Targeted Therapy in Head & Neck Cancer

Anti-EGFR Treatment

Jan B. Vermorken, MD, PhD

University Hospital Antwerp

Edegem, Belgium

Nucleus

Anti-receptor Antibodies

± Toxins

Tyrosine Kinase Inhibitors

Hormone Agonists/ Antagonists

Farnesyl Transferase

Inhibitors

Apoptosis Agonists

Antisense

Angiogenesis Inhibitors (Angiostatin, Endostatin

& Anti-VEGF)

Metalloproteinase Inhibitors

Matrix Degradation(Collagenases,Gelatinases &Stromelysins)

Immune System Activation (Vaccines,

Monoclonal antibodies)

Tumor Cell

Growth Factor Receptors

Intracellular Signaling Molecules

Overview: Targeted Therapies

AntimetabolitesMicrotubule inhibitors

EGFTGF

Amphiregulin-cellulinHB-EGF

EpiregulinHeregulins

NRG2NRG3

Heregulins-cellulin

Cysteine-richdomains

Tyrosine kinasedomain

ErbB-1Her1

EGFR

ErbB-2Her2neu

ErbB-3Her3

ErbB-4Her4

C-terminus

100

100

100

44

82

33

36

59

24

48

79

28

The EGFR (ErbB) family and ligands

EGFR Expression in Human Tumors

• NSCLC 40-80%

• Prostate 40-80%

• Head & Neck 90-100%

• Gastric 33-74%

• Breast 14-91%

• Colorectal 75-89%

• Pancreatic 30-95%

• Ovarian 35-77%

• Bladder 31-72%

• Glioma 40-63%

• Invasion

• Metastasis

• Late-stage disease

• Chemotherapy resistance

• Poor outcome

EGFR expression High expression generallyassociated with

Prognostic significance of EGFR expression in SCCHN

High levels of EGFR and TGF result in reduced disease-free and overall survival

EGFR TGF

Low

Medium

High

p=0.0001

1.

0

0.

8

0.

6

0.

4

0.

2

0.

0

Pro

po

rtio

n s

urv

ivin

g w

ith

NE

D

0 1 2 3 4 5 6

Years after surgery

p=0.0001

Low

Medium

High

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n s

urv

ivin

g w

ith

NE

D

0 1 2 3 4 5 6

Years after surgery

Grandis et al, 1998

Anti-EGFR Therapies

Signal transduction

Signal transduction

Celldeath

MAbs TKIsToxin

conjugates Antisense

Proteinsynthesis

KKKK

Ligand

KK TKIKK

Ligand Ligand Ligand

Synergistic Effects of Cetuximab + Cisplatin on Human Epidermoid Cancer Cell Line A431

6

4

2

0

Tu

mo

r si

ze (

cm3 )

Cetuximab

Cisplatin

Days0 20 40 60 80 180

Days

100

50

0

Su

rviv

al (

%)

Control

Cetuximab

Cisplatin

Cetuximab + cisplatin

Fan Z et al, 1993

0 5 15 25 35

Cetuximab + Radiation – Synergistic Effects on Human Epidermoid Cancer Cell Xenografts

Saleh et al., 1999

0 10 50 100 150 200 250

400

300

200

100

0

Control

10 Gy

Cetuximab

Cetuximab + 10 Gy

Time (days)

Per

cen

t o

f o

rig

inal

tu

mo

r

Anti-EGFR Agents in Phase III Evaluation

Agent Drug type Status Tumor type

Cetuximab EGFR mAb launched CRC

phase III pancreatic, H&N, NSCLC

Panitumumab EGFR mAb phase III CRC and lung

phase I head and neck

Gefinitib EGFR-TKI launched NSCLC

phase III head and neck

Erlotinib EGFR-TKI phase III NSCLC, pancreatic

phase II head and neck

Lapatinib EGFR-TKI / phase III breast and renal

ERBB²-TKI phase II head and neck

Cetuximab (Erbitux) – Summary of Clinical Studies in Head and Neck Cancer

Disease Type of study Treatment Reference

R/M SCCHN phase II Erbitux Trigo2004*

Pt-refractory + platinum Baselga 2005

Herbst 2005

R/M SCCHN phase I/III Pt-based CT Burtness 2002

Pt-sensitive + Erbitux Humblet 2004

Vermorken 2006

LA-SCCHN phase III RT + Erbitux Bonner 2004

vs RT* Updated Vermorken et al, 2006

Disease progression

Patients with recurrent and/or metastatic SCCHN that had

progressed on platinum-based therapy

ERBITUX 400 mg/m2

followed by

250 mg/m2 weekly

Best supportive care

or single agent/

combination

chemo-

or radiotherapy

ERBITUX 400 mg/m2

followed by

250 mg/m2 weekly

+

Cisplatin/carboplatin

Stable disease or response

ERBITUX 400 mg/m2

followed by

250 mg/m2 x 4 cycles

+

Cisplatin

75 or 100 mg/m2 q 3 weeks

ERBITUX +

cisplatin/carboplatin until disease progression

ERBITUX alone until

disease progression

Trigo Baselga Herbst León

Study Designs

Tumor Response

Treatment NCR+PR (%)

[95% CI]CR+PR+NC (%)

[95% CI]

ERBITUX monotherapy1 103 13% [7-21] 46% [36-56]

ERBITUX + cisplatin

or carboplatin296 10% [5-18] 53% [43-63]

ERBITUX + cisplatin3 79 10% [5-19] 56% [44-67]

Retrospective analysis4

All patients 151 3% [1-7] 15% [10-22]

Patients with CT only 43 0% [0-8] 9% [3-22]

1 Trigo/Vermorken et al 2004/2006, 2 Baselga et al 2005, 3 Herbst et al 2005, 4 León et al 2005

Overall Survival and Time to Progression

Treatment NMedian OS

months [95% CI]

Median TTP

months [95% CI]

ERBITUX monotherapy1 103 5.9 [3.2-9.8] 2.3 [1.6-3.1]

ERBITUX + cisplatin

or carboplatin296 6.1 [4.9-7.0] 2.8 [2.2-3.8]

ERBITUX + cisplatin3 79 5.2 [3.1-6.0] 2.2 [1.9-3.0]

Retrospective analysis4

All patients 151 3.4 [2.6-4.2] N/A

Patients with CT only 43 3.5 [3.3-4.2]N/A

1 Trigo/Vermorken et al 2004/2006, 2 Baselga et al 2005, 3 Herbst et al 2005, 4 León et al 2005

Cetuximab (Erbitux) in Platinum-Sensitive R/M SCCHN

Author Type of No. of Treatment RR (CR)MS

(year) study pts arms %mo

Burtness Ph III 60 Pt + Erbitux 26 (2)9.3

(2002/2004 63 Pt + placebo 108.0

Humblet Ph I/II 27 PF + Erbitux 33 (4)10.6

(2004) 26 CF + Erbitux 38 (4)8.5

Vermorken Ph III 222 Pt/5FU + Erbitux TETE

(2006) 220 Pt/5FU TETE

Cetuximab (Erbitux): Grade 3-4 adverse toxicity

Category ERBITUX1 ERBITUX

+ CDDP/carbo (n=96)2

ERBITUX + CDDP (n=79)3Alone

(n=103)

+ platinum (n=53)

Any

Fatigue

Nausea/vomiting

Mucositis

Skin reactions

Hypersensitivity

Respiratory

34%

16%

3%

1%

1%

1%

15%

45%

21%

6%

0%

4%

0%

23%

43%

19%

6%

2%

3%

0%

13%

N/A

18%

6%

N/A

4%

N/A

22%

1 Trigo et al 2004, 2 Baselga et al 2005, 3 Herbst et al 2005

Studies with other EGFR Inhibitors in SCCHNPhase I and II studiesDose Study Pts RR

Agent(s) mg Phase N % Reference

Gefitinib 500 qd II 47 11 Cohen, 2003

Gefitinib 250 qd II 56 3.5 Kane, 20041

Gefitinib+ 250-500 qd I 18 22 Wirth, 2005Celecoxib 200-400 bid

Erlotinib 150 qd II 115 4.3 Soulieres, 2004

Erlotinib 150 qd I 10 1/9 Mauer, 20042

Bevacizumab 5, 10, 15/kg II 45 11 Vokes, 2005*iv q 3 wks

ASCO 2004 (abstract 1#5586, 2#5539), * ASCO 2005 (#5504)

Patient Characteristics

56 (34–81)58 (35–83) Median age (range)

561727

631324

Primary tumor site (%)OropharynxHypopharynxLarynx

81 / 1979 / 21Male / Female (%)

ERBITUX + RTRT

Bonner J et al. New. Engl J Med [Submitted]

Patients (n) 213 211

A Phase III Study of RT ± ERBITUX

1.0

0.8

0.7

0.9

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Months

Locoregional Control

Pro

bab

ilit

y

ERBITUX + RT

RT

ERBITUX + RT90

36 m69%56%

RT105

19 m59%48%

EventsMedian1-Year2-Year

0 6 12 18 24 30 36 42

Log rank p 0.02

A Phase III Study of RT ± ERBITUX

Months

Pro

bab

ilit

y

1.0

0.8

0.7

0.9

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Survival

ERBITUX + RT

RT

ERBITUX + RT93

54 m62%57%

RT117

28 m55%44%

EventsMedian2-Year3-Year

0 6 12 18 24 30 36 42 48 54 60

Log rank p 0.02

0 12 18

Grade 3/4 acute toxicity

Type RT (%) Erbitux + RT (%)

Skin 18 34

Mucosal 52 54

Dysphagia 30 25

Xerostomia 3 4

Fatigue 5 4

Infusion reaction — 3

• Acute toxicity acceptable (skin, infusion reactions, no additional mucositis)

Bonner J et al. New. Engl J Med [Submitted]

1.0

Pro

bab

ilit

y

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 6 12 18 24 30 36 42 48 54 60

Months

Hazard ratio = 0.62; p=0.13

Patients

Laryngectomies

78

12

RT

93

8

ERBITUX + RT

A Phase III Study: ERBITUX and larynx preservation

Bonner et al. J Clin Oncol, ASCO Annual Meeting Proceedings 2005; 23:Abstract 5533. Updated information presented at ASCO (poster)

A Phase III Study: ERBITUX and Wound Healing

• Subgroup of n=39 patients undergoing neck dissections

• No significant prolongation in key parameters in the RT alone and ERBITUX + RT groups, respectively:

– average length of hospital stay following dissection (2.1 days vs 2.8 days)

– average time until neck drain removal (3.3 days vs 3.1 days)

• ERBITUX does not significantly affect wound healing following neck dissection

Harari et al. Int J Radiat Oncol Biol Phys 2003; 57: S245-S246

Anti-EGFR Treatment in H&N CancerConclusions (1)

• Synergism with platinum compounds and RT • Survival benefit in R/M SCCHN?• Survival benefit in LA-SCCHN! (one trial)• EGFR inhibitors + RT could replace RT alone for the

treatment of intermediate risk LA-SCCHN• EGFR inhibitors + RT offers an alternative for patients

with high-risk LA-SCCHN* who are unable to tolerate concurrent CT and RT

* Stage III, IV disease, excluding T1-2N1 and T3N0

Anti-EGFR Treatment in H&N CancerConclusions (2)

Future need of clinical trials

• Chemoradiation vs EGFR inhibitors + RT• Chemoradiation + EGFR inhibitors• Induction CT CRT + EGFR inhibitors• Induction CT + EGFR inhibitors• Interaction of EGFR inhibitors – other CT agents• Interaction of EGFR inhibitors – other biologicals