Cco metastatic colorectal_cancer_cases_slides

Treating the Patient With Newly
Diagnosed, Metastatic Colorectal Cancer:
Case Presentations

This program is supported by an educational grant from

Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer
clinicaloptions.com/oncology

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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


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.


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

Clinical Management of a Patient Newly
Diagnosed With Liver-Limited Metastatic
Colorectal Cancer


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


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


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


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


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.


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.


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.


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.


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

Is There an “Optimal”
Cytotoxic Regimen?


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.


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.


Which biologic agent would you
recommend?
A. Bevacizumab
B. Cetuximab
C. Panitumumab
D. None


Which biologic agent would you
recommend if a KRAS mutation were
detected?
A. Bevacizumab
B. Cetuximab
C. Panitumumab
D. None


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


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.


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.


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.


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.


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.


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



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) –



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.


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


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


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

Treatment Conundrums for a
KRAS-WT Metastatic Colorectal
Carcinoma Patient


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


What would you do next?
A. Consider PET/CT
B. Neoadjuvant chemotherapy
C. Liver resection
D. Radiofrequency ablation of the liver


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


Case Study: CT Images
11/3/11, CEA: 1.3 ng/mL Preoperative CT


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


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.


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.


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.


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.


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.


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


How would you proceed following her
response?
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


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.


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.


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.


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


Now what would you recommend?
B. FOLFOX/cetuximab
C. FOLFOX/panitumumab
D. FOLFIRI/cetuximab
E. FOLFIRI/panitumumab
F. Irinotecan
G. Cetuximab
H. Panitumumab


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.


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



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


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.


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

Impact of KRAS and BRAF Mutations on
Treatment Decisions in Patients With
Metastatic Colorectal Cancer


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


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


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


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)


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


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
 Multivariate OR (95% CI)* 1 [Reference] NC NC
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)
 Multivariate OR (95% CI)* 1 [Reference] 8.63 (0.71-105.6) 0.22 (0.05-0.97)
*ORs are expressed for comparison of KRAS p.G13D mutation vs other status.
De Roock W, et al. JAMA. 2010;304:1812-1820.


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.


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.


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.

Please now assume the patient in
the case study has the following
KRAS and BRAF pattern


Case Study, Part B: KRAS Testing
 Specimen type: unstained colon biopsy
– 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


Case Study, Part B: BRAF Testing
 Specimen type: unstained colon biopsy
– 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


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


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


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.


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.


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.


Current “Cutting Edge”
Dana-Farber Cancer Center OncoMap

Cost (Dollars)

10,000

1000
100,000
10,000,000
100,000,000

1,000,000
Jul 01
Oct 01
Jan 02
Apr 02

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

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


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.


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

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


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