management of metastatic colorectal cancer: focus on targeted therapy

Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy


Jimmy Hwang, MDAssociate Professor, Hematology/Oncology

John L. Marshall, MDAssociate Professor, Hematology/Oncology

Department of MedicineLombardi Cancer CenterGeorgetown University HospitalWashington, DC

clinicaloptions.com/oncology


Colorectal Cancer: Epidemiology

Data from the United States (2006)[1]

– 148,610 new cases: third highest cancer incidence

– 55,170 deaths: second leading cause of cancer-related death in men, third leading cause in women

Worldwide (2002)[2]

– 1,023,256 new cases: third highest incidence after lung, breast cancer

– 529,020 deaths: fourth overall cause of cancer-related death after lung, gastric, liver cancer

1. Jemal A, et al. CA: Cancer J Clin. 2006;56:106-130.2. Kamangar F, et al. J Clin Oncol. 2006; 24:2137-2150.



Pathophysiology of Colorectal Cancer

Normal colonic epithelial cells transformed by histopathologic, molecular events

Adenomatous polyps

– Intermediate stage in carcinogenic process

– Polyps occur in 33% of general population by age 50

– 50% incidence by age 70

Genetic basis for adenoma transformation to colorectal cancer

– Mutations in APC, K-ras, at earlier, nonmalignant stages

– p53 mutation appears to trigger malignancyJanne PA, et al. N Engl J Med. 2000;342:1960-1968.Vogelstein B, et al. N Engl J Med. 1988;319:525-532.



The Adenoma-Carcinoma Process

Mutations leading to formation of colorectal tumor

Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87. Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.

Normal colonic epithelium

Dysplastic aberrant crypt foci

Initial adenoma develops

Intermediate adenoma

Late adenoma

Carcinoma

Metastasis

Mutation in APC

Mutation in K-ras

Mutation in DCC

Mutation in p53

Other alteration?



Screening and Cancer Prevention

Screening with colonoscopy may detect precancerous polyps and other early-stage disease[1]

– Recommended beginning at age 50, every 10 years

– May begin at 40 years for patients at increased risk

Aspirin, cyclooxygenase-2 (COX-2) inhibitors associated with reduction in incidence of colorectal adenomas[2,3]

Despite these techniques, ~ 25% of patients present with metastatic disease[4]

– Nearly one half of patients with colorectal cancer require systemic therapy

1. Regula J, et al. N Engl J Med. 2006;355:1863-1872. 2. Baron JA, et al. N Engl J Med. 2003;348:891-899. 3. Bertagnolli MM, et al. N Engl J Med. 2006;355:873-874.



Chemotherapy for Metastatic Colorectal Cancer Thymidylate synthase inhibitors

– Fluoropyrimidines: 5-FU (intravenous), capecitabine (oral)

– Raltitrexed

Topoisomerase I inhibitors

– Irinotecan

Alkylating agents

– Oxaliplatin

Traditional 5-FU–based chemotherapy associated with modestly improved survival

– Newer agents (ie, irinotecan, oxaliplatin) lengthen survival outcomes



Fluoropyrimidines in Metastatic Disease No increase in survival benefit regardless of schedule

– Median survival: ~ 12 months

Regimen Response, %Bolus 5-FU 7-15

Infusional 5-FU 20-30

5-FU/LV

Mayo, Roswell schedules

de Gramont (LV5-FU2)

AIO (once weekly, 24-hour infusion)

12-35

28-33

25-44

Capecitabine 20-25

Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.



Multiple Active Agents Associated With Increased Survival Combinations of multiple active agents associated with better

outcome

– 5-FU, irinotecan, oxaliplatin

Compared with 5-FU/LV, use of all 3 active therapies associated with improved survival

– Median survival with triple-drug regimens: ~ 20 months

First-line doublet chemotherapy

– Associated with increased exposure to all 3 active agents during therapeutic course

Grothey A, et al J Clin Oncol. 2005;23:9441-9442.



Chemotherapy Efficacy Plateau

Median survival with addition of newer agents appears to plateau at 20 months

Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308. Saltz LB, et al. N Engl J Med 2000;343:905-914. de Gramont A, et al. J Clin Oncol. 2000;18:2938-2947. Goldberg RM, et al. J Clin Oncol. 2002;20:4591-4596. Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

Combination Therapy Active Agents Median Survival, mos

5-FU/LV 1 drug 11-12

Irinotecan/5-FU 2 drugs 14-15

Oxaliplatin/5-FU ± irinotecan 3 drugs 17-20



Molecular Targets in Metastatic Colorectal Cancer Epidermal growth factor receptor (EGFR)

Vascular endothelial growth factor receptor (VEGFR)

COX-2

Other targets

– Carcinoembryonic antigen

– Protein kinase C

– Matrix metalloproteinases

– Ras

– Cyclin dependent kinase



EGFR Inhibitors in Colorectal Cancer

EGFR overexpression found in up to 90% of metastatic tumors

– Activation of EGFR ultimately results in inhibition of apoptosis, malignant cell proliferation, migration, and angiogenesis

– EGFR-expressing tumors more aggressive with worse prognosis

Monoclonal antibodies targeting EGFR

– Cetuximab, panitumumab

Tyrosine kinase inhibitors (TKIs) of EGFR

– Gefitinib, erlotinib

Venook A. Oncologist. 2005;10:250-261 Mayer A, et al. Cancer. 1993;71:2454-2560.



EGFR Inhibitors in Colorectal Cancer (cont’d) To date, few promising results with EGFR-targeted TKIs in

colorectal cancer setting

Phase II gefitinib study in 110 patients with refractory disease [1]

– 2 doses studied, only 1 response noted in higher-dose (500 mg) group

No objective responses noted in study of erlotinib in second-line setting[2]

To date, monoclonal antibodies have exhibited better activity in metastatic disease

1. Rothenberg ML, et al. J Clin Oncol. 2005;23:9265-9274.2. Townsely CA, et al. Br J Cancer. 2006;94:1136-1143.



Cetuximab ± Irinotecan: The BOND Study

Cunningham D, et al. N Engl J Med. 2004;351:337-345.

Patients with progressive

colorectal cancer on or within 3 months of

irinotecan-based chemotherapy

(N = 329)

Irinotecan dose and schedule used during progression

Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week

(n = 218)

Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week

(n = 111)

Irinotecan dose and schedule used during

progression Cetuximab 400 mg/m2

1st infusion, then 250 mg/m2/week

PD

PD, progressive disease.Primary endpoint: response.



The BOND Study: Efficacy

Improved response, disease control, median TTP with irinotecan + cetuximab

Cunningham D, et al. N Engl J Med. 2004;351:337-345.

Irinotecan +

Cetuximab

Cetuximab Alone P Value

PR, % (95% CI) 22.9 (17.5-29.1) 10.8 (5.7-18.1) .0074

Disease control*,% (95% CI) 55.5 (48.6-62.2) 32.4 (23.9-42.0) .0001

Median TTP, mos 4.1 1.5 < .0001

Median survival, mos (95% CI) 8.6 (7.6-9.6) 6.9 (5.6-9.1) .48

*Disease control = complete and partial responses + stable disease.



The BOND-2 Study

Saltz L, et al. ASCO 2005. Abstract 3508.

Bevacizumab/Cetuximab + Irinotecan*Cetuximab 400 mg/m2 loading dose followed by

250 mg/m2 weeklyBevacizumab 5 mg/kg every other week

Irinotecan at same dose and schedule given just before study entry

(n = 41)

Bevacizumab/Cetuximab*Cetuximab 400 mg/m2 loading dose followed by

250 mg/m2 weeklyBevacizumab 5 mg/kg every other week

(n = 40)

Metastatic colorectal cancer patients refractory

to irinotecan

(N = 81)

*Patients received cetuximab on Day 1 (plus irinotecan, if randomized to that arm) and bevacizumab on Day 2.



BOND-2 Efficacy Results

Significant response for bevacizumab + cetuximab

– Addition of irinotecan improved responses

Saltz L, et al. ASCO 2005. Abstract 3508.

0

20

40

60

80

100

Par

tial

Res

po

nse

(%

)

37

232311

P = .05

P = .03

CET*

CET/BEV CET/IRI/BEV

CET/IRI*

*Historical controls.

Bevacizumab extends time to tumor progression vs historical controls

Median TTP

Time to Tumor Progression (Mos)

0 2 4 6 8 10 12

7.9

5.61.5

4.0

P < .01

P < .01

CET*

CET/BEV CET/IRI/BEV

CET/IRI*



BOND and BOND-2: Safety

BOND: overall incidence of adverse events higher in cetuximab-irinotecan arm; 65% vs 44%; P < .001

– Diarrhea, neutropenia more common with combination therapy

Acne-like rash in 80% of patients in each treatment arm

– Rash appeared within first 3 weeks of cetuximab treatment in majority of cases (89%)

BOND-2: no synergistic toxicity noted for combined therapies

– No antibody-related grade 3 allergic reactions; 17% to 20% incidence of antibody-related grade 3 rash

– Most common irinotecan-related toxicity; grade 3/4 diarrhea (24%), neutropenia (22%)

Cunningham D, et al. N Engl J Med. 2004;351:337-345.Saltz L, et al. ASCO 2005. Abstract 3508.



CALGB 80203: Study Design

Venook A, et al. ASCO 2006. Abstract 3509.

Patients with untreated metastatic

colorectal cancer

(N = 238)*

FOLFOXOxaliplatin 85 mg/m2 Days 1, 8

LV 20 mg/m2 over 2 hours Days 1, 85-FU 500 mg/m2 bolus, Days 1, 8

every 3 weeks

FOLFIRIIrinotecan 180 mg/m2 Day 1

LV 400 mg/m2 over 2 hours Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion

Days 1-2 every 3 weeks

Cetuximab 400 mg/m2 loading

dose, then 250 mg/m2 once weekly

(n = 55)

Placebo(n = 58)

Cetuximab 400 mg/m2 loading

dose, then 250 mg/m2 once weekly

(n = 55)

Placebo(n = 58)

*Original accrual goal of 2200 patients; after bevacizumab received FDA approval, study closed and redesigned in January 2005 as phase II randomized trial.

Primary endpoint: OS.Secondary endpoints: PFS, RR.



CALGB 80203: Preliminary Data

PFS, OS: more follow-up needed

Addition of cetuximab appears to increase response

Venook A, et al. ASCO 2006. Abstract 3509.

Response, % FOLFOX + Cetuximab

FOLFIRI + Cetuximab FOLFOX FOLFIRI

ORR (CR + PR) 60 44 40 36

Response, % (P = .029) Chemotherapy + Cetuximab Chemotherapy Alone

ORR (CR + PR) 52 38



CALGB/SWOG 80405: Study Design


colorectal cancer

(N = 2289)*

Patient/physician choice: mFOLFOX6

orFOLFIRI

Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weekly

Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weeklyBevacizumab 5 mg/kg IV

every 2 weeks

Bevacizumab 5 mg/kg IV

every 2 weeks

*~300 patients enrolled as of November 2006.

Primary endpoint: OS.Secondary endpoints: PFS, RR.

Study open through CTSU.org



Panitumumab in Colorectal Cancer

Activity in phase II studies

Panitumumab 2.5 mg/kg weekly in 148 previously treated patients

– PR: 9%; SD: 29%

– PFS: 3.1 mos; OS: 9.4 mos

Panitumumab combined with first-line IFL (n = 19), FOLFIRI (n = 24)

– Well tolerated in combination with FOLFIRI

– PR: 33%; SD: 46%

Based on these results, phase III study conductedMalik I, et al. ASCO 2005 Abstract 3520. Hecht J. ASCO GI 2006. Abstract 237.



Panitumumab vs BSC in Metastatic Colorectal Cancer

Peeters M, et al. AACR 2006. Abstract CP-1.

Patients with metastatic colorectal cancer who failed prior standard

chemotherapy(N = 463)

Panitumumab 6 mg/kg every 2 weeks +BSC

(n = 231)

BSC*

(n = 232)Stratification by ECOG score

(0-1 vs 2) and geographic locale

BSC, best supportive care.*Patients who experienced progressive disease eligible for crossover to panitumumab in optional, separate trial.



Panitumumab vs BSC: Main Findings

PFS significantly better for panitumumab-treated patients*

– HR: 0.54 (95% CI: 0.44-0.66; P < .000000001)


*Median follow-up: 19 weeks.

0

10

20

30

40

50

Wk 8 Wk 12 Wk 16 Wk 24 Wk 32 Wk 40 Wk 48

Pro

gre

ssio

n F

ree

(%)

Panitumumab + BSCBSC

1 1 1 30 49 35 14 26 9 18 5 10 4 4



Panitumumab vs BSC: Main Findings (cont’d) Panitumumab efficacy consistent across all subgroups

42% of 174 BSC patients who switched over to separate panitumumab study achieved disease control


OutcomePanitumumab + BSC

(n = 231)BSC Alone(n = 232)

Disease control, n (%) 83 (36) 24 (10)

Partial response 19 (8) 0 (0)

Stable disease 64 (28) 24 (10)

Median time to response, wks (min, max) 8 (7, 15) --

Median duration of response, wks (min, max) 17 (4, 40) --



Panitumumab vs BSC: Other Outcomes Panitumumab generally well tolerated

– No patients experienced grade 3/4 infusion reactions


Safety Outcome, %Panitumumab + BSC

(n = 229)BSC Alone(n = 234)

Any grade 3/4 adverse event 34 19

Grade 3/4 skin toxicity 14 0

Dermatitis acneiform 7 0

Erythema 5 0

Pruritus 2 0

Rash 1 0

Grade 3/4 hypomagnesemia 3 0



VEGF-Targeted Therapy

VEGF pathway implicated in angiogenesis

– Inhibition of VEGF curbs angiogenesis, slows production of new blood vessels necessary for tumor growth

Monoclonal antibody against VEGF

– Bevacizumab

Anti-VEGFR TKIs

– Sunitinib

– Sorafenib



Bevacizumab-Irinotecan in Metastatic Colorectal Cancer

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.


colorectal cancer

(N = 923)

IFLPlacebo(n = 411)

IFLBevacizumab 5 mg/kg;

every 2 weeks(n = 402)

5-FU/LVBevacizumab 5 mg/kg;


PD

PD*

PD*

Primary endpoint: survival.

*Patients receiving bevacizumab could continue therapy past disease progression in combination with second-line therapy.



Bevacizumab-Irinotecan in Metastatic Colorectal Cancer (cont’d)

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

*By stratified log-rank test.†By chi2 test.

IFL + Placebo

(n = 411)

IFL + Bevacizumab (5

mg/kg, q2w)

(n = 402) P Value HR

Median survival, mos 15.6 20.3 < .001* 0.66

PFS, mos 6.4 10.6 < .001* 0.54

ORR, % 35 45 < .01†

Median duration of response, mos 7.1 10.4 .001 0.62 (for relapse)



The BICC-C Study: Original Design

Fuchs C, et al. ASCO 2006. Abstract 3506.

Patients with previously untreated metastatic

colorectal cancer

(N = 430)

FOLFIRI Irinotecan 180 mg/m2 Day 1

LV 100 mg/m2 over 2 hours Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion Days 1, 2 every 2 weeks

(n = 144)

mIFLIrinotecan 125 mg/m2 Days 1, 8

LV 20 mg/m2 over 2 hours Days 1, 85-FU 500 mg/m2 bolus Days 1, 8


CapIRIIrinotecan 250 mg/m2 Day 1

Capecitabine 1000 mg/m2 twice daily Days 1-14 every 3 weeks

(n = 145)

Celecoxib 400 mg twice daily

Placebo

Primary endpoint: PFS for FOLFIRI vs mIFL.

Second randomization (all subjects)



The BICC-C Study: Modified Design


Patients with previously untreated metastatic

colorectal cancer

After May 2004, patients

randomized to FOLFIRI or mIFL

plus bevacizumab

(N = 117)

FOLFIRI Bevacizumab 5.0 mg/kg;


mIFLBevacizumab 7.5 mg/kg;


CapIRIevery 3 weeks

Celecoxib 400 mg twice daily

Placebo

Second randomization (all subjects)



The BICC-C Study: Results

Longer median PFS with FOLFIRI vs mIFL or CapIRI (prior to addition of bevacizumab)

– FOLFIRI vs mIFL: 8 mos vs 6.2 mos; P = .01

– FOLFIRI vs CapIRI: 8 mos vs 5.7 mos; P = .01

Significant improvement in OS with FOLFIRI + bevacizumab compared with mIFL + bevacizumab

– HR: 2.5 (95% CI: 1.3-5.0; P = .01)

– Median OS not reached for FOLFIRI + bevacizumab vs 18.8 mos for mIFL + bevacizumab

No effect with celecoxib




BICC-C: Safety and Tolerability

More discontinuations in CapIRI group due to toxicity vs FOLFIRI or mIFL groups

– 17% vs 7% and 12%, respectively

Selected grade 3/4 events (prior to addition of bevacizumab)


Grade 3/4 Adverse Events, % FOLFIRI (n = 144)

mIFL(n = 141)

CapIRI (n = 145)

Neutropenia 40 39 31

Febrile neutropenia 2 7 5

Diarrhea 13 19 48

Hand-foot syndrome 0 0 10

Dehydration 6 7 19



TREE 1 Study Design

mFOLFOXOxaliplatin 85 mg/m2 Day 1

LV 350 mg/m2 Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion

Days 1, 2 every 2 weeks(n = 50)

bFOLOxaliplatin 85 mg/m2 Days 1, 15

LV 20 mg/m2 over 2 hours Days 1, 8, 155-FU 500 mg/m2 bolus Days 1, 8, 15 every 4 weeks

(n = 50)

CapeOxOxaliplatin 130 mg/m2 Day 1

Capecitabine 1000 mg/m2 twice daily Days 1-15 every 3 weeks

(n = 50)

Patients with inoperable, metastatic colorectal cancer

No prior chemotherapy for metastatic disease

(N = 223)

Primary endpoint: grade 3/4 toxicity.Secondary endpoints: RR, TTP, TTF.

Hochster HS, et al. ASCO 2006. Abstract 3510.



TREE 2 Study Design*

mFOLFOX Bevacizumab 5.0 mg/kg


bFOL Bevacizumab 5.0 mg/kg


CapeOx†

Bevacizumab 7.5 mg/kgevery 3 weeks

(n = 74)

*TREE 1 study modified to include bevacizumab.†Reduced dose of capecitabine used in TREE 2: 850 mg/m2 Days 1-15.

Patients with inoperable, metastatic colorectal

cancer

(N = 223)




TREE Study: Efficacy Data


TREE 1 TREE 2*

5 6

810

89

*With bevacizumab.

0

10

20

30

40

50

60

Overall Response Rate

Pat

ien

ts (

%)

Mo

nth

s

TREE 1 TREE 2*

17

22

43

48

41

53

TREE 1 TREE 2*

1719

27

20

26

35

CapeOx bFOL mFOLFOX

Median TTP Median OS

0

5

10

15

20

25

30



TREE: Summary of Safety and Tolerability Fewer treatment-related events in bFOL arm vs CapeOx or

FOLFOX during first 12 weeks of treatment

Increased hypertension with addition of bevacizumab

Tolerability of CapeOx improved with capecitabine dose reduction in TREE 2


Treatment-Related Events, % (95% CI) FOLFOX bFOL CapeOx

TREE 1 59 (44-73) n = 49

36 (23-51)n = 50

67 (52-80)n = 48

TREE 2 59 (47-71)n = 71

51 (39-64)n = 70

56 (43-67)n = 72



ECOG E3200: Bevacizumab for Previously Treated Metastatic Disease

Giantonio BJ, et al. ASCO 2005. Abstract 2.

Previously treated, bevacizumab-naive

patients with metastatic CRC

(N = 822)

FOLFOX4 Oxaliplatin 85 mg/m2 Day 1

Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus, then 600 mg/m2

over 22-hr continuous infusion Days 1-2 every 2 weeks(n = 290)

Bevacizumab 10 mg/kg every 2 weeks(n = 243)

FOLFOX4 + Bevacizumab Oxaliplatin 85 mg/m2 Day 1

Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus, then 600 mg/m2

over 22-hr continuous infusion Days 1-2 every 2 weeks Bevacizumab 10 mg/kg every 2 weeks

(n = 289)

Terminated in March 2003 due to

inferiority vs other arms



ECOG E3200: Outcome With Addition of Bevacizumab Progression-free and overall survival increased with bevacizumab +

FOLFOX4

Increased toxicity with bevacizumab +FOLFOX4

– 3 bowel perforations reported in this groupEfficacy and Tolerability of FOLFOX4 ± Bevacizumab

Outcome FOLFOX4 + Bevacizumab FOLFOX4 P ValueMedian OS, mos 12.9 10.8 .0018Median PFS, mos 7.2 4.8 < .0001Overall response rate, % 21.8 9.2 < .001

Adverse event, % FOLFOX4 + Bevacizumab FOLFOX4 P Value

Grade 3/4 hypertension 5/1 2/< 1 .018

Grade 3/4 bleeding 3/1 < 1/0 .011Grade 3/4 neuropathy 16/< 1 9/< 1 .016Grade 3/4 vomiting 9/1 3/< 1 .010

Giantonio BJ, et al. ASCO 2005. Abstract 2.



Valatinib in Untreated Patients With Metastatic Colorectal Cancer

Hecht J, et al. ASCO 2005. Abstract LBA3.

FOLFOX4/ValatinibOxaliplatin 85 mg/m2 Day 1

Leucovorin 200 mg/m2 IV over 2 hrs +5-FU 400 mg/m2 bolus, followed by

5-FU 600 mg/m2 continuous infusion over 22 hrs on Days 1-2 every 2 weeks

Valatinib 1250 mg orally once daily(n = 585)

FOLFOX4Leucovorin 200 mg/m2 IV over 2 hrs +

5-FU 400 mg/m2 bolus5-FU 600 mg/m2 continuous infusion

over 22 hrs on Days 1-2 every 2 weeks Placebo orally once daily

(n = 583)

Patients with previously untreated

metastatic CRC

(N = 1168)

Stratification by PS (0/1 vs 2) and low vs high LDH (≤ 1.5 vs > 1.5 x ULN)



Valatinib in Untreated Patients With Metastatic Colorectal Cancer (cont’d) Adding valatinib to FOLFOX4 did not improve response

– CR + PR = 42% vs 46% with FOLFOX4 alone

– Slight improvement in PFS in secondary investigator analysis

Patients with high LDH levels treated with FOLFOX4/valatinib showed improved PFS

– HR: 0.67; P = .010 by independent assessment

– HR: 0.61; P = .002 by investigator analysis

More patients on valatinib + FOLFOX4 discontinued treatment due to adverse events

– Most common grade 3/4 adverse events included hypertension, neutropenia, and diarrhea

Hecht J, et al. ASCO 2005. Abstract LBA3.



Conclusions

EGFR-, VEGF-targeting agents plus chemotherapy

– Associated with improved activity, survival in metastatic disease

Nontraditional adverse events (eg, hypertension, delayed wound-healing, rash) with targeted therapy

Ongoing studies investigating

– Maintenance therapy with targeted agents between chemotherapy-free intervals

– Combinations of several targeted agents

management of metastatic colorectal cancer: focus on targeted therapy

Documents

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