scch&n cancer report

111

Study of target therapy “Cetuximab”on the squamous cell carcinomas of

the head and neck (SCCHN)

Student ID : Student : HDate :2009

22

Outline

Introduction Squamous cell carcinomas of the head and neck

(SCCHN) EGFR’s role on SCCHN RT/CT’s influence on SCCHN Cetuximab was used on the locally advanced SCCHN Cetuximab was used on the first line recur/meta

SCCHN Cetuximab was used on the 2nd line recur/meta

SCCHN Conclusions

33

Cancers arising in the upper aerodigestive tract, including the oral cavity, pharynx and larynx

Tumors are further classified byHistological type (Adenocarcinomas,

Squamous cell carcinomas )

Brain tumors are excluded as they behave, and are treated,very differently

3

44

Squamous cell carcinomas are derived from: The epithelium lining the aerodigestive tract Account for approx. 90% of primary head and neck

cancers

SCCHN occur in a range of different sites resulting in: Distinct clinical presentations and outcomes. Are treated differently than other head and neck

cancers4

55

Stage of tumor is determined at diagnosis Staging helps assess prognosis and different treatment

TNM system is often used in all solid tumors: T – size of primary tumor N – involvement of lymph nodes M – presence of metastases

T definitions are specific to the site of each primary tumor

N and M definitions in SCCHN are as same as for other tumors

5American joint committee on cancer staging (AJCC),

666

Squamous cell carcinomas head& neck

Prof J-L Lefebvre, personal communication

77

Factors contributing to the etiology of H&N cancersresearches Dep. collected the following data:

Agent/factor Cancer site Agent/factor Cancer site

Tobacco Oral, larynx Occupational Exposure:

Textile industryPrinting tradeAsbestosWoodNickelMustard gasSulfuric acid

Oral, pharyngealOral, pharyngealLarynxNasal (Larynx)NasalLarynxLarynx

Alcohol Oral, larynx

Areca nuts Oral

Oral snuff Oral

Infectious agents:

HPVHSVEBV

OralOralNasopharynx

Radiation Salivary gland7Cancer of the larynx, www.FIRSTConsult.com, Elsevier, (07.11.09).

88

PatientENT / Oral (Surgeon)

Radiation oncologist

Oncologist

Data source: 2007 Oct 20 1st wave survey by APR

70% patients are diagnosed by ENT and oral surgeonsSome successful experience in penetrating radiation oncologist andENT surgeon segmentsTreatment strategy generally follow protocol in multidisciplinary team

Diagnosis & surgery CT

RT & CT

ENT and Oral surgeons represent majorpatients source and treat trend

99http://www.fda.gov/Cetuximab combined RT used in locally advanced H & N Ca,Cetuximab monotherapy used in the Recur / meta H & N after platinum failure

1010

“Evidence for a role for the EGFrin the inhibition and

pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor.”*EGFr message transmission result in cancer cells----

Bernier J. and Schneider D.(2006)

1111

EGFr is expressed in a variety of solid tumors

Lung(NSCLC)

Colorectal

Head & Neck(SCC)

Head & neck cancer 90 – 100%

Lung cancer (NSCLC) 40 – 91%

Colorectal cancer 72 – 84%

Breast cancer 14 – 91%

Ovarian cancer 35 – 70%

Renal cell cancer 50 – 90%

Cunningham et al. 2004; Grandis et al.1996; Salomon et al. 1995; Walker & Dearing.1999; Folprecht et al.2004

1212

Cetuximab is an IgG1 MAbtargeting the EGFr

Binding blocks EGFrsignaling, the message transmission and inhibits proliferation, angiogenesis ,metastasis, stimulates apoptosis and differentiation

combined chemotherapy or radiation , can enhance the anti-tumor effect

Fc region may induce antibody-dependent cell-mediated cytotoxicity(ADCC) (immune response)

Bernier J. and Schneider D.(2006)

1313

IgG1 IgG1 ((cetuximabcetuximab))

Lysis of antibody-coated cell

MAXIMIZE ANTI-TUMOUR ACTIVITY

EGFR MEDIATED Anti-tumour Activity

IgG1 MEDIATED ADCC

Fan Z, et al. Fan Z, et al. Cancer ResCancer Res.1993;53:4322.1993;53:4322--8 8

Cetuximab: IgG1-Induced Antibody-Dependent Cell Cytotoxicity (ADCC)

Attachment

IgG1 attachment surface antigen ,trigger NK identify ca.cell by antibody

1414Ang K. K, et al. 2002

High EGFr expression in SCCHN is linked to lower survival and increased risk of locoregional relapse

0

25

50

75

100

0 1 2 3 4 5

Years from randomization

p=0.0006Overall survival

n=155EGFr>median

EGFrmedian

Locoregional relapse

Aliv

e (%

)

Years from randomization

0

25

50

75

100

0 1 2 3 4 5

EGFr>median

EGFrmedian

p=0.003

n=155Fa

iled

(%)

inhibit EGFr pathway extened tumor progression

1515

Treatment modalities in SCCHN

CTSurgery RT Alone PalliationRT + CT

locally advrec/met SCCHN

refractory

• Early disease is treated with surgery or radiotherapy alone• Locally advanced SCCHN

• Radiotherapy for patients at intermediate risk• Chemoradiotherapy for high-riska disease

• Recurrent and/or metastatic disease• Chemotherapy is main treatment

• Combination therapies are associated with increased toxicities– eg mucositis and swallowing dysfunction

aStage III–IV disease, excluding T1–2 N1 and T3 N0

16Cooper ,J.S., et al. 2004

Acute adverse effects: grade 3 or higher 34% with RT alone vs 77% with CRT (p<0.001)

Subj

ects

(%)

Hematologic

Mucous membrane

Pharynx and esophagus

Nausea and vomiting

Upper GI tr

actSkin

Infection

Salivary gland (xerostomia)

Neurologic

Genitourin

ary tract

Anemia0

20

40

60

RT alone (n=231)Combined RT + cisplatin (n=228)

80

1717

Early deaths due to treatment-related complications

Late deaths due to treatment-related complications

45%

21%9%

10% 9%

6%

Cause of death Time of occurrence, years median (range)

Disease progression 1.5 years (0.3–8.6)

Comorbidities 1.9 years (0.07–8.8)

Treatment-related 0.3 years (0.03–3.4)

Second primary tumors 3.5 years (1.5–10.1)

Unknown 5.1 years (1.1–9.5)

Argiris ,A., et al. 2004

15% of patient died for the SE of CT/RT not for cancer.

1919

BONNER Study 2006

Bonner,J .A., et al. 2006

2020

354:567-78, 2006

2121

Stratified by

KPS (Karnofsky performance status)

Nodal involvement Tumor stage RT fractionationa

Stage III and IV non metastatic

SCCHN(n=424)

RT (n=213)

Cetuximab + RT (n=211)Cetuximab initial dose (400 mg/m2)1 week before RTCetuximab (250 mg/m2) + RT (weeks 2–8)b

Cetuximab + RT in locally advanced SCCHN: phase III study design


R

• Primary endpoint: duration of locoregional control

• Secondary endpoints: OS, PFS, RR, and safety

2222

Months

Cetuximab + RT (n=211)

Loco

regi

onal

cont

rol (

%)

100

80

60

40

20

00 10 20 30 40 50 60 70

RT (n=213)14.9 24.4

Hazard ratio = 0.68 (95% CI: 0.52–0.89)Log-rank p=0.005

Phase III study: locoregional control

Cetuximab + RT RT p-value

Locoregionalcontrol rate 3-year 47% 34% <0.01


2323

Months

Cetuximab + RT (n=211)

Ove

rall

surv

ival

(%)

100

80

60

40

20

00 10 20 30 40 50 60 70

RT (n=213)29.3 49.0

Hazard ratio = 0.74 (95% CI: 0.57–0.97)Log-rank p=0.03

Cetuximab + RT RT p-value

Survival rate 3-year 55% 45% 0.05

Phase III study: overall survival


2424

Side effectRT

(n=212)Cetuximab

+ RT p-valuea

Mucositis/stomatitis 52% 56% 0.44

Dysphagia 30% 26% 0.45

Radiation dermatitis 18% 23% 0.27

Xerostomia 3% 5% 0.32

Fatigue/malaise 5% 4% 0.64

Acne-like rash 1% 17% <0.001

Infusion-related reactionsb 0% 3% 0.01

Bonner,J .A., et al. 2006will not increase the incidence of RT side effects

2525

EXTREME StudyPlatinum-Based Chemotherapy

± Cetuximab in Head and Neck Cancer

Vermorken,J .B., et al. N Engl J Med 2008

First line R /M SCCHN

2626

Randomized phase III multicenter study

Treatment: platinum (cisplatin or carboplatin) plus 5-FU, with or without cetuximab

80 sites in 17 European countries

No prior EGFr testing was required for study entry

Patients were stratified according to: Prior chemotherapy KPS (< 80 vs ≥ 80)

Vermorken,J .B., et al. 2006

2727

RANDOMIZED

Group ACetuximab 400 mg/m2 initial dose

then 250 mg/m2 weekly +EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)

+ 5-FU (1000 mg/m2/day IV, d1-4): 3-week cycles

(6 cycles maximum)

Group B

EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)

+ 5-FU (1000 mg/m2/day IV, d1–4):3-week cycles

(6 cycles maximum)

No treatment

Cetuximab

Progressive disease or

unacceptable toxicity

Patients stratified according to:• KPS (<80 vs ≥80)• Prior chemotherapy (yes vs no)


2828

Primary endpoint Overall survival time

Secondary endpoints Duration of response Time to progression Response rate Assessment of quality of life (QoL) Safety


2929

Cetuximab +platinum / 5-FU

(n=222)Platinum / 5-FU

(n=220)Median age (range) 56 years (37–80) 57 years (33–78)

Men / women 89% / 11% 92% / 8%

Recurrence/metastasisLocoregional recurrenceMetastasisa

54%46%

54%46%

Primary metastatic disease 8% 7%aIncluding also distant metastasis and locoregional recurrence


distribution of diseases are average

3030

10.1 months

7.4 months

Patients at risk Survival time (months)

220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3

HR (95% CI): 0.797 (0.644; 0.986)Strat. log-rank test: 0.0362

CTX onlyCetuximab + CTX

Surv

ival

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 3 6 9 12 15 18 21 24

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EXTREME: overall survival


First time R/M SCCHN over 10M in survival.

3131

EXTREME: Progression-free survival (PFS)

Patients at risk PFS time (months)

220 103 29 8 3 1222 138 72 29 12 7

HR (95%CI): 0.538 (0.431, 0.672)Strat. log-rank test: <0.0001

CTX onlyCetuximab + CTX

Prog

ress

ion

free

(%)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

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5.6 months3.3 months


3232

Cetuximab + platinum/5-FU

(n=222)Platinum/5-FU

(n=220) p-valuea

ORR [CR + PR], % [95% CI]

35.6[29.3–42.3]

19.5[14.5–25.4]

0.0001

DCR [CR + PR + SD], %[95% CI]

81.1[75.3–86.0]

60.0[53.2–66.5]

<0.0001


3333

0

5

10

15

20

25

Anemia

Neutro

penia

Thrombo

cytop

enia

Nause

a

Vomitin

g

Diarrhe

aStom

atitis

Dyspn

eaPne

umon

iaAcn

e-like

rash

Infus

ion re

actio

nMos

t rel

evan

t gra

de 3

/4 a

dver

se e

vent

s (%

)

Platinum / 5-FU (n=215) Cetuximab + platinum / 5-FU (n=214)


3535

Type of study Disease Treatment ReferencePhase I Mixed CDDP + cetuximab Shin 2001

Phase I/II/III Pt-sensitive Pt-based CT ±cetuximab

Paclitaxel + cetuximab

Burtness 2005Bourhis 2006

Vermorken 2007Hitt 2007

Phase II Pt-refractory Cetuximab alonePlatinum + cetuximab

Vermorken 2007Baselga 2005Herbst 2005

Cetuximab: summary of clinical studiesin recurrent/metastatic SCCHN

three clinical trials confirm the efficacy, refractory of patientsthe side effects and efficacy hard to balance.

3636

Grades (General Definitions)

· 0 = No adverse event or within normal limits · 1 = Mild adverse event · 2 = Moderate adverse event · 3 = Severe and undesirable adverse event · 4 = Life-threatening or disabling adverse event · 5 = Death related to adverse event

severity of side effects were divided into Grade0-5

Cetuximab side effects of most below the Grade 3,side effects and survival appear positively related .

3737Herbst ,R.S., et al. 2005

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Time (months)0 3 6 9 12 15 18 21 24 27

Prop

ortio

n

28 12 6 3 1 1Grade 024 16 11 5 3 1 1Grade 127 22 15 9 7 4 1 1 1Grade 2/3

Grade 0 Grade 1

Grade 2/3

No. of eventsMedian survival

[95% CI]2.2 months

[1.9–4.3]

27 (96%)Grade 0

24 (100%)5.4 months

[2.7–6.7]

Grade 125 (93%)

7.1 months[4.1–11.1]

Grade 2/3

Overall survival by severity of skin rash

balance the side effects and efficacy, SE can tolerance, handle, encouraged treat

3838

Phase III study: change of QoL* as a function of time Cetuximab + RT significantly improves locoregional control and overall

survival without adversely affecting QoL, maintain quality of life.

Curran ,D., et al. 2007*Postbaseline scores for the QLQ-C30

Glo

bal h

ealth

sta

tus

/ QoL

scor

e 100

80

60

40

20

0

-20

Visit

RadiotherapyRadiotherapy / ERBITUX

Baseline Week 4 Month 4 Month 8 Month 12

3939

TreatmentNo. of

patients RR DCR MSTTP

(median)

Cetuximab1 103 13% 46% 5.9 months 2.3 months

Cetuximab + platinum2 96 10% 53% 6.2 months 2.8 months

Cetuximab + CDDP3 79 10% 56% 5.2 months 2.2 months

Retrospective study4

All patients 151 3% 15% 3.4 months N/A

CT only 43 0% 9% 3.6 months N/A

1. Vermorken JB, et al. 2007; 2. Baselga J, et al. 2005;23:5568–5573. Herbst RS, et al. 2005; 4. Vermorken JB, et al. 2005;

Cetuximab ±CDDP or a variety of second-linetreatments:clinical outcomes

4040

Cetuximab is also active in second-line setting in patients with platinum-refractory SCCHN

In second-line setting Cetuximab + platinum showed similar results to Cetuximab monotherapy

Vermorken JB, et al. 2007; Baselga J, et al. 2005;Herbst RS, et al. 2005; Vermorken JB, et al. 2005;

Conclusions: platinum-refractory second-line

4141

only proposal of the target treatment on 2008 NCCN guideline

National Comprehensive Cancer Network

Cetuximab as the most effective treatment for different stages of SCCHN,either LA,RT,R/M +cisplain+5Fu and monotherapy.

42

ThanksThanksfor your attentionfor your attention

scch&n cancer report

Health & Medicine

neck cancers scchn

advanced scchn cetuximab

renal cell cancer

line recurmeta scchn

advanced scchn radiotherapy

neck scchn egfrs role

breast cancer

egfr binding blocks