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

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

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Faculty

Edward Chu, MDChief Division of Hematology/OncologyUniversity of Pittsburgh School of MedicineDeputy DirectorUniversity of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania

Cathy Eng, MDAssociate Professor Department of Gastrointestinal Medical OncologyThe University of Texas M. D. Anderson Cancer CenterHouston, Texas

Peter C. Enzinger, MDClinical Director, Gastrointestinal Cancer CenterDana-Farber Cancer InstituteAssistant Professor of MedicineHarvard Medical SchoolBoston, Massachusetts

John L. Marshall, MDChief, Division of Hematology/OncologyDepartment of MedicineGeorgetown University HospitalWashington, DC


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

30% synchronous metastasesAdditional ~ 50% will develop metastases

30% to 35% “liver only” metastases

75% to 90%not candidates for surgeryPALLIATIVE THERAPY

R0 resection not possible

10% to 25%candidates for

SURGERYAim: R0 resection

Cure rate: 20% to 30%5-yr survival: 40% to 60%

70% to 80% relapsewithin 2 yrs

400,000 CRC cases/yr (US/Europe)


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

0 41 2 3 5

Pat

ien

ts (

%)

Yrs

Progression (n = 58)Stabilization (n = 39)PR (n = 34)95

55

37

30

8

44

92

63

12

0

20

40

60

80

100

Adam R, et al. Ann Surg. 2004;240:1052-1061.


Adam R. Ann Oncol. 2003;14(suppl 2):ii13-ii16.

Survival After Primary or Secondary Resection of Liver Metastases

Initially nonresectable (n = 95)Resectable (n = 425)

Survival Time (Yrs)

100

80

60

40

20

0

Pat

ien

ts S

urv

ivin

g (

%)

0 1 2 3 4 5 6 7 8 9 10

54

3427

192934

50


Response Correlates With Resectionin Initially Unresectable mCRC

Studies including all patients (solid line) r = 0.74; P = .001

Studies including selected patients(liver metastases only, no extrahepatic disease)r = 0.96; P = .002

Phase III studies(dashed line)r = 0.67; P = .024

Folprecht G, et al. Ann Oncol. 2005;16:1311-1319.

Response Rate

Res

ecti

on

Rat

e

0.6

0.3

0.5

0.4

0.3

0.2

0.1

00.4 0.5 0.6 0.7 0.8 0.9


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(n = 122)

FOLFOXIRI(n = 122)

P Value

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

Van Cutsem E, et al. ASCO 2007. Abstract 4000

No Residual Tumor in PatientsWith Liver Metastases

ITT Population Liver Metastases Only Population

FOLFIRI alone Cetuximab + FOLFIRI

OR: 3.0 (95% CI: 1.4-6.5; P = .0034)

Pat

ien

ts (

%)

109876543210

Pat

ien

ts (

%)

109876543210

2.5

6.0

1.5

4.3

Surgery WithCurative Intent

No ResidualTumor AfterResection

n = 599 / Group n = 599 / Group

122134n =

4.5

9.8


Final Analysis Pmab + FOLFOX4(n = 325)

FOLFOX4(n = 331)

Patients with liver-only metastases at baseline, n (%)

61 (19) 57 (17)

ORR, % 57 48

Patients with complete liver resection, n (%)

17 (28%) 10 (18%)

PRIME: R0 Resection in Pts With WT KRAS Tumors and Liver-Limited Disease

Douillard JY, et al, ASCO 2011. Abstract 3510.


Events, n (%) Median Mos (Range)

Liver complete resection 3/27 (11) Not reached (NA)

No liver complete resection

54/91 (59) 23.6 (19.4-30.9)

Douillard JY, et al. ASCO 2011. Abstract 3510.

OS After R0 Surgical Resection for Pts With Liver-Limited Disease and WT KRAS

Kap

lan

-Mei

er

Est

ima

te

Mos

1.00.90.80.70.60.50.40.30.20.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 303234 36 38 40 42 44 4648 50 52 5456


First BEAT and N016966 BEV Trials: Patients Undergoing ResectionsStudy/Patient Population, %

Surgery With Curative Intent

R0 Resections

Hepatic Resections With Curative Intent

R0 Hepatic Resections

First BEAT (BEV + CT)

All evaluable pts(n = 1914)

11.8 9.0 7.6 6.0

BEV + oxaliplatin CT (n = 949)

16.1 12.2 10.4 8.0

BEV + irinotecan CT (n = 662)

9.7 7.4 6.5 5.1

N016966

BEV + CAPOX or FOLFOX4

8.4 6.3 N/A N/A

CAPOX or FOLFOX4

6.1 4.9 N/A N/A

Okines A, et al. Br J Cancer. 2009;101:1033-1038.


Clinical Practice*: 2-Yr OS by Hepatic Metastasectomy and R0 Resection

*BEAT (nonrandomized study): first bevacizumab expanded access trial.

OS

Est

imat

e

Mos

Hepatic metastasectomy and R0 resection (n = 114)

Hepatic metastasectomy total (n = 145)

No curative hepatic metastasectomy (n = 1769)

47

89

86

Okines A, et al. Br J Cancer. 2009;101:1033-1038.

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30


Role of Bevacizumab in Conversion Therapy Nonrandomized phase II trial: CAPOX + BEV

– 56 patients with potentially resectable liver metastases

– Objective response rate: 73.2%

– pCR: 8.9%

– No long-term follow-up reportedGruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.

B B B B B B B B B B B

B = bevacizumab

Assessment Surgery

5 wks 5 wksCAPOXNo treatment


Bevacizumab in Potentially Resectable mCRC: OS in Resected Patients

ResponseCRPRSD

100%94.4%

63.6%

OS

Est

imat

e

Mos

1.0

0.8

0.6

0.4

00 20 40

0.2

Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.


Event

Patients, n (%)

All Patients (n = 52)

Synchronous Patients (n = 11)

No complications 42 (79) 8 (73)

Complications Sepsis Hyperbilirubinemia Biliary leak Postoperative bowel perforation Anastomotic leakage Wound infection Hematoma

11 (21) 3 (6)2 (4)1 (2)1 (2)1 (2)1 (2)1 (2)

3 (27)1 (9)

–––

1 (9)1 (9)

–

Bevacizumab in Potentially Resectable Metastatic CRC: Surgical Complications

No increased bleeding; only 3 patientsrequired blood transfusions (6%)

Postoperative liver function andregeneration normal in 98% of patients(assessed perioperatively and 3 mos

after surgery followed by chemotherapy)

Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.


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

Kesmodel SB, et al. J Clin Oncol. 2008;26:5254-5260.

Complication

Day From Last BEV Dose to Surgery

≤ 60 Days, % (n = 40)Median: 49 days

> 60 Days, % (n = 35)Median: 74 days

P Value

Any 55 46 .43

Wound 33 29 .70

Hepatobiliary 8 3 .39


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-typeKRAS 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


Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786. Fuchs CS, et al. J Clin Oncol. 2008;26:689-690.

Mos Mos

PFS OS

Phase III BICC-C Trial of FOLFIRI + Bevacizumab in mCRC: Survival

10 20 300

25

50

75

100

Pro

gre

ssio

n F

ree

(%)

FOLFIRImIFLCapelri

FOLFIRI vs mIFL P = .004FOLFIRI vs capelri P = .015mIFL vs capelri P = .46

10 20 300

0.4

0.6

0.8

1.0

Pro

po

rtio

n o

f P

atie

nts

W

ho

Su

rviv

ed

P = .037

FOLFIRI + bevacizumabmIFL + bevacizumab

0.2

300


0.5

1.0

0.4

0.3

0.2

0.1

0

0.6

0.7

0.8

0.9

80 2 4 6 10 16

Pro

po

rtio

n A

live

Wit

ho

ut

Pro

gre

ssio

n

Mos

KRAS WT

KRAS mutant

12 14

OS: 20% reduction in risk of death

with WT vs mutant KRAS

Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019.

HR: 0.63 (P = .007)

Median Survival, Mos

KRAS WT(n = 172)

KRAS Mutant

(n = 105)HR

P Value

PFS 9.9 8.4 0.70 .0012

OS 23.5 20.0 0.80 .0093

PFS

Phase III CRYSTAL Study of Cetuximab +FOLFIRI in mCRC: KRAS Update and OS


Primary endpoints

PFS

OS

Secondary endpoints

ORR

DOR

Safety

Outcome in KRAS WT Patients

FOLFIRI + Panitumumab

(n = 325)

FOLFIRI (n = 221)

P Value

RR, % 35 10 < .001

PFS, mos 5.9 3.9 .004(HR: 0.73)

OS, mos 14.5 12.5 .12

Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.

Patients with mCRC (55% KRAS WT), 1 prior regimen,

ECOG PS ≤ 2(N = 1186)

Panitumumab 6.0 mg/kg+ FOLFIRI* q2w

(n = 591)

FOLFIRI* q2w (n = 595)

*180 mg/m2 irinotecan, 400 mg/m2 leucovorin, 500 mg/m2 5-FU

Phase III Study of Second-line FOLFIRI ± Panitumumab in mCRC


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.

Adverse Event Incidence With Bev Across Indications,[1] %

Comments

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 hemorrhagic event

1.2-4.6† Bevacizumab not recommended for pts with serious hemorrhage or recent hemoptysis

Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors

Wound complications

15‡ Discontinue 4-8 wks before surgery, resume 6-8 wks postsurgery

Potential for increased VTE risk controversial, increased risk noted in 1 study, but not in others [2,3]

*Predominantly grade 3.†May apply more to NSCLC.‡When surgery conducted during bevacizumab therapy.

Bevacizumab Associated Toxicity


Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095. Segaert S, et al. Ann Oncol. 2005;16:1425-1433.

Acneiform Eruption Associated With EGFR Inhibitors Preventive measures include the use of antibiotics (monocycline,

doxycycline) and moisturizers/sunscreens


Case Study: Status After 8 Cyclesof 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? 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


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)

Díaz-Rubio E, et al. Oncologist. 2012;17:15-25.

Phase III MACRO Trial of Bevacizumab ± CAPOX as Maintenance in mCRC: PFS

1.00

0.25

0

0.50

0.75

120 3 6 9 15 48

Su

rviv

al P

rob

abil

ity

42 453936333027242118

CensoredCAPOX + bevacizumab (n = 239)Bevacizumab (n = 241)

Mos


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)

Phase III MACRO Trial of Bevacizumab ± CAPOX as Maintenance in mCRC: OS

Díaz-Rubio E, et al. Oncologist. 2012;17:15-25.

1.00

0.25

0

0.50

0.75

120 3 6 9 15 54

Su

rviv

al P

rob

abil

ity

42 453936333027242118

Censored

Mos48 51

CAPOX + bevacizumab (n = 239)Bevacizumab (n = 241)


PD

PD

CR

PR

SD

Patients with untreated,

unresectable mCRC,

ECOG PS ≤ 2 (planned N =

640)

FOLFOX + Bev

FOLFIRI + Bev

CAPOX + Bev R

5-FU/LV orCapecitabine

+ Bev

Bev

Bev + Erlotinib

RecruitmentJanuary 2007 - June 2010

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

Status: to be presented at ASCO 2012

Phase III DREAM Study: First-line Bev + Chemo ± Erlotinib in Unresectable mCRC

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?

A. FOLFOX/bevacizumab

B. FOLFOX/cetuximab

C. FOLFOX/panitumumab

D. FOLFIRI/cetuximab

E. FOLFIRI/panitumumab

F. Irinotecan

G. Cetuximab

H. Panitumumab


In a multivariate analysis, BBP was independently associated with increased survival beyond first progression (P < .001)

All Patients(N = 1953)

No Post-PDTreatment (n = 253)

No BBP(n = 531)

BBP(n = 642)

Deaths, n (%) 932 (48) 168 (66) 306 (58) 260 (40)

Median OS, mos (95% CI)

25.1 (23.4-27.5)

12.6 (10.6-15.7)

19.9 (18.0-22.0)

31.8 (27.9-NA)

1-yr survival rate, % (95% CI)

74.7 (72.7-76.7)

52.5 (46.2-58.8)

77.3 (73.7-80.9)

87.7 (85.2-90.3)

Median survival beyond first PD, mos (95% CI)

12.0(11.1-13.3)

3.6(2.7-4.3)

9.5(8.4-11.2)

19.2(16.8-20.7)

Grothey A, et al. J Clin Oncol. 2008;26:5326-5334.

BRiTE Observational Cohort Registry Study: Post-PD Therapy Survival Outcomes


Primary endpoint: PFS

Secondary endpoints: OS, ORR, safety

Status: completed; to be presented at ASCO 2012

Patients with progressive mCRC

after first-line bevacizumab/chemotherapy

(planned N = 822)

Bevacizumab* +standard second-line chemotherapy†

(n = 591)

Standard second-line chemotherapy‡

(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.

Phase III ML18147 Study: Bevacizumab + Crossover Fluoropyrimidine Chemo in mCRC



Phase III VELOUR Study: FOLFIRI ± Aflibercept as Second-line Therapy in mCRC

Primary endpoint: OS

Secondary endpoints: PFS, ORR, safety, immunogenicity

No correlatives

Patients with mCRC progressing on first-line Ox-based

chemotherapy*(planned N = 1226)

Arm A: FOLFIRI + Aflibercept 4 mg/kg q2w(n = 600)

Arm B: FOLFIRI + Placebo q2w(n = 600)

*30% had prior bevacizumab.

Stratified by previous bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)



Phase III VELOUR Study of FOLFIRI ± Aflibercept in mCRC: OS

Tabernero J, et al. ECCO-ESMO 2011. Abstract LBA6. Courtesy of Van Cutsem E.

0.1

0

0.2

0.8

120 3 6 9 15

Pro

po

rtio

n o

f S

urv

ivin

g P

atie

nts

33 363027242118

Median: 12.06 mosMedian: 13.50 mos

Mos39

0.3

0.4

0.5

0.6

0.7

0.9

1.0

Placebo/FOLFIRIAflibercept/FOLFIRI

Stratified HR: 0.817 (95.34% CI: 0.713-0.937;Log-rank P = .0032)


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

De Roock W, et al. JAMA. 2010;304:1812-1820.

Objective Response KRAS p.G13DMutation (n = 45)

Other KRAS Mutation (n = 265)

KRAS WT(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.

KRAS Mutation


KRAS p.G13D Mutation and OS With Cetuximab in mCRC

De Roock W, et al. JAMA. 2010;304:1812-1820.

Pe

rce

nta

ge

Ali

ve 100

80

60

40

20

0

Months Since Randomizationor Start of Cetuximab

0 5 10 15 20 25

p.G13D Mutation

Any cetuximab therapyNo cetuximab therapy*Log-rank P < .001


Other KRAS Mutation

Log-rank P = .49

0 5 10 15 20 25Months Since Randomization

or Start of Cetuximab

KRAS WT

Log-rank P < .001

0 5 10 15 20 25

Pe

rce

nta

ge

Ali

ve 100

80

60

40

20

0


0 2 4 6

Cetuximab monotherapyNo cetuximab therapy

Log-rank P = .02


0 2 4 10 12 14

Log-rank P > .99


0

Log-rank P < .001

6 8 2 4 10 12 146 8

*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.


Pooled Data From CRYSTAL and OPUS: KRAS p.G13D Mutations

Tejpar S, et al. ASCO 2011. Abstract 3511.

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]P < .0001

0.66 [0.55-0.80]P < .0001

0.81 [0.69-0.94]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]P = .0748

0.60 [0.32-1.12]P = .1037

0.80 [0.49-1.3]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]P = .0037

1.42 [1.10-1.83]P = .0069

1.14 [0.93-1.40]P = .1964


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

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


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


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

Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712.

WT KRAS Mutant KRAS

WT BRAF Mutant BRAF

62%

6%

32%

41%32%

27%

45%

28%

27%

73%

0%

27%

PR

mCRC patients treated with panitumumab or cetuximab (N = 113)

KRAS mutational status

BRAF mutational statuson WT KRAS tumors

Mutant KRAS34/113 (30%)

Wild-Type KRAS 79/113 (70%)

Responders 2/34 (6%)* 22/79 (28%)†

Nonresponders 32/24 (94%)† 57/79 (72%)†

Mutant BRAF11/79 (14%)

WT BRAF 68/79 (86%)

Responders 0/11 (0%)* 22/68 (32%)*

Nonresponders 11/11 (100%)* 46/68 (68%)*

*P < .05 (P = .029).†P < .05 (P = .011).

SD PD

KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting epidermal growth factor receptor


PFS OS

Aliv

e W

ith

ou

t P

rog

ress

ion

(%

)

Aliv

e (%

)

Patients With WT KRAS and Mut BRAF Fare Worse With Anti-EGFR MoAbs vs WT BRAF

Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712.

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300400 500 600 700 800 900

Days Since Start of Treatment

WT BRAFMutant BRAF

P = .0010

0

10

20

30

40

50

60

70

80

90

100

0 200 400 600 800 1,0001,2001,400

Days Since Start of Treatment

WT BRAFMutant BRAF

P < .0001


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).

Laurent-Puig P, et al. J Clin Oncol. 2009;27:5924-5930.

Pro

bab

ilit

y o

f P

FS

0

0.25

0.50

0.75

1.00

0 8 16 24 32 40 48 56 64 96Wks Since Treatment

V600E mutationNon-mutated

72 80 88

Pts at Risk, nMNM

5109

4104

180

066

044

026

017

09

06

03

03

02

01

Pro

bab

ilit

y o

f O

S0

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 48

V600E mutationNon-mutated

42

Pts at Risk, n MNM

5110

399

068

045

027

014

06

03

01

Wks Since Treatment


CRYSTAL: OS by BRAF Mutation Status

“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.

Ove

rall

Su

rviv

al (

pro

po

rtio

n) 1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48 54 60

Time (months)

FOLFIRI BRAF MT (n = 33)Cetuximab + FOLFIRIBRAF MT (n = 26)FOLFIRI BRAF WT (n = 289)Cetuximab + FOLFIRIBRAF WT (n = 277)

Events33

22229

207

Median(months)

10.3

14.121.6

25.1

95% CI8.4 to 14.9

8.5 to 18.520.0 to 24.9

22.5 to 28.7


Current “Cutting Edge” Dana-Farber Cancer Center OncoMap


Rapid Technology Improvement Enables Study of the CRC Genome

Cost per Genome

100,000,000

10,000,000

1,000,000

100,000

10,000

1000

Jul 0

1O

ct 0

1Ja

n 02

Apr

02

Jul 0

2O

ct 0

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n 03

Apr

03

Jul 0

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n 04

Apr

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Jul 0

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ct 0

4Ja

n 05

Apr

05

Jul 0

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ct 0

5Ja

n 06

Apr

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Jul 0

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ct 0

6Ja

n 07

Apr

07

Jul 0

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ct 0

7Ja

n 08

Apr

08

Jul 0

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ct 0

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Apr

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ct 0

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n 10

Apr

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ct 1

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Apr

11

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ct 1

1

Moore’s Law

Co

st (

Do

llar

s)

Date


Exome Sequencing

Timmerman B, et al. PLoS One. 2010;5:e15681.

The “Cutting Edge” in the Near Future

Double-stranded DNA

Fragmentationof Genomic DNA

Ligation of Linker

Exon

Intron

Linker Hybridization on capture array for target enrichment Target-enrichment

and amplification

SequenceDNA

P

P

P

AcGTCTAAcGTCTA


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 referenceauthored by John L. Marshall, MD

clinicaloptions.com/oncology

http://www.clinicaloptions.com/oncology

cco metastatic colorectal_cancer_cases_slides

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