1 Study of target therapy “Cetuximab” on the squamous cell carcinomas of the head and neck (SCCHN) Student ID : Student : H Date :2009
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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.
1818
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
Bonner,J .A., et al. 2006
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
Bonner,J .A., et al. 2006
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
Bonner,J .A., et al. 2006
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)
Vermorken,J .B., et al. 2006
2828
Primary endpoint Overall survival time
Secondary endpoints Duration of response Time to progression Response rate Assessment of quality of life (QoL) Safety
Vermorken,J .B., et al. 2006
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
Vermorken,J .B., et al. 2006
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
Vermorken,J .B., et al. 2006
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
Vermorken,J .B., et al. 2006
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
Vermorken,J .B., et al. 2006
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)
Vermorken,J .B., et al. 2006
34
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.
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ThanksThanksfor your attentionfor your attention