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1. Treating the Patient With Newly
Diagnosed, Metastatic Colorectal Cancer:
Case Presentations
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2. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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3. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Faculty
Edward Chu, MD Peter C. Enzinger, MD
Chief Clinical Director, Gastrointestinal
Division of Hematology/Oncology Cancer Center
University of Pittsburgh School of Dana-Farber Cancer Institute
Medicine Assistant Professor of Medicine
Deputy Director Harvard Medical School
University of Pittsburgh Cancer Institute Boston, Massachusetts
Pittsburgh, Pennsylvania
John L. Marshall, MD
Cathy Eng, MD Chief, Division of Hematology/Oncology
Associate Professor Department of Medicine
Department of Gastrointestinal Medical Georgetown University Hospital
Oncology Washington, DC
The University of Texas M. D.
Anderson Cancer Center
Houston, Texas
4. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Disclosures
Edward Chu, MD, has no significant financial relationships to
disclose.
Cathy Eng, MD, has disclosed that she has received consulting
fees from Amgen and Genentech and fees for contracted research
from Amgen, Daiichi, and Kerxy.
Peter C. Engzinger, MD, has disclosed that he has received
consulting fees from Boehringer Ingelheim, Genentech, sanofi-
aventis, and Taiho.
John L. Marshall, MD, has disclosed that he has received
consulting fees and fees for contracted research from Amgen and
Genentech.
5. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Overview
Three case-based presentations originally presented as
part of a live, CME-certified educational symposium
1. Clinical Management of a Patient Newly Diagnosed With
Liver-Limited Metastatic Colorectal Cancer
2. Treatment Conundrums for a Patient With Wild-Type KRAS
3. Impact of KRAS and BRAF Mutations on Treatment
Decisions in Patients With Metastatic Colorectal Cancer
6. Clinical Management of a Patient Newly
Diagnosed With Liver-Limited Metastatic
Colorectal Cancer
7. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Patient Case
68-yr-old male presents with sigmoid colon
adenocarcinoma
CT scan: multiple suspicious lesions in both lobes of the
liver
History of hypertension, under good control
Abnormal kidney function, secondary to AODM
– CrCl: 35 mL/min
No previous history of chemotherapy
No previous history of bleeding or arterio-embolic events
8. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Patient Case
Feels well, c/o RUQ pain
ECOG PS of 1
Serum chemistries and CBC are normal
Serum CEA: 150 ng/mL; ALP: 250 IU/L; LDH: 300 IU/L;
serum bilirubin:
2.2 mg/dL
Assessment of colon adenocarcinoma reveals wild-type
KRAS
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Should one of the liver lesions be biopsied?
A. No
B. Yes, to confirm the diagnosis of metastatic disease
C. Yes, to confirm KRAS mutation status
D. Yes, to confirm diagnosis and KRAS status
10. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Liver-Limited mCRC: Scope of Problem
400,000 CRC cases/yr (US/Europe)
30% synchronous metastases
Additional ~ 50% will develop metastases
30% to 35% “liver only” metastases
10% to 25% 75% to 90%
candidates for not candidates for surgery
SURGERY PALLIATIVE THERAPY
Aim: R0 resection R0 resection not possible
Cure rate: 20% to 30% 70% to 80% relapse
5-yr survival: 40% to 60% within 2 yrs
11. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Response to Neoadjuvant Therapy of Liver
Metastases Prior to Resection Is Important
131 (of 441) patients with CRC and > 4 liver metastases
underwent (mostly) FOLFOX-based neoadjuvant therapy
Survival outcome by response to chemotherapy
Response SD PD P Value
Patients, n (%) 58 (44) 39 (30) 34 (26)
Hepatic relapse, % 55 77 82
1-yr OS, % 95 92 63
5-yr OS, % 37 30 8 < .0001
Adam R, et al. Ann Surg. 2004;240:1052-1061.
12. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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OS Based on Initial Response to
Chemotherapy
100 95 PR (n = 34)
92 Stabilization (n = 39)
80 Progression (n = 58)
Patients (%)
63
60 55
40 44 37
30
20
12
8
0
0 1 2 3 4 5
Yrs
Adam R, et al. Ann Surg. 2004;240:1052-1061.
13. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Survival After Primary or Secondary
Resection of Liver Metastases
100 Resectable (n = 425)
Initially nonresectable (n = 95)
Patients Surviving (%)
80
60 54
50 34
40
27
20 34
29
19
0
0 1 2 3 4 5 6 7 8 9 10
Survival Time (Yrs)
Adam R. Ann Oncol. 2003;14(suppl 2):ii13-ii16.
14. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Response Correlates With Resection
in Initially Unresectable mCRC
0.6
Studies including
selected patients
0.5 (liver metastases only,
no extrahepatic disease)
r = 0.96; P = .002
Resection Rate
0.4
0.3 Studies including all
patients (solid line)
r = 0.74; P = .001
0.2
Phase III studies
0.1
(dashed line)
r = 0.67; P = .024
0
0.3 0.4 0.5 0.6 0.7 0.8 0.9
Response Rate
Folprecht G, et al. Ann Oncol. 2005;16:1311-1319.
15. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Which cytotoxic chemotherapy regimen
would you recommend for this patient?
A. 5-FU/LV
B. Capecitabine
C. FOLFIRI
D. FOLFOX
E. CAPIRI
F. CAPOX
G. FOLFOXIRI
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Clinical Efficacy of Cytotoxic Regimens
Regimen, % Response Rate Resection Rate
FOLFOX 40-50 25-35
FOLFIRI 40-50 25-30
FOLFOXIRI 50-60 30-50
Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249. Barone C, et al. Br J Cancer. 2007;97:1035-1039.
De La Cámara R, et al. ASCO 2004. Abstract 3593. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
Abad A, et al. ASCO 2005. Abstract 3618. Ho WM, et al. Med Oncol. 2005;22:303-312.
18. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Phase III Trial of FOLFOXIRI vs FOLFIRI as
First-line Therapy of Advanced CRC
FOLFIRI FOLFOXIRI P Value
(n = 122) (n = 122)
RR, % 34 60 < .0001
CR + PR + SD, % 68 81
R0 resection (all patients), % 6 15 .033
R0 resection (liver limited), % 12 36 .017
PFS, mos 6.9 9.8 .0006
OS, mos 16.7 22.6 .032
Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
19. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Which biologic agent would you
recommend?
A. Bevacizumab
B. Cetuximab
C. Panitumumab
D. None
20. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Which biologic agent would you
recommend if a KRAS mutation were
detected?
A. Bevacizumab
B. Cetuximab
C. Panitumumab
D. None
21. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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CRYSTAL Trial: Liver Resection
Increased With Addition of Cetuximab
FOLFIRI alone Cetuximab + FOLFIRI
ITT Population Liver Metastases Only Population
10
OR: 3.0 10 9.8
9 (95% CI: 1.4-6.5;
8 9
P = .0034)
8
Patients (%)
7 6.0
Patients (%)
6 7
5 4.3 6
4 5 4.5
3 2.5 4
2 1.5 3
1 2
0 1 n= 134 122
Surgery With No Residual 0
Curative Intent Tumor After No Residual Tumor in Patients
Resection With Liver Metastases
n = 599 / Group n = 599 / Group
Van Cutsem E, et al. ASCO 2007. Abstract 4000
22. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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PRIME: R0 Resection in Pts With WT
KRAS Tumors and Liver-Limited Disease
Final Analysis Pmab + FOLFOX4 FOLFOX4
(n = 325) (n = 331)
Patients with liver-only metastases
61 (19) 57 (17)
at baseline, n (%)
ORR, % 57 48
Patients with complete liver
17 (28%) 10 (18%)
resection, n (%)
Douillard JY, et al, ASCO 2011. Abstract 3510.
23. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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OS After R0 Surgical Resection for Pts
With Liver-Limited Disease and WT KRAS
1.0
0.9
Kaplan-Meier Estimate
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56
Mos
Events, n (%) Median Mos (Range)
Liver complete resection 3/27 (11) Not reached (NA)
No liver complete 54/91 (59) 23.6 (19.4-30.9)
resection
Douillard JY, et al. ASCO 2011. Abstract 3510.
24. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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First BEAT and N016966 BEV Trials:
Patients Undergoing Resections
Study/Patient Surgery With R0 Hepatic Resections R0 Hepatic
Population, % Curative Intent Resections With Curative Intent Resections
First BEAT (BEV + CT)
All evaluable pts
11.8 9.0 7.6 6.0
(n = 1914)
BEV + oxaliplatin
16.1 12.2 10.4 8.0
CT (n = 949)
BEV + irinotecan
9.7 7.4 6.5 5.1
CT (n = 662)
N016966
BEV + CAPOX or
8.4 6.3 N/A N/A
FOLFOX4
CAPOX or
6.1 4.9 N/A N/A
FOLFOX4
Okines A, et al. Br J Cancer. 2009;101:1033-1038.
25. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Clinical Practice*: 2-Yr OS by Hepatic
Metastasectomy and R0 Resection
1.00
89 Hepatic
metastasectomy
86
and R0 resection
0.75 (n = 114)
OS Estimate
Hepatic
0.50 metastasectomy
total (n = 145)
47
No curative hepatic
0.25 metastasectomy
(n = 1769)
0
0 5 10 15 20 25 30
Mos
*BEAT (nonrandomized study): first bevacizumab expanded access trial.
Okines A, et al. Br J Cancer. 2009;101:1033-1038.
26. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Role of Bevacizumab in Conversion
Therapy
Nonrandomized phase II trial: CAPOX + BEV
– 56 patients with potentially resectable liver metastases
Assessment Surgery
B B B B B B B B B B B
CAPOX 5 wks 5 wks
No treatment
B = bevacizumab
– Objective response rate: 73.2%
– pCR: 8.9%
– No long-term follow-up reported
Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
27. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Bevacizumab in Potentially Resectable
mCRC: OS in Resected Patients
1.0 100%
94.4%
0.8
OS Estimate
0.6 63.6%
0.4 Response
CR
PR
0.2 SD
0
0 20 40
Mos
Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
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Bevacizumab in Potentially Resectable
Metastatic CRC: Surgical Complications
Patients, n (%)
Event All Patients Synchronous Patients
(n = 52) (n = 11)
No increased bleeding; only 3 patients
No complications required blood 42 (79)
transfusions (6%) 8 (73)
Complications 11 (21) 3 (27)
Sepsis 3 (6) 1 (9)
Hyperbilirubinemia Postoperative liver function and
2 (4) –
Biliary leak regeneration normal in 98% of patients
1 (2) –
Postoperative bowel(assessed perioperatively and 3 mos
perforation 1 (2) –
after surgery followed (2) chemotherapy) 1 (9)
Anastomotic leakage 1 by
Wound infection 1 (2) 1 (9)
Hematoma 1 (2) –
Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
29. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Postoperative Complications Following
Neoadjuvant Bevacizumab
Retrospective analysis of neoadjuvant BEV to evaluate potential association
with postoperative complications
– Patients with colorectal cancer who underwent hepatic surgery for liver metastases
Findings
– No significant increase in hepatobiliary, wound, or other postoperative
complications with BEV + CT vs CT alone
Day From Last BEV Dose to Surgery
Complication ≤ 60 Days, % (n = 40) > 60 Days, % (n = 35) P Value
Median: 49 days Median: 74 days
Any 55 46 .43
Wound 33 29 .70
Hepatobiliary 8 3 .39
Kesmodel SB, et al. J Clin Oncol. 2008;26:5254-5260.
30. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Treatment-Associated Liver Toxicity
5-FU: steatosis
Irinotecan: steatohepatitis
Oxaliplatin: sinusoidal/vascular injury
Bevacizumab
– Potential wound healing complications
– Need to wait 6-8 wks before surgical resection
Cetuximab: no acute or chronic effects to date
Incidence of postoperative complications increases with
prolonged use
31. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Summary: Take-Home Messages
Conversion chemotherapy appears to enhance long-term
outcomes
Multiagent chemotherapy regimens provide similar clinical
benefit with resection rates in the 30+% range
pCR appears to be 5% with current regimens
Active area of clinical investigation
Multidisciplinary team approach required
32. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Conversion Therapy: Practical Issues
Role of FOLFOX better established than FOLFIRI
– Better toxicity profile, more clinical data
FOLFOXIRI attractive but at expense of increased toxicity
Limit duration of preoperative therapy to 3-4 mos
– Treat to resectability and not to best response
– Minimizes hepatotoxicity
Role of biologics is evolving
– Data with cetuximab appears to be most mature in wild-type
KRAS CRC
– Bevacizumab is an appropriate option in setting of mutant KRAS
– If bevacizumab is used, discontinue 6-8 wks before planned surgery
34. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study
K.L. is a woman aged 65 yrs with a history of:
– 2008: stage III colon cancer, treated with adjuvant
5-FU
– 2009: single left liver metastasis resected, followed by
6 mo of adjuvant FOLFOX
– November 2011: new right hepatic lesion, segment V,
16 × 15 mm
– Biopsy: moderately differentiated adenocarcinoma consistent
with colon cancer
– CEA: 1.3 ng/mL
– ECOG PS: 0
35. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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What would you do next?
A. Consider PET/CT
B. Neoadjuvant chemotherapy
C. Liver resection
D. Radiofrequency ablation of the liver
36. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study
Patient is to go on to surgical resection for the single liver
lesion
Preoperative studies include:
– CEA: rose to 6.5 ng/mL
– CT chest: within normal limits
– CT abdomen/pelvis: 10 new hepatic lesions
(mostly < 1 cm, but bilobar)
Systemic chemotherapy is discussed
Biomarker analysis: KRAS WT, BRAF WT
37. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study: CT Images
11/3/11, CEA: 1.3 ng/mL Preoperative CT
38. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Which of the following regimens would
you choose?
A. FOLFOX/bevacizumab
B. FOLFIRI/bevacizumab
C. 5-FU/bevacizumab
D. FOLFOXIRI
E. FOLFOX/cetuximab or panitumumab
F. FOLFIRI/cetuximab or panitumumab
G. 5-FU/cetuximab or panitumumab
39. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Phase III BICC-C Trial of FOLFIRI +
Bevacizumab in mCRC: Survival
PFS OS
FOLFIRI vs mIFL P = .004
100 1.0
FOLFIRI + bevacizumab
Proportion of Patients
Progression Free (%)
FOLFIRI vs capelri P = .015 mIFL + bevacizumab
0.8
Who Survived
mIFL vs75
capelri P = .46
0.6
50 FOLFIRI
mIFL 0.4
25 Capelri
0.2
P = .037
0 0
10 20 30 0 10 20 30 30
Mos Mos
Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786. Fuchs CS, et al. J Clin Oncol. 2008;26:689-690.
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Phase III CRYSTAL Study of Cetuximab +
FOLFIRI in mCRC: KRAS Update and OS
Median KRAS
KRAS WT P
Survival, Mutant HR
(n = 172) Value
Mos (n = 105)
PFS
Proportion Alive Without Progression
1.0 PFS 9.9 8.4 0.70 .0012
0.9 OS 23.5 20.0 0.80 .0093
0.8
0.7
KRAS WT OS: 20% reduction
0.6
0.5 KRAS mutant in risk of death
0.4 with WT vs mutant
0.3 KRAS
0.2
0.1 HR: 0.63 (P = .007)
0
0 2 4 6 8 10 12 14 16
Mos
Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019.
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Phase III Study of Second-line FOLFIRI ±
Panitumumab in mCRC
Panitumumab 6.0 mg/kg
+ FOLFIRI* q2w
Patients with mCRC (55% (n = 591)
KRAS WT), 1 prior regimen,
ECOG PS ≤ 2
(N = 1186) FOLFIRI* q2w
(n = 595)
Primary endpoints
*180 mg/m2 irinotecan, 400 mg/m2
PFS leucovorin, 500 mg/m2 5-FU
OS Outcome in FOLFIRI + FOLFIRI P Value
KRAS WT Panitumumab (n = 221)
Secondary endpoints Patients (n = 325)
ORR RR, % 35 10 < .001
PFS, mos 5.9 3.9 .004
DOR (HR: 0.73)
Safety OS, mos 14.5 12.5 .12
Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.
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Bevacizumab Associated Toxicity
Adverse Event Incidence With Bev Comments
Across Indications,[1] %
Grade ≥ 3 ATE 2.6 Risk of ATE increased in pts 65 yrs of age or older or
with ATE history
Grade 3/4 HTN 5-18* Patients should receive otherwise standard CV
prophylaxis and have BP monitored and managed
GI perforations 0.3-2.4
Grade ≥ 3 1.2-4.6† Bevacizumab not recommended for pts with serious
hemorrhagic hemorrhage or recent hemoptysis
event Risk of major bleeding does not appear to be
increased in pts receiving full-dose anticoagulation tx
without other risk factors
Wound 15‡ Discontinue 4-8 wks before surgery, resume 6-8 wks
complications postsurgery
*Predominantly grade 3.
†
May apply more to NSCLC.
‡
When surgery conducted during bevacizumab therapy.
Potential for increased VTE risk controversial, increased risk noted in 1 study, but not in others [2,3]
1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA. 2008;300;2277-
2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.
43. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Acneiform Eruption Associated With
EGFR Inhibitors
Preventive measures include the use of antibiotics (monocycline,
doxycycline) and moisturizers/sunscreens
Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.
Segaert S, et al. Ann Oncol. 2005;16:1425-1433.
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Case Study: Status After 8 Cycles
of FOLFIRI/Bevacizumab
Results:
CEA: 1.4 ng/mL
ECOG PS: 0
Despite her response, her
surgeon has deferred any future
resection
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How would you proceed following her
response?
A. FOLFOX/bevacizumab
B. FOLFIRI/bevacizumab
C. 5-FU/bevacizumab
D. FOLFOXIRI
E. FOLFOX/cetuximab or panitumumab
F. FOLFIRI/cetuximab or panitumumab
G. 5-FU/cetuximab or panitumumab
H. Single-agent bevacizumab
I. Radiofrequency ablation
J. Stop all therapy and observe
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Phase III MACRO Trial of Bevacizumab ±
CAPOX as Maintenance in mCRC: PFS
1.00 Median PFS, Mos (95% CI)
CAPOX + bevacizumab: 10.41 (9.36-11.88)
Bevacizumab: 9.66 (8.30-10.58)
HR: 1.098 (P = .381)
0.75
Survival Probability
Censored
CAPOX + bevacizumab (n = 239)
Bevacizumab (n = 241)
0.50
0.25
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Mos
Díaz-Rubio E, et al. Oncologist. 2012;17:15-25.
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Phase III MACRO Trial of Bevacizumab ±
CAPOX as Maintenance in mCRC: OS
1.00 Median OS, Mos (95% CI)
CAPOX + bevacizumab: 23.20 (19.79-26.01)
Bevacizumab : 19.99 (17.08-23.25)
HR: 1.098 (P = .381)
0.75
Survival Probability
Censored
CAPOX + bevacizumab (n = 239)
Bevacizumab (n = 241)
0.50
0.25
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Mos
Díaz-Rubio E, et al. Oncologist. 2012;17:15-25.
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Phase III DREAM Study: First-line Bev +
Chemo ± Erlotinib in Unresectable mCRC
FOLFOX +
Patients with Bev 5-FU/LV or
untreated,
Bev PD
Capecitabine
unresectable + Bev CR
mCRC, CAPOX +
ECOG PS ≤ 2 Bev PR R
(planned N =
640) Bev +
SD PD
FOLFIRI Erlotinib
+ Bev
Primary endpoint: PFS
Secondary endpoints: duration of disease control, OS, ORR, chemotherapy-free interval,
salvage surgery rates, safety, QOL, pharmacogenetics, pharmacoeconomics
Patients stratified by ECOG PS, number of metastatic sites (1 vs >1), age, previous
adjuvant chemotherapy, and baseline alkaline phosphatase
Recruitment
Status: to be presented at ASCO 2012 January 2007 - June 2010
ClinicalTrials.gov. NCT00265824.
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Case Study: Status After 8 Cycles of
Maintenance 5-FU/bevacizumab
Patient K.L. develops PD in the liver
She resumes FOLFIRI/bevacizumab, but after 2 months of
therapy she develops lung metastases
ECOG PS = 0
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Now what would you recommend?
A. FOLFOX/bevacizumab
B. FOLFOX/cetuximab
C. FOLFOX/panitumumab
D. FOLFIRI/cetuximab
E. FOLFIRI/panitumumab
F. Irinotecan
G. Cetuximab
H. Panitumumab
51. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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BRiTE Observational Cohort Registry
Study: Post-PD Therapy Survival Outcomes
All Patients No Post-PD No BBP BBP
(N = 1953) Treatment (n = 531) (n = 642)
(n = 253)
Deaths, n (%) 932 (48) 168 (66) 306 (58) 260 (40)
Median OS, mos 25.1 12.6 19.9 31.8
(95% CI) (23.4-27.5) (10.6-15.7) (18.0-22.0) (27.9-NA)
1-yr survival rate, % 74.7 52.5 77.3 87.7
(95% CI) (72.7-76.7) (46.2-58.8) (73.7-80.9) (85.2-90.3)
Median survival 12.0 3.6 9.5 19.2
beyond first PD, (11.1-13.3) (2.7-4.3) (8.4-11.2) (16.8-20.7)
mos (95% CI)
In a multivariate analysis, BBP was independently associated with increased survival
beyond first progression (P < .001)
Grothey A, et al. J Clin Oncol. 2008;26:5326-5334.
52. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Phase III ML18147 Study: Bevacizumab +
Crossover Fluoropyrimidine Chemo in
mCRC
Bevacizumab* +
Patients with standard second-line chemotherapy†
progressive mCRC (n = 591)
after first-line
bevacizumab/
chemotherapy Standard second-line chemotherapy‡
(planned N = 822) (n = 595)
*5 mg/kg on Days 1, 14 of 4-wk cycle or 7.5 mg/kg on Days 1, 22 of 6-wk cycle.
†
AIO-IRI, FOLFIRI, CAPIRI, or XELIRI.
‡
FUFOX, FOLFOX, or CAPOX.
Primary endpoint: PFS
Secondary endpoints: OS, ORR, safety
Status: completed; to be presented at ASCO 2012
ClinicalTrials.gov. NCT00700102.
53. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Phase III VELOUR Study: FOLFIRI ±
Aflibercept as Second-line Therapy in
mCRC
Stratified by previous bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
Arm A: FOLFIRI + Aflibercept 4 mg/kg q2w
Patients with mCRC (n = 600)
progressing
on first-line
Ox-based
chemotherapy*
Arm B: FOLFIRI + Placebo q2w
(planned N = 1226)
(n = 600)
*30% had prior
bevacizumab.
Primary endpoint: OS
Secondary endpoints: PFS, ORR, safety, immunogenicity
No correlatives
ClinicalTrials.gov. NCT00561470.
54. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Phase III VELOUR Study of FOLFIRI ±
Aflibercept in mCRC: OS
1.0
0.9 Placebo/FOLFIRI Median: 12.06 mos
Proportion of Surviving Patients
0.8 Aflibercept/FOLFIRI Median: 13.50 mos
0.7 Stratified HR: 0.817 (95.34% CI: 0.713-0.937;
Log-rank P = .0032)
0.6
0.5
0.4
0.3
0.2
0.1
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Mos
Tabernero J, et al. ECCO-ESMO 2011. Abstract LBA6. Courtesy of Van Cutsem E.
55. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Conclusions
Treatment for all patients with mCRC should be individualized
– Multidisciplinary management must occur early
Anti-VEGF and anti-EGFR therapy options for a patient with KRAS
WT may vary
– First line
– Second line
– Third line
ASCO 2012 will highlight the TML and DREAM trials, which may
change second line and maintenance therapies as well as the role of
EGFR tyrosine kinase inhibitors
If approved by the FDA, aflibercept will be another option
56. Impact of KRAS and BRAF Mutations on
Treatment Decisions in Patients With
Metastatic Colorectal Cancer
57. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
clinicaloptions.com/oncology
Case Study
A.S. is an artist aged 56 yrs and a mother of 2 who recently developed fatigue, weight
loss, and abdominal discomfort
Her history is remarkable for
– Hypertension
– CCY
– Type 2 diabetes
– Remote smoking history: 22 pack-yrs
– Paternal uncle with CRC at age 76
Workup reveals
– Transverse colon cancer
– Diffuse liver metastases
– Lung nodules
Examination is notable for an enlarged, moderately tender liver
CEA: 243 ng/mL
ECOG PS: 1
58. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study: First-line Treatment
Treatment with first-line FOLFOX + bevacizumab
produces an initial partial response
She then develops severe peripheral neuropathy and is
switched to 5-FU/LV + bevacizumab
59. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study
She eventually has POD in
lungs & liver, still has
severe neuropathy with an
ECOG PS of 1
She is switched to FOLFIRI
+ bevacizumab, but quickly
develops POD
CEA is now 473 ng/mL
60. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study: KRAS Testing
Specimen type: Unstained colon biopsy
Test information
– Genomic DNA was extracted from paraffin-embedded tumor tissue and
KRAS sequence analysis was performed on a PCR product using primers
spanning exon 2. Sequence was analyzed by pyrosequencing using a
Biotage Pyromark MD instrument
Result
– Amino acid substitution at position 13 in KRAS, from a glycine (G) to an
aspartic acid (D)
Interpretation
– Mutation of codon 13: KRAS c.38G > A (G13D)
61. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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What therapy would you recommend
for this patient?
A. FOLFOX + bevacizumab
B. Cetuximab ± irinotecan-based therapy
C. Panitumumab
D. BSC and wait for regorafinib approval
E. BSC and wait for FOLFIRI + aflibercept approval
F. Consider hospice
G. Consider clinical trial
62. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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KRAS p.G13D Mutation and Response to
Cetuximab in Refractory mCRC
KRAS Mutation
Objective Response KRAS p.G13D Other KRAS Mutation KRAS WT
Mutation (n = 45) (n = 265) (n = 464)
Any cetuximab-based treatment, n 32 188 345
Response rate, % (95% CI) 6.3 (0-14.6) 1.6 (0-3.3) 26.4 (21.7-31.0)
Univariate OR (95% CI)* 1 [Reference] 4.28 (0.69-26.70) 0.19 (0.05-0.82)
Fisher exact test P value .15 .02
Multivariate OR (95% CI)* 1 [Reference] 3.64 (0.53-25.13) 0.16 (0.04-0.72)
Logistic regression P value .19 .02
Cetuximab monotherapy, n 10 89 146
Response rate, % (95% CI) 0 2.3 (0-5.3) 15.8 (9.8-21.7)
Univariate OR (95% CI)* 1 [Reference] NC NC
Fisher exact test P value .94 .36
Multivariate OR (95% CI)* 1 [Reference] NC NC
Logistic regression P value .97 .97
Cetuximab + chemotherapy, n 22 99 199
Response rate, % (95% CI) 9.1 (0-21.1) 1.0 (0-3.0) 34.2 (27.6-40.80)
Univariate OR (95% CI)* 1 [Reference] 10.42 (0.90-120.8) 0.20 (0.05-0.90)
Fisher exact test P value .08 .03
Multivariate OR (95% CI)* 1 [Reference] 8.63 (0.71-105.6) 0.22 (0.05-0.97)
Logistic regression P value .09 .046
*ORs are expressed for comparison of KRAS p.G13D mutation vs other status.
De Roock W, et al. JAMA. 2010;304:1812-1820.
63. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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KRAS p.G13D Mutation and OS
With Cetuximab in mCRC
p.G13D Mutation Other KRAS Mutation KRAS WT
100 Any cetuximab therapy
Percentage Alive
No cetuximab therapy* Log-rank P = .49 Log-rank P < .001
80 Log-rank P < .001
60
40
20
0
0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20 25
Months Since Randomization Months Since Randomization Months Since Randomization
or Start of Cetuximab or Start of Cetuximab or Start of Cetuximab
100
Percentage Alive
80 Log-rank P < .001
60 Log-rank P > .99
40 Log-rank P = .02
20 Cetuximab monotherapy
No cetuximab therapy
0
0 2 4 6 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Months Since Randomization Months Since Randomization Months Since Randomization
or Start of Cetuximab or Start of Cetuximab or Start of Cetuximab
*The no-cetuximab group for all patients from the pooled data set is the best supportive care group from the CO.17 trial.
Horizontal axis in blue indicates range of time since randomization from 0 though 6 mos.
De Roock W, et al. JAMA. 2010;304:1812-1820.
64. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Pooled Data From CRYSTAL and OPUS:
KRAS p.G13D Mutations
Response, % PFS, mo OS, mo
N CT CT + cet CT CT + cet CT CT + cet
KRAS wt 845 38.5 57.3 7.6 9.6 19.5 23.5
OR/HR [95%, CI] 2.17 [1.64-2.86] 0.66 [0.55-0.80] 0.81 [0.69-0.94]
P < .0001 P < .0001 P = .0063
KRAS G13D 83 22.0 40.5 6.0 7.4 14.7 15.4
OR/HR [95%, CI] 2.41 [0.90-6.45] 0.60 [0.32-1.12] 0.80 [0.49-1.3]
P = .0748 P = .1037 P = .37
Other KRAS mt 450 43.8 30.5 8.5 6.4 17.7 15.5
OR/HR [95%, CI] 0.56 [0.38-0.83] 1.42 [1.10-1.83] 1.14 [0.93-1.40]
P = .0037 P = .0069 P = .1964
Tejpar S, et al. ASCO 2011. Abstract 3511.
65. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Mutant KRAS Codon 12 and 13 alleles in
mCRC: Response to Panitumumab
The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S,
G12V, G13D) were detected in tumor biopsies from pts enrolled in 3 phase III
clinical trials (combined N = 2606) investigating panitumumab
– Phase III studies (20050203, 20050181, and 20020408): Pts randomized to receive
FOLFOX4, FOLFIRI, or BSC +/- panitumumab 6.0 mg/kg Q2W
MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096, study
20050203), 45% (486/1083, study 20050181), and 43% (184/427, study
20050181)
No MT KRAS allele consistently prognostic for PFS or OS in the control or
panitumumab arms
Investigator conclusion: “The lack of consistent results across three lines of
therapy indicates pts with MT KRAS codon 12 or 13 alleles are unlikely to
respond to panitumumab therapy”
Peeters M, et al. ASCO 2012. Abstract 383.
66. Please now assume the patient in
the case study has the following
KRAS and BRAF pattern
67. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study, Part B: KRAS Testing
Specimen type: unstained colon biopsy
Test information
– Genomic DNA was extracted from paraffin-embedded tumor tissue and
KRAS sequence analysis was performed on a PCR product using primers
spanning exon 2. Sequence was analyzed by pyrosequencing using a
Biotage Pyromark MD instrument
Result
– Only WT sequences were detected
Interpretation
– No mutation was detected at codons 12 and 13 of KRAS
68. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Case Study, Part B: BRAF Testing
Specimen type: unstained colon biopsy
Test information
– Genomic DNA was extracted from formalin-fixed, paraffin-embedded colon
tissue (60% tumor)
BRAF mutational status was assessed by PCR-based amplification of
exon 15, followed by pyrosequencing of PCR products using a
commercial assay (Qiagen)
Result
– BRAF V600E
Interpretation
– BRAF V600E mutation is detected
69. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Now what therapy would you
recommend?
A. FOLFOX + bevacizumab
B. Cetuximab ± irinotecan-based therapy
C. Panitumumab
D. BSC and wait for regorafinib approval
E. BSC and wait for FOLFIRI + aflibercept approval
F. Consider hospice
G. Consider clinical trial
70. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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KRAS and BRAF Mutations and Response
to Anti-EGFR MoAbs
mCRC patients treated with KRAS and BRAF mutations correlate
panitumumab or cetuximab (N = 113) with lack of response to treatment
with monoclonal antibodies targeting
KRAS mutational status epidermal growth factor receptor
WT KRAS Mutant KRAS
Mutant KRAS Wild-Type KRAS
34/113 (30%) 79/113 (70%) 6%
28%
Responders 2/34 (6%)* 22/79 (28%)†
45% 32%
Nonresponders 32/24 (94%) †
57/79 (72%)† 62%
27%
*P < .05 (P = .029). BRAF mutational status WT BRAF Mutant BRAF
†
P < .05 (P = .011).
on WT KRAS tumors 0%
Mutant BRAF WT BRAF 68/79 32% 27%
11/79 (14%) (86%) 41%
Responders 0/11 (0%)* 22/68 (32%)* 27% 73%
Nonresponders 11/11 (100%)* 46/68 (68%)*
Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712. PR SD PD
71. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Patients With WT KRAS and Mut BRAF Fare
Worse With Anti-EGFR MoAbs vs WT BRAF
PFS OS
100 100
Alive Without Progression (%)
WT BRAF WT BRAF
90 90
Mutant BRAF Mutant BRAF
80 80
P = .0010 P < .0001
70 70
Alive (%)
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 100 200 300 400 500 600 700 800 900 0 200 400 600 800 1,0001,2001,400
Days Since Start of Treatment Days Since Start of Treatment
Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712.
72. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Anti-EGFR MoAbs in mCRC With WT
KRAS ± BRAF V600E Mutation: Survival
In patients with KRAS WT tumors (n = 116), BRAF mutations (n = 5) were
weakly associated with lack of response (P = .063) but strongly associated
with shorter PFS (P < .001) and shorter OS (P < .001).
1.00 1.00
Probability of PFS
Probability of OS
0.75 V600E mutation 0.75 V600E mutation
Non-mutated Non-mutated
0.50 0.50
0.25 0.25
0 0
0 8 16 24 32 40 48 56 64 72 80 88 96 0 6 12 18 24 30 36 42 48
Wks Since Treatment Wks Since Treatment
Pts at Risk, n Pts at Risk, n
M 5 4 1 0 0 0 0 0 0 0 0 0 0 M 5 3 0 0 0 0 0 0 0
NM 109 104 80 66 44 26 17 9 6 3 3 2 1 NM 110 99 68 45 27 14 6 3 1
Laurent-Puig P, et al. J Clin Oncol. 2009;27:5924-5930.
73. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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CRYSTAL: OS by BRAF Mutation Status
1.0 Median
Overall Survival (proportion)
Events (months) 95% CI
FOLFIRI BRAF MT (n = 33) 33 10.3 8.4 to 14.9
0.8 Cetuximab + FOLFIRI
BRAF MT (n = 26) 22 14.1 8.5 to 18.5
0.6 FOLFIRI BRAF WT (n = 289) 229 21.6 20.0 to 24.9
Cetuximab + FOLFIRI
BRAF WT (n = 277) 207 25.1 22.5 to 28.7
0.4
0.2
0
0 6 12 18 24 30 36 42 48 54 60
Time (months)
“There was no evidence of an independent treatment by tumor BRAF mutation status
interaction. Thus, with the current data set, BRAF mutation status cannot be shown to
be predictive of treatment effects of cetuximab plus FOLFIRI.”
Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019.
74. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Current “Cutting Edge”
Dana-Farber Cancer Center OncoMap
75. Cost (Dollars)
10,000
1000
100,000
10,000,000
100,000,000
1,000,000
Jul 01
Oct 01
Jan 02
Apr 02
clinicaloptions.com/oncology
Jul 02
Oct 02
Jan 03
Apr 03
Jul 03
Oct 03
Jan 04
Apr 04
Jul 04
Oct 04
Jan 05
Apr 05
Jul 05
Oct 05
Jan 06
Apr 06
Jul 06
Date
Oct 06
Jan 07
Study of the CRC Genome
Cost per Genome
Apr 07
Jul 07
Oct 07
Jan 08
Apr 08
Jul 08
Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
Oct 08
Jan 09
Apr 09
Jul 09
Oct 09
Jan 10
Apr 10
Jul 10
Oct 10
Jan 11
Moore’s Law
Rapid Technology Improvement Enables
Apr 11
Jul 11
Oct 11
76. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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The “Cutting Edge” in the Near Future
Double-stranded DNA
Exome Sequencing
Fragmentation Exon
of Genomic DNA
Intron P
P
Linker Hybridization on P
capture array for
Ligation of target enrichment
Linker Target-enrichment
and amplification
Sequence
DNA
AcGTCTA
AcGTCTA
Timmerman B, et al. PLoS One. 2010;5:e15681.
77. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
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Conclusions
The understanding of the implications of KRAS and BRAF
mutations in CRC is evolving and currently uncertain
The preponderance of data at the current time suggests
that patients with KRAS G13D–mutated tumors may
respond to EGFR antibodies
– Although not all studies support this conclusion
Patients with BRAF V600E–mutated tumors have a worse
prognosis than patients with BRAF WT tumors
– This effect is probably independent of response to EGFR
antibody therapy
78. Go Online for More Education on
Metastatic Colorectal Cancer
Interactive Decision Support Tool: 5 experts make treatment
recommendations for newly diagnosed mCRC based on specific
patient and disease characteristics
CCO inPractice™ Chapter, “Colorectal
Cancer: Medical Management”
Comprehensive point-of-care reference
authored by John L. Marshall, MD
clinicaloptions.com/oncology
Notas do Editor
This slide lists the faculty who were involved in the production of these slides.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.
Adam et al. Proc Am Soc Clin Oncol . 2003;23:296. Abstract 1188.
ASCO, American Society of Clinical Oncology; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; mCRC, metastatic colorectal cancer; VEGF, vascular endothelial growth factor; WT, wild-type.