EGFR Inhibitors in Colorectal Cancer

John L. Marshall, MD

Lombardi Comprehensive Cancer Center

EGF TGF

Ligand Binding

Phosphorylation

and ActivationDimerization

HeterodimerHomodimer

ATPATP ATP

High

affinity

binding

Ligand Binding and Dimerization Results in TK Activation

Source: With permission from Amgen Inc.

P13K

FKHR

Akt

mTOR

PTEN

MEK 1/2

MAPK

BADGSK-3

SOS

Grb-2

Shc

Grb-2

SOS Ras

Raf

JunFOS Myc

p27

Cyclin D-1

LigandLigand

Signal

Adapters

and Enzymes

Signal

Cascade

EGFr dimer

MAPK = mitogen-activatedprotein kinase

P13k = phosphatidylinositol

3-kinase

TranscriptionFactors

EGFR Activation and Signaling Pathways

Source: With permission from Amgen Inc.

Proliferation

Angiogenesis

Cell

Survival

Metastatic

Spread

EGFr ActivationTumor

Tumor

Blood

Vessel

Blood

Vessel

Spread of

cancer cells

EGFR Activation Mediates Several Processes

Source: With permission from Amgen Inc.

•NSCLC •40-80

•SCCHN •95

•Colorectal •25-77

•Glioblastoma •40-60

•Breast •14-91

•Prostate •41-100

•Ovarian •35-70

•Esophageal •35-88

•Pancreatic •30-50

SCCHN = squamous cell carcinoma head and neck.

Arteaga C. Semin Oncol. 2003;30(suppl 7):3-14.

EGFR Expression (%)Tumor Type

EGFR Expression Correlates With Poor Prognosis in Selected Solid Tumors

*Responses observed in various solid tumors for gefitinib, erlotinib, and cetuximab.

Anti-EGFr Monoclonal Antibodies

Mendelsohn J. J Clin Oncol. 2002;20(suppl 18):1s-13s. Tewes M, et al. Proc Am Soc Clin Oncol. 2002. Abstract 378. Sridhar SS, et al. Lancet Oncol. 2003;4:397-406. Vanhoefer U, et al. J Clin Onc 2004;22(1):175-184www.clinicaltrials.gov.

Monoclonal Antibody Description Status

Cetuximab (C-225)

Chimeric IgG1

Approved: Colorectal cancer Submitted: Head and Neck (H&N) cancer Phase 2: NSCLC, Others

Matuzumab(EMD 72000)

Humanized IgG1

Phase 2 Trials: Recurrent ovarian cancer, NSCLCPhase I-2 Trials: Colorectal cancer

Panitumumab (ABX-EGF)

Fully human IgG2Phase 2-3 Trials: Colorectal cancer, NSCLC, Others

Properties of Cetuximab IgG1 MAb (chimerized) Binds specifically to EGFR

and its heterodimers Binds to EGFR with high affinity

(Kd = 2.0 x 10–10 M): 1 log higher than the natural ligand

Following the recommended doseregimen (400 mg/m2 initial dose/250 mg/m2

weekly dose), the mean half-life was 114 hours (range 75-188 hours)

Competitively inhibits ligand binding to EGFR Stimulates receptor internalization Blocks receptor dimerization, tyrosine kinase

phosphorylation, and signal transductionShitara K, et al. Cancer Immunol Immunother. 1993;36:373-380.

LoBuglio AF, et al. Proc Natl Acad Sci U S A. 1989;86:4220-4224. ERBITUX Package Insert, June 2004.Data on file. ImClone Systems Incorporated and Bristol-Myers SquibbCompany; 2004.

Patients with EGFR-expressing metastatic CRC progressed after

receiving irinotecan-based chemotherapy

RANDOMIZATION

CETUXIMABwith irinotecan

n = 218

Cetuximab Randomized Pivotal Trial in Metastatic Colorectal Cancer

Randomized Phase II Study Design

ERBITUX Package Insert, June 2004.

CETUXIMAB as a single agent

n = 111

Cetuximab Randomized Pivotal

Trial in Metastatic Colorectal Cancer

Characteristic All Patients (n = 329)

Gender, %MaleFemale

6337

Age, yMedianRange

5926-84

Karnofsky Performance Status, %

< 80 80

1288

Prior oxaliplatin treatment, % 63

Patient Baseline Demographics

ERBITUX Package Insert, June 2004.

Cetuximab/C225 in Colon Cetuximab/C225 in Colon CancerCancer

CPT-11 + C225

C225 alone

2:1

RR TTP OS

22.9 4.1 8.6

10.8 1.5 6.9

54 pts crossover

Source: Cunningham D et al. N Engl J Med 2004;351:337-45.

The “Bond” TrialsThe “Bond” TrialsC225 C225 AloneAlone

C225 + C225 + BevBev

PP

ValueValue

C225 + C225 + CPT-11CPT-11

C225 + C225 + CPT-11 CPT-11 + Bev+ Bev

P ValueP Value

PRPR 11%11% 23%23% 0.05 23%23% 38%38% 0.03

TTPTTP 1.5 1.5 momo

5.6 5.6 momo

>0.01 4.1 4.1 momo

7.9 7.9 momo

>0.01

OSOS 6.9 6.9 momo

NRNR - 8.6 8.6 momo

NRNR -

Sources: Cunningham D et al. N Engl J Med 2004;351:337-45.Saltz L et al. Presentation. ASCO GI Symposium 2005. Abstract 169b

Cetuximab in the first line?Cetuximab in the first line?

• FOLFIRI + Cetuximab– 59% PR (13/22) 36% SD (8/23)59% PR (13/22) 36% SD (8/23)

• Raoul et al ECCO 2003

• FOLFOX + Cetuximab– 81% PR81% PR

• ASCO 2004

– 82% CR/PR, 12.5 median PFS• ASCO 2005

Sources: Raoul et al. Proc ECCO 2003;Abstract 289.Tabernero JM et al. Proc ASCO 2004;Abstract 3512.Rubio ED et al. Proc ASCO 2005. Abstract 3535

Monoclonal Antibodies as Targeted Therapy: Evolution to Fully Human Antibody

100% Mouse Protein 34% Mouse Protein 10% Mouse Protein 100% Human Protein

Mouse

Fully HumanHumanizedChimeric

cetuximab matuzumab panitumumabmousehuman

Panitumumab Phase 2 Study: Monotherapy for CRC - Methods

• Eligibility requirements:– Metastatic colorectal carcinoma, ECOG 0-1– Measurable disease– Failed prior therapy with a fluoropyrimidine

+/- leucovorin, and either irinotecan, oxaliplatin or both

– EGFr overexpression by immunohistochemistry

• Cohort A: 2+ or 3+ in > 10% of tumor cells• Cohort B: 2+ or 3+ in < 10%, but 1+, 2+ or 3+ in

>10% of tumor cells

Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511. - poster

Panitumumab Phase 2 Study: Monotherapy for CRC - Methods

• Dose: 2.5 mg/kg– Infused over 1 hour– No loading dose– Administered without premedication– Given weekly until disease progression or

unacceptable toxicity

• Assessments:– Toxicity assessed weekly – Tumor assessment every 8 weeks

Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511. - poster

Panitumumab Phase 2 Study:Monotherapy for CRC – Toxicity

(Treatment-related Adverse Events)

Selected Treatment-emergent adverse events reported through cycle 2 as possibly, probably, or definitely related to panitumumab

Events starting before cycle 1 or after the first infusion in cycle 3 are excluded.

Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511, poster. Data on file.

Toxicity All Grade Grade 3 Grade 4

Rash 140 (95%) 5 (3%) 0

Fatigue 34 (23%) 3 (2%) 0

Diarrhea 30 (20%) 1 (1%) 0

Vomiting 10 (7%) 2 (1%) 0

Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study: Methods

• Multicenter, open-label, single-arm study consisting of 2 parts:– Part 1: Patients (N=19) received 1st line panitumumab/IFL

therapy:

• Panitumumab 2.5 mg/kg/week administered intravenously over 1 hour in 6-week courses (days 1, 8, 15, 22, 29 and 36), immediately followed by:

• IFL regimen: irinotecan (IR) 125 mg/m2, leucovorin (LV) 20 mg/m2, 5-fluorouracil (5FU) 500 mg/m2 on days 1, 8, 15 and 22

• Enrollment for Part 1 is closed

– Part 2: Patients received 1st line panitumumab/FOLFIRI therapy

• Part 2 is ongoing with enrollment closed (N=24); patients are continuing therapy

Berlin J, et al. ESMO 2004. a265

Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study, Part 1: Skin Toxicity

Skin Toxic All Patients

(N=19)

Worst Severity

Mild

Moderate

Severe

Life-Threatening

9 (47%)

7 (37%)

3 (16%)

0 ( 0%)

Median (95% CI) Time to Onset,

days

11.0 (7.0, 15.0)

Berlin J, et al. ESMO 2004. a265

Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study, Part 1: Efficacy

All Patients

(N=19)

Overall Response 9 (47%)

Partial Response

Complete Response8 (42%)

1 ( 5%)

Stable Disease 6 (32%)

Progressive Disease 1 ( 5%)

No Assessment 3 (16%)

Treated pts received at least 1 dose of panitumumab or 1 dose of IFL

Berlin J, et al. ESMO 2004. a265

Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC

BSC PD Follow-up

RRAANNDDOOMMIIZZEE

Optional Optional Panitumumab Panitumumab

Crossover StudyCrossover Study

Randomization stratificationRandomization stratification• ECOG score:ECOG score: 0-1 vs. 20-1 vs. 2• Geographic region:Geographic region: Western EU vs. Western EU vs.

Central & Eastern EU vs.Central & Eastern EU vs.Rest of World Rest of World

Randomized Controlled Phase 3 Trial in mCRC

1:1

Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Study Endpoints

Primary • Progression-free survival (per blinded central radiology assessment of modified-RECIST criteria)

Secondary • Overall survival time and best overall objective response (central radiology) - co-secondary

• Duration of and time to response

Safety • Incidence of adverse events (including all, grade 3/4, treatment related events), antibody formation

Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1

• Metastatic colorectal adenocarcinoma (mCRC)

• ECOG score 0 to 2

• Radiologic documentation of disease progression after fluoropyrimidine, irinotecan, and oxaliplatin

– During or within 6 months following most recent chemotherapy regimen

– Failure after prespecified doses of irinotecan and oxaliplatin

• EGFr membrane staining on ≥ 1% tumor cells (IHC, central laboratory)

• Adequate hematologic, renal, and hepatic function

Key Eligibility Criteria

Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Demographics and Disease CharacteristicsPanitumumab

Plus BSC(N=231)

BSC Alone

(N=232)

Sex – n (%)MenWomen

146 (63)85 (37)

148 (64)84 (36)

Median (range) age – years 62 (27, 82) 63 (27, 83)

ECOG status – n (%)0-1≥ 2

201 (87)30 (13)

195 (84)37 (15)

Number of metastatic sites – n (%)1-23-5

161 (70)70 (30)

161 (70)69 (30)

Prior adjuvant chemotherapy – n (%) 86 (37) 78 (34)

Prior chemotherapy – n (%)At least 2 linesAt least 3 lines 230 (100)

84 (36)232 (100)

88 (38)

Mean (SD) % of tumor cells with EGFr membrane staining 32.5 (29.3) 27.5 (26.1)

Intensity of EGFr staining – n (%)

3+ (strong)2+ (moderate)1+ (weak)0 (none)

47 (20)122 (53)60 (26)

2 (1)

41 (18)113 (49)78 (34)

0 (0)

Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Eve

nt-

free

Pro

bab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

Hazard ratio=0.54 (95% CI: 0.44, 0.66)

Stratified log-rank testp < 0.000000001

Progression-Free Survival

Panitumumab

BSC

Patients at risk:PanitumumabBSC

231 118 49 31 13 5 1232 75 17 7 3 1 1

Primary Analysis, All Randomized Analysis Set, Central Radiology

Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1

0%

10%

20%

30%

40%

50%

60%

Kaplan- Meier Progression-Free Survival Rates at Prespecified Time Points

49%49%

30%30%35%35%

14%14%

26%26%

9%9%5%5%

18%18%

4%4%1%1%1%1% 1%1%

4%4%

10%10%

Panitumumab (N=231)Panitumumab (N=231)

BSC (N=232)BSC (N=232)

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

Primary Analysis, All Randomized Analysis Set, Central Radiology

% P

rog

ress

ion

Fre

e (9

5 %

CI)

Patients at risk:Patients at risk:PanitumumabPanitumumabBSCBSC

118118 4949 3131 1313 55 117575 1717 77 33 11 11

76763131

Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1

% S

urvi

vin

g

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from Randomization

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Panitumumab (N=231)

BSC (N=232)

Hazard ratio=0.93 (95% CI 0.73, 1.19)

Stratified log-rankp = 0.6065

Patients at risk:PanitumumabBSC

231 219 204 170 136 103 81 60 47 31 21 16 11 6 5 3 0 0 0232 221 199 175 139 98 76 60 41 29 20 18 12 8 7 5 3 1 0

00

Overall Survival – Interim Analysis(All Randomized Analysis Set)

Note: There were 250 events

Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Note: BSC patients censored at the time that they received their first dose of panitumumab; Included confirmed and unconfirmed responses by investigator (RECIST criteria)

HR= 0.78 (95% CI: 0.61, 1.01) HR= 0.78 (95% CI: 0.61, 1.01)

PanitumumabPanitumumab

BSCBSC

Patients at risk:PanitumumabBSC

231 219 204 170 136 103 81 60 47 31 21 16 11 6 5 3 0 0 0 0

232 219 194 149 113 71 51 38 26 17 10 8 5 2 2 2 2 0 0 0

Sur

viva

l Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19Months from Randomization

Overall Survival: Censored BSC PatientsWho Subsequently Responded After Crossing Over

Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Safety – Grade 3/4 Adverse Events

Panitumumab (N = 229)

BSC(N = 234)

Grade 3 Grade 4 Grade 3 Grade 4

Patients with any grade 3or 4 event

75 (33) 4 (2) 41 (18) 4 (2)

Abdominal pain 17 (7) 0 (0) 8 (3) 3 (1)Fatigue 10 (4) 0 (0) 7 (3) 0 (0)Dyspnea 9 (4) 2 (1) 8 (3) 0 (0)Anorexia 7 (3) 0 (0) 5 (2) 0 (0)Jaundice 7 (3) 1 (0) 3 (1) 1 (0)Asthenia 6 (3) 1 (0) 5 (2) 0 (0)Vomiting 5 (2) 0 (0) 2 (1) 0 (0)Ascites 3 (1) 1 (0) 2 (1) 0 (0)Diarrhea 3 (1) 0 (0) 0 (0) 0 (0)Intestinal obstruction 3 (1) 4 (2) 2 (1) 0 (0)Paronychia 3 (1) 0 (0) 0 (0) 0 (0)Deep vein thrombosis 2 (1) 1 (0) 0 (0) 0 (0)Pulmonary embolism 0 (0) 1 (0) 0 (0) 0 (0)

MedDRA version 8.0 preferred terms; graded per NCI CTCAE version 2.0Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Grade 2-4Grade 1

Sur

viva

l Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from Randomization0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Patients at risk:Grade 2-4Grade 1

152 150 138 120 99 71 58 39 29 17 13 9 6 5 1 0 057 55 47 34 24 20 12 8 5 4 3 2 0 0 0 0 0

Overall Survival by Worst Grade of Skin Toxicity in the Panitumumab Patients

a Hazard ratio for Grade 2-4 relative to Grade 1, stratified by ECOG and geographic region

Hazard ratio = 0.61a (95% CI: 0.40, 0.95)p = 0.0278

Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1

Conclusions and Questions

• EGFR antibodies are active in colon cancer

• Skin rash toxicity is the biggest barrier to more widespread use

• Approval(s) in “last line” therapy– Role in 1st line or adjuvant to be determined