolerable, but still toxic
– Lower doses more tolerable in U.S. (850 mg/m2 bid)
• Reasons for discrepancy?
– United States diet fortified with folic acid
– Vitamin/nutritional supplements
• Folic acid exacerbates capecitabine toxicity
– Pharmacogenetic differences in folate metabolism, DPD?
– Other?
Abstract 4012
Sequential Compared to Combination
Chemotherapy with Capecitabine, Irinotecan,
and Oxaliplatin in Advanced Colorectal Cancer:
A Dutch Colorectal Caner Group (DCCG)
Phase III Study
C. J. Punt, M. Koopman, J. Douma, J. Wals, A. H. Honkoop, F. L.
Erdkamp, R. S. de Jong, C. J. Rodenburg, L. Mol, N. F. Antonini
CAIRO Study Design
CAPIRI
CAPOX
(N = 378)
(N = 213)
mCRC
No prior therapy
(N = 820)
Capecitabine
Irinotecan
CAPOX
(N = 397)
(N = 251)
(N = 143)
• Primary Endpoint: Survival
• Secondary Endpoints: PFS, RR, Safety, QoL
• Sample Size: 1,298 patients in 221 centers
Punt CJ, et al. ASCO 2007. Abstract #4012.
CAIRO Study
Clinical Efficacy
Combination
Sequence
P-value
OS (mos.)
17.4
16.3
n.s.
1-yr Survival
67%
64%
n.s.
PFS (mos.)
7.8
5.8
0.0002
41%
20%
< 0.0001
RR (%)
Punt CJ, et al. ASCO 2007. Abstract #4012.
CAIRO Study
Conclusions
• Median OS equivalent between sequential and
combination strategies
• Highlights the role of effective salvage treatments in
mCRC
• Sequential therapy is a reasonable treatment option for
patients with mCRC
– Consider in good risk patients
– Role of biologics in improving clinical efficacy and maintaining
safety profile
Punt CJ, et al. ASCO 2007. Abstract #4012.
Abstract 4013
Final Results of OPTIMOX2, a Randomized
Phase II Study of Maintenance Therapy of
Chemotherapy-Free Intervals (CFI) after
FOLFOX in Patients with Metastatic
Colorectal Cancer
F. Maindrault-Goebel, G. Lledo, B. Chibaudel, L. Mineur, T. Andre, M.
Bennamoun, M. Mabro, P. Artru, C. Louvet, A. de Gramont
OPTIMOX1 Study
FOLFOX4
R
6x FOLFOX7 → 12x sLV5FU2 → 6x FOLFOX7
620 pts
Cum. Oxaliplatin
(%)
FOLFOX4
RR
PFS
DDC
OS
G3/4 N-Tox
58.5
9.0
9.0
19.3
17.9
780
1,560
FOLFOX7
58.3
8.7
10.6
21.2
13.3
Primary
endpoint
Tournigand et al, JCO 2006.
OPTIMOX Studies
FOLFOX 4 until TF
OPTIMOX1
FOLFOX7
FOLFOX7
sLV5FU2
mFOLFOX7
mFOLFOX7
sLV5FU2
OPTIMOX2
mFOLFOX7
mFOLFOX7
CFI
CFI: Chemotherapy-Free Interval
OPTIMOX2 Study
Continuous vs. Intermittent Chemotherapy
• mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin
• Comparison: maintenance therapy vs. chemotherapyfree intervals (CFI)
• Primary endpoint: Duration of disease control (DDC)
• Planned trial size, N = 600
– After bevacizumab approved downsized to a randomized phase
II trial (N = 200)
Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.
FOLFOX Regimens
B 400
B 400
FOLFOX4
200
600
200
600
85
B 400
FOLFOX6
400
100
2,400-3,000
FOLFOX7
400
130
2,400
mFOLFOX7
400
100
3,000
Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.
OPTIMOX2
Clinical Efficacy
OPTIMOX
Maintenance
5-FU/LV
Chemo-Free
Interval
P-value
RR (%)
60
61
n.s.
PFS (mo)
8.3
6.7
0.008
DDC (mo)
12.0
9.0
n.s.
OS (mo)
26.0
19.0
0.0549
Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.
OPTIMOX2
Conclusions
• Stop-and-go with maintenance is associated with
prolonged OS and DDC vs. chemotherapy-free interval
• Incidence of grade 3 neurotoxicity similar between 2 arms
• Break in chemotherapy not recommended
– May consider for patients with “good” tumor biology
– Role of biologics in maintenance strategy needs to be explored in
phase III trials (Dream Study)
Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.
Targeted Therapy
VEGF Inhibitors
Abstracts 4028 and 4030
Bevacizumab in Combination with XELOX or
FOLFOX4: Updated Efficacy Results from
XELOX-1/NO16966, a Randomized Phase III
Trial in First-Line Metastatic Colorectal Cancer
Abstract 4028: L. Saltz et al.
Abstract 4030: J. Cassidy et al.
Phase III NO16966 Trial: XELOX ±
Bevacizumab vs. FOLFOX4 ± Bevacizumab
Recruitment
June 2003 – May 2004
Recruitment
Feb 2004 – Feb 2005
XELOX
(N = 317)
XELOX + Placebo
(N = 350)
XELOX +
Bevacizumab
(N = 350)
FOLFOX4
(N = 317)
FOLFOX4 + Placebo
(N = 351)
FOLFOX4 +
Bevacizumab
(N = 350)
Initial 2-arm
open-label study
(N = 634)
Protocol amended to 2x2 placebocontrolled design after bevacizumab
phase III data became available
(N=1,401)
XELOX/BV vs. FOLFOX/BV: PFS
(ITT)
1.0
HR = 1.01 [97.5% CI: 0.83–1.23] (ITT)
HR = 1.04 [97.5% CI: 0.84–1.27] (EPP)
PFS Estimate
0.8
0.6
0.4
0.2
9.3
9.4
0
0
5
10
15
20
25
Months
FOLFOX + bevacizumab N = 349; 255 events
XELOX + bevacizumab
N = 350; 258 events
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
XELOX vs. FOLFOX4 ± Bevacizumab
Safety Profile
FOLFOX/XELOX
+ Placebo
FOLFOX/XELOX
+ Bevacizumab
(N = 675)
(N = 694)
74.8%
80.0%
Gastrointestinal perforations grade 3/4
0.3%
0.6%
Bleeding grade 3/4
1.2%
1.9%
Arterial thromboembolic events grade 3/4
1.0%
1.7%
Hypertension grade 3/4
1.2%
3.7%
–
0.6%
0.3%
0.1%
Discontinuations due to AE
20.7%
30.7%
All-cause 60-day mortality
1.6%
2.0%
Treatment-related mortality up to 28 days after
last dose
1.5%
2.0%
Grade 3/4 AEs
Proteinuria grade 3/4
Wound-healing complication grade 3/4
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
Effect of Bevacizumab on PFS
1.0
PFS Estimate
HR = 0.83 [97.5% CI 0.72–0.95]
0.8
P = 0.0023
0.6
0.4
0.2
8.0
9.4
0
0
3
6
9
12
15
18
21
Months
XELOX + Placebo
(X+P)
FOLFOX-4 + Placebo
(F+P)
VS.
XELOX + Bevacizumab
(X+A)
FOLFOX-4 + Bevacizumab
(F+A)
Effect of Bevacizumab on PFS
PFS Estimate
XELOX and FOLFOX Subgroups
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
7.4
9.3
8.6
0
9.4
0
0
5
10
15
Months
20
25
XELOX + Placebo
N = 350; 270 events
XELOX + Bevacizumab N = 350; 258 events
XELOX subgroup
HR = 0.77 [97.5% CI 0.63–0.94] (ITT)
P = 0.0026
0
5
10
15
20
25
Months
FOLFOX + Placebo
N = 351; 277 events
FOLFOX + Bevacizumab N = 349; 255 events
FOLFOX subgroup
HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
P = 0.1871
Phase III NO16966 Trial
Conclusions
• First study to show that XELOX and FOLFOX
regimen are clinically equivalent
• Provides first evidence that bevacizumab confers
clinical benefit to FOLFOX chemotherapy
• Safety profile in line with previous trial results in CRC
• Supports the use of bevacizumab in combination with
standard first-line chemotherapy
Saltz L, et al. ASCO 2007. Abstract #4028.
Cassidy J, et al. ASCO 2007. Abstract #4030.
Abstract 4027
Updated Results of BICC-C Study
Comparing First-Line
Irinotecan/Fluoropymidine Combinations with
or without Celecoxib in mCRC
C. Fuchs, J. Marshall, E. Mitchell, R. Wierzbicki, V. Ganju, M. Jeffery,
J. Schultz, D. A. Richards, R. Soufi-Mahjoubi, J. Barrueco
Phase III Study of Three Irinotecan
Regimens in First-Line mCRC (BICC-C)
Original Design (Period 1: 2/03-4/04)
R
A
N
D
O
M
I
Z
A
T
I
O
N
N = 1,000 (430)
3 x 2 design
ARM A: FOLFIRI
Irinotecan 180 mg/m2 D 1 q 2wk
5-FU 400 mg/m2 (bolus) D1 q 2 wk
LV 400 mg/m2 D 1 q 2 wk
5-FU 400 mg/m2 bolus/2.4 g/m2 (46 hr infusion)
D 1 q 2 wk
± Celecoxib
400 mg bid
± Celecoxib
400 mg bid
ARM B: Modified Saltz
Irinotecan: 125 mg/m2
5-FU: 500 mg/m2
LV: 20 mg/m2
D 1, 8, q 3 wks
ARM C: XELIRI
Irinotecan: 250 mg/m2 d1 q 3 wks
Capecitabine: 1,000 mg/m2 bid d1-14 q 3 wks
± Celecoxib
400 mg bid
Fuchs C, et al. ASCO 2007. Abstract #4027.
Phase III Study of Three Irinotecan
Regimens in First-Line mCRC (BICC-C)
Amended Design (Period 2: 5/04-12/04)
R
A
N
D
O
M
I
Z
A
T
I
O
N
N = 117
2 x 2 design
ARM A: FOLFIRI + BV
± Celecoxib
400 mg bid
ARM B: Modified Saltz
IFL + BV
± Celecoxib
400 mg bid
ARM C: XELIRI
This arm was discontinued
Fuchs C, et al. ASCO 2007. Abstract #4027.
BICC-C Study
Clinical Efficacy
FOLFIRI +
mIFL +
Bevacizumab Bevacizumab
P-value
Median PFS
11.2 mos.
8.3 mos.
0.28
Median OS
Not reached
19.2 mos.
0.01
Fuchs C, et al. ASCO 2007. Abstract #4027.
BICC Study
Update on Clinical Efficacy
TTP
(months)
OS
(months)
FOLFIRI + BV
≤ 65
> 65
11.2
11.1
Not reached
FOLFIRI
≤ 65
> 65
7.6
7.5
24.3
20.1
Barrueco J, et al, ASCO 2007, Abstract #4076.
FOLFIRI + BV vs. FOLFOX + BV
Clinical Efficacy
BICC-C Trial
NO16966 / TREE-2 Trials
FOLFIRI + BV
FOLFOX + BV
OS
NR
21.3 / 26 mos.
PFS
11.2 mos.
9.4 / 9.9 mos.
RR
54%
47% / 53%
Bevacizumab Therapy
Conclusions
• Bevacizumab can be safely and effectively used in
combination with 5-FU-, irinotecan-, and oxaliplatinbased chemotherapy for the first-line treatment of mCRC
• VEGF and the VEGF-signaling pathway are rational
targets for anticancer therapy
• Agents in clinical development target the VEGF ligand,
VEGF receptors, and VEGFR-TK
Bevacizumab Therapy
Arterial Thromboembolic Events
Arterial TE events*
Chemotherapy
alone
Bevacizumab +
Chemotherapy
2.0% (15/741)
4.5% (45/1004)
• Risk factors for arterial thromboembolic events* included:
–
–
History of prior arterial thromboembolic events such as stroke or
heart attack
Age of 65 years or older
*Pooled analysis of 5 randomized trials
Bevacizumab
Recommendations
• Recommended dose is 5 mg/kg every 14 days as an IV
infusion until disease progression
• Bevacizumab therapy should not be initiated for at least
28 days following surgery
• Bevacizumab should be permanently discontinued in
patients who develop:
–
–
–
–
–
Gastrointestinal perforation
Wound dehiscence requiring medical intervention
Serious bleeding
Nephrotic syndrome
Hypertensive crisis
Bevacizumab Therapy
Issues
• Should bevacizumab be continued at time of disease
progression?
• What dose of bevacizumab should be used in secondline and disease refractory setting?
• What are the biomarkers of response to bevacizumab
therapy?
Targeted Therapy
EGFR Inhibitors
Abstract 4000
Randomized Phase III Study of Irinotecan and
5-FU/FA with or without Cetuximab in the FirstLine Treatment of Patients with Metastatic
Colorectal Cancer (mCRC): The CRYSTAL Trial
E. Van Cutsem, M. Nowacki, I. Lang, S. Cascinu, I. Shchepotin, J.
Maurel, P. Rougier, D. Cunningham, J. Nippgen, C. Köhne
CRYSTAL Trial
Study Design
FOLFIRI q2w
mCRC
EGFR positive
(N = 1,217)
PFS
FOLFIRI q2w +
Cetuximab
Primary Endpoint: PFS
Secondary Endpoints: ORR, OS, QoL, Safety
Van Cutsem E, et al. ASCO 2007. Abstract #4000.
CRYSTAL Trial
Grade 3/4 Toxicity
FOLFIRI
N = 602, %
Cetuximab + FOLFIRI
N = 600, %
Any
59.5
78.0
Neutropenia
23.3
26.7
2.2
2.7
Diarrhea
10.5
15.2
Vomiting
5.0
4.5
Fatigue
4.5
5.0
Skin reactions
0.2
18.7
0
2.3
Febrile neutropenia
Infusion-related reactions
Van Cutsem E, et al. ASCO 2007. Abstract #4000.
CRYSTAL Trial
Progression-Free Survival
1.0
Cetuximab + FOLFIRI (N = 609)
0.9
FOLFIRI (N = 608)
PFS Estimate
0.8
HR = 0.851; 95% CI = [0.726-0.998]
Log-rank P-value = 0.0479
0.7
0.6
8.9 mos.
0.5
1-year PFS rate
34% vs. 23%
8.0 mos.
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
Progression-Free Survival (months)
Van Cutsem E, et al. ASCO 2007. Abstract #4000.
CRYSTAL Trial
Clinical Efficacy
FOLFIRI
(N = 609)
Cetux + FOLFIRI
(N = 608)
P-value
8.0
8.9
0.0479
PFS, grade 0/1 ST
-
5.4 (N = 244)
PFS, grade 2 ST
-
9.4 (N = 243)
PFS, grade 3 ST
-
11.3 (N = 112)
ORR, %
38.7
46.9
0.0038
R0 resection, %
1.5
4.3
0.0034
4.5 (N = 134)
9.8 (N = 122)
-
PFS
R0, liver mets only, %
Van Cutsem E, et al. ASCO 2007. Abstract #4000.
CRYSTAL Trial
Surgery with Curative Intent
6
Percentage (%)
6
5
4.3
4
3
2.5
2
12
P = 0.0034
odds ratio = 3.0
1.5
8
6
2
0
0
FOLFIRI
No residual tumor
after resection
N = 599
Cetuximab + FOLFIRI
4.5
4
1
Surgery with
curative intent
N = 599
9.8
10
Percentage (%)
7
Liver Metasteses Only
Population (exploratory)
ITT Population
(pre-planned)
No residual tumor in patients with
liver metastases
N = 134 / N = 122
Van Cutsem E, et al. ASCO 2007. Abstract #4000.
CRYSTAL Trial
Conclusions
• Cetuximab can be safely and effectively combined with
FOLFIRI in the first-line setting
• Addition of cetuximab to FOLFIRI improves RR and PFS
• Skin reactions correlate with clinical activity
• Significant 3-fold increase in R0 resection rate for
patients with initially unresectable disease
• QoL and biomarker analysis is ongoing
• Cetuximab should be considered for first-line and
neoadjuvant therapy, esp. in liver-limited disease
Van Cutsem E, et al. ASCO 2007. Abstract #4000.
Phase III CALGB/SWOG 80405 Trial
First-Line mCRC
FOLFOX
FOLFIRI
N = 2,289
(600+ enrolled)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Primary endpoint: OS
Secondary endpoint: PFS, RR
Cetuximab
Bevacizumab
Bevacizumab
+ Cetuximab
Anti-EGFR Abstract
Conclusions
• Cetuximab has been safely and effectively combined
with irinotecan and oxaliplatin for first-, second-, and
third-line treatment
• Cetuximab is a reasonable treatment alternative to
bevacizumab in the first-line and neoadjuvant setting
(liver-limited disease)
• CALGB/SWOG 80405 currently enrolling patients to
confirm role of cetuximab, bevacizumab, and
cetuximab/bevacizumab in first-line setting
• Panitumumab active in the disease refractory setting
• Panitumumab can not be reasonably substituted for
cetuximab in combination with chemotherapy
– Await further clinical studies