Multimodale Therapie des Kopf

Multimodale Therapie des Kopf-Hals
Karzinoms
Dr. med Konrad Klinghammer
Charité
Klinik für Hämatologie, Onkologie und Immunologie
Campus Benjamin Franklin
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
1
Inzidenz und Mortalität
Inzidenz
4400
11000
male
10500
Mortalität
4200
4000
10000
3800
9500
3600
9000
3400
8500
2002
2004
2006
2008
3200
1995
2010
2000
2005
2010
2000
2005
2010
1400
4500
female
4000
1300
1200
3500
1100
3000
2500
2002
1000
2004
2006
2008
2010
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
900
1995
2
Fallbeispiel 1
Chirurgie
64 Jahre, männlich
Raucher
Oropharynx CA
T3N2M0 – PECA
p16 negativ
Komorbiditäten:
Herzinfarkt vor 2 Jahren
Induktionschemotherapie
Bestrahlung
Radiochemotherapie
Radioimmuntherapie
Radioimmuno-chemotherapie
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
3
Woran orientiert sich die Entscheidung
zur Therapie ?
Chirurgie
Induktionschemotherapie
TNM - Tumorstadium
Alter
Performance status!
Wunsch des Patienten
Radiochemotherapie
Radioimmuno-chemotherapie
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
Bestrahlung
Radioimmuntherapie
4
Die Rolle der Tumorbiologie als
Wegweiser für eine Therapiemodalität?
Die prognostische / prädiktive Bedeutung von
-> HPV
-> p53
-> EGFR
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
Biologisch und klinisch distinkte
Gruppe:
•  p53 und andere genomische
Veränderungen seltener
• Ausmaß der field cancerization
reduziert (seltener Raucher/Trinker)
5
HPV
•  ca. 20 % aller Kopf-Hals-Karzinome (Prevalenz in D unklar!)
•  4- bis 5-fach erhöhtes Risiko eines Kopf-Hals-Karzinoms
nach HPV-Infektion
•  HPV-16 in >90% der HPV+ Fälle
•  vorallem Oropharynxkarzinome (Tonsillen, Zungengrund)
•  steigende Inzidenz in Ländern mit effektiven
Antiraucherprogrammen
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
6
HPV
•  relevanter prognostischer Biomarker (p16/INK4 IHC als
Surrogatmarker)
•  Bessere Therapiewirksamkeit der
-> OP Licitra, J Clin Oncol 2006
-> Rtx Lassen, J Clin Oncol 2009
-> RCtx Ang, NEJM 2010
-> ICT Fakhry, JNCI 2008
-> ICT gefolgt von RCT Fakhry, JNCI 2008
•  Prädiktiver Stellenwert unklar
-> EGFR Blockade schlechter bei HPV+?
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
7
Potentielle prädiktive Biomarker
Die prognostische / prädiktive Bedeutung von
-> HPV
-> p53
-> EGFR
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
8
p53
Prävalenz von p53 Mutationen nach Tumorentität
HNC 41.1%
(2395/5829)
IARC TP53 Mutation Database, T13 Release, Nov 2008
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
9
Potentielle Biomarker
Die prognostische / prädiktive Bedeutung von
-> HPV
-> p53
-> EGFR
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
10
EGFR Signalweg
Cetuximab, Panitumumab...
Ligandenbindung
4 Rezeptoren
EGFR (Her1)
Her2
Her3
Her4
Dimerisierung
Autophosphorylierung
Inhibition von
Tumorwachstum,
DNA Reparatur,
Zellüberleben
Andocken von weiteren Signalmolekülen
Aktivierung des Signalweges
13 Liganden
EGF
HB-EGF
NRG-1α, 1β, 2α, 2β, 3, 4
Epigen
Epiregulin
Betacellulin
TGF-alpha
Amphiregulin
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
11
Mögliche Biomarker für
Wirksamkeit von EGFR Therapie
Bindung von Ligand/EGFR
SNP R521K Klinghammer, CCR 2010
Qualität/Quantität des Liganden
Amphiregulin Tinhofer et al, CCR 2011
Quantität des Rezeptors
Bonner Lancet Oncol 2010, Vermorken
NEJM 2008
EGFR Variante III
Sok, Clin Cancer Res 2006; Tinhofer,
CCR2011
EGFR Mutation
NSCLC [Lynch, NEJM 2004, Paez,
Science 2004]; Oral SCC [Sheu, Cancer
Res 2009]
Her3 Aktivierung
Schäfer, Cancer Cell 2011
Src kinase Aktivierung
Benavente, Clin Cancer Res 2009;
Wheeler, Cancer Biology & Therapy 2009
PI3KCA Mutation
CRC [Jhawer, Cancer Res 2008;
Perrone, Ann Oncol 2009; SartoreBianchi, Cancer Res 2009]
K-Ras Mutation
CRC [Lievre, Cancer Res 2006 & JCO
2008, De Rook, Annal Oncol 2008)
Ras Überexpression
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
12
Resektabel?
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
13
Resektabel – Chirurgie!
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
14
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
15
Induktionschemotherapie
VOLUME
31
!
NUMBER
23
!
AUGUST
10
2013
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Taxane-Cisplatin-Fluorouracil As Induction Chemotherapy
in Locally Advanced Head and Neck Cancers: An Individual
Patient Data Meta-Analysis of the Meta-Analysis of
Chemotherapy in Head and Neck Cancer Group
Pierre Blanchard, Jean Bourhis, Benjamin Lacas, Marshall R. Posner, Jan B. Vermorken,
Juan J. Cruz Hernandez, Abderrahmane Bourredjem, Gilles Calais, Adriano Paccagnella, Ricardo Hitt,
and Jean-Pierre Pignon on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer, Induction
Project, Collaborative Group
See accompanying editorial on page 2844
Pierre Blanchard, Jean Bourhis, Benjamin
A B S T R A C T
Lacas, Abderrahmane Bourredjem, and
Jean-Pierre Pignon, Institut Gustave
Purpose
Roussy, Villejuif; Gilles Calais, Centre
Cisplatin plus fluorouracil (PF) induction chemotherapy has been compared with taxane (docetaxel
Hospitalier Regional Universitaire, Tours,
or paclitaxel), cisplatin, and fluorouracil (Tax-PF) in randomized trials in locoregionally advanced
France; Marshall R. Posner, Mount Sinai
School of Medicine, New York, NY; Jan B.
head and neck cancers (LAHNCs). The aim of this meta-analysis was to study the efficacy and
Vermorken, Antwerp University Hospital,
toxicity of Tax-PF and PF and identify differences in outcomes in subsets of patients.
Edegem, Belgium; Juan J. Cruz HernanMethods
dez, Spanish Head and Neck Cancer CoopFive randomized trials representing 1,772 patients were identified. Updated individual patient data
erative Group, Madrid; Ricardo Hitt, Centro
Integral Oncológico
Clara
Campal,
Madrid,
(IPD)
were retrieved for all trials. The log-rank test, stratified by trial, was used for comparison. 16
COMPREHENSIVE CANCER CENTER
I UNIVERSITÄTSTUMORZENTRUM
Spain; and Adriano Paccagnella, Ospedale
5 randomisierte Studien, die >1700 Patienten eingeschlossen
haben zeigen, dass TPF besser ist als PF...
Induktionschemotherapie
Oral Oncology 48 (2012) 1076ç 1084
Contents lists available at SciVerse ScienceDirect
Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology
Review
Induction chemotherapy decreases the rate of distant metastasis in patients
with head and neck squamous cell carcinoma but does not improve survival
or locoregional control: A meta-analysis
Jie Ma a,d, Ying Liu a,d, Xiao-Lu Huang a, Zhi-Yuan Zhang a,c, Jeffrey N. Myers b, David M. Neskey b,
Lai-Ping Zhong a,⇑
a
Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People' s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine,
Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China
b
Department of Head & Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
i n f o
s u m m a r y
Induktionschemotherapie
ist kein therapeutischer Standard
und sollte lediglich im Rahmen von Studien für definierte
Gruppen evaluiert werden
a r t i c l e
Article history:
Received 2 March 2012
Received in revised form 16 June 2012
Accepted 19 June 2012
Available online 15 July 2012
The deÄ nitive effect of induction chemotherapy (IC) on locally advanced head and neck squamous cell
carcinoma (HNSCC) remains uncertain and although randomized controlled trials are supposed to provide high levels evidence for clinical guidelines, the data thus far has been conÅ icted. In an effort to elucidate the potential beneÄ t of IC, a meta-analysis of randomized controlled trials (1965ç 2011) was
performed investigating the impact of IC on survival, locoregional control, distant metastasis, and toxicity
in HNSCC. Kaplanç Meier curves were read by a digitizing software-Engauge Digitizer. Data combination
Keywords:
was performed using the software-RevMan and trial level log hazard ratio (HR) and variance were pooled
CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
17
Head and neck COMPREHENSIVE
squamous cell carcinoma
and presented. Among the 40 eligible trials, 28 trials encompassing 4189 patients receiving locoregional
Radioimmuntherapie
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Patients Randomly Assigned to Radiotherapy plus Cetuximab or Radiotherapy Alone.
The hazard ratio for locoregional progression or death in the radiotherapyplus-cetuximab group as compared with the radiotherapy-only group was
0.68 (95 percent confidence interval, 0.52 to 0.89; P = 0.005 by the logrank test). The dotted lines indicate the median durations of locoregional
control.
original article
100
Overall Survival (%)
Radiotherapy plus Cetuximab for SquamousCell Carcinoma of the Head and Neck
James A. Bonner, M.D., Paul M. Harari, M.D., Jordi Giralt, M.D.,
Nozar Azarnia, Ph.D., Dong M. Shin, M.D., Roger B. Cohen, M.D.,
Christopher U. Jones, M.D., Ranjan Sur, M.D., Ph.D., David Raben, M.D.,
Jacek Jassem, M.D., Ph.D., Roger Ove, M.D., Ph.D., Merrill S. Kies, M.D.,
T h e n e w e ng l a n d j o u r na l
Jose Baselga, M.D., Hagop Youssoufian,
M.D., Nadia Amellal, M.D.,
Eric K. Rowinsky, M.D., and K. Kian Ang, M.D., Ph.D.*
29.3 vs 49 months
80
60
Radiotherapy plus cetuximab
40
Radiotherapy
20
of
m e dic i n e
0
0
10
20
30
40
50
60
47
61
22
24
Months
No. at Risk
100
DIS
CUS SION
213
Radiotherapy
A BS T R AC T
211
Radiotherapy
plus cetuximab
162
177
122
136
97
116
73
98
70
timely comp
improvemen
therapy plu
therapy alo
centage poi
with the gr
been demo
compared w
The sup
therapy reg
underperfor
efficacy res
results with
poraneous
some trials
control with
similar or s
trials that u
schemes an
Furthermor
locoregiona
sistent sepa
the additio
radiotherap
ter the comp
the numbe
years after
further foll
How do
cols for the
For many ye
able option
vanced hea
Locoregional Control (%)
An exceptional feature of this randomized, phase
3 trial, which was
carried
among
patients
Figure
2. Kaplanñout
Meier
Estimates
of Overall Survival among All Patients
14.9 vs 24.4 months
Randomly
Assigned
to Radiotherapy
plus Cetuximab or Radiotherapy
BACKGROUND
with head and neck
cancer
who were
treated with
Alone.
We conducted
alone
From was
the Department
of Medicine,
Uni60 a multinational, randomized study to compare radiotherapy
curative
intent,
the finding
of a survival
adThe
hazard ratio
for death
in the radiotherapy-plus-cetuximab group as
versity of
Alabama,
Birmingham
( J.A.B.,
with radiotherapy plus cetuximab, a monoclonal
antibody
against
the
epidermal
Radiotherapy plus cetuximab
vantage associated
with with
theofthe
use
ofOncola molecular
compared
radiotherapy-only
group was 0.74 (95 percent confiR.O.); the
Department
Human
growth factor
receptor, in the treatment of locoregionally advanced squamous-cell
dence interval,
0.57 to 0.97;
P = 0.03
by the log-rank test). The dotted lines
ogy, University
of Wisconsin,
Madison
targeting agent,
cetuximab,
delivered
in
conjunc40
carcinoma of the head and neck.
(P.M.H.);
the Services
of Radiation
indicate
median
survivalOntion with radiation.
Wethefound
that
thetimes.
addition
cology ( J.G.) and Oncology ( J.B.), Vall
dí Hebron
University Hospital,
Barcelona; signifiof cetuximab
to high-dose
radiotherapy
Radiotherapy
METHODS 20
ImClone Systems, New York (N.A., H.Y.,
cantly
increased
both
the
duration
of control of
Patients with locoregionally advanced head and neck cancer were randomly as- E.K.R.); the Divisions of Cancer Medicine
locoregional
disease
and
survival
among
patients
(D.M.S.,
M.S.K.)
and
Radiation
Oncology
0
signed to treatment
with high-dose radiotherapy alone (213 patients) or high-dose
(K.K.A.),
University of Texas M.D. Ander0
10
20
30
40
50
60
70
574
n engl j med 354;6 www.nejm.org febru
withmglocoregionally
head and neck canradiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400
per son Cancer advanced
Center, Houston; the DepartMonths by 250 mg per square metercer.
These
were achieved
without
square meter of body-surface area, followed
weekly
for benefits
ment of Medicine,
University of
Virginia, the pro(R.B.C.);often
Radiological
Asthe atduration
of radiotherapy. The primary end point was the duration ofhibitive
control in-field
of Charlottesville
No.
Risk
toxic effects
associated
with
sociates of Sacramento, Sacramento,
The New England Journal of Medicine
213
122
80 end51points30were overall
10
Radiotherapy
locoregional disease;
secondary
survival, progression-free
high-dose
radiotherapy
the
head
and
neck.
Calif.
(C.U.J.);
the to
Department
of RadiaDownloaded
from
www.nejm.org
at CHARITE
CAMPUS
CHARITE MITTE MEDIZINISCHE BIBLIO on Septem
211
143
101
66
35
9
Radiotherapy
survival,
the response rate, and safety.
tion Oncology; University
of WitwatersCopyright © 2006 Massachusetts Medical Society. All rig
Moreover, concomitant
treatment
with radiotherplus cetuximab
rand, Johannesburg (R.S.); the Departapy and cetuximab
did
not
adversely
affect
the
ment of Radiation Oncology, University
RESULTS
Figure
1. Kaplanñ Meier Estimates of Locoregional Control among All
of Colorado,
Aurora (D.R.);radiotherapy.
the Departtimely completion
of definitive
The
Patients
Randomly
Assigned
Radiotherapycontrol
plus Cetuximab
Radio- among patients ment of Oncology and Radiotherapy,
The median
duration
of to
locoregional
was 24.4or months
improvements in outcome achieved with radiotherapy
treatedAlone.
withCOMPREHENSIVE
cetuximab plus
radiotherapy
14.9 months among those given ra- Medical University of Gdansk, Gdansk,
CANCER
CENTER and
I UNIVERSITÄTSTUMORZENTRUM
18
(J.J.); and Merck,
Darmstadt, Gertherapy plusPoland
cetuximab,
as compared
with radio80
Synergismus von
Bestrahlung und EGFR
Blockade erstmalig
etabliert
Contents lists available at ScienceDirect
Oral Oncology
Platin basierte Radio-Chemotherapie
journal homepage: www.elsevier.com/locate/oraloncology
Review
Concomitant platinum-based chemotherapy or cetuximab with
radiotherapy for locally advanced head and neck cancer: A systematic
review and meta-analysis of published studies
Fausto Petrelli a,⇑, Andrea Coinu a,1, Valentina Riboldi b,2, Karen Borgonovo a,1, Mara Ghilardi a,1,
Mary Cabiddu a,1, Veronica Lonati a,1, Enrico Sarti b,3, Sandro Barni a,1
a
b
Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio, BG, Italy
F. Petrelli et al. / Oral Oncology xxx (2014)
Radiotherapy Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio, BG, Italy
a r ortSubgroup
i c l e
Study
Favour CDDP + RT Favour Cetuximab + RT
Risk Ratio
s u m m
a rWeight
y
M-H, Random, 95% CI Year
Total
Events
Total
i n fEvents
o
103
35
Caudell
Article2008
history:
Received 6 June 2014
125
9
Koutcher
2011/Riaz 2014
Received in revised form 9 August 2014
38
16
Jensen
201112 August 2014
Accepted
Available online xxxx
79
33
Beijer
2012
113
25
Borchiellini
2012
Keywords:
Head
261
107
Ghi
2013and neck cancer
Locally advanced
46
22
Pajares
2013 HPVChemoradiotherapy
Cisplatin
18
3
Ley
2013
Cetuximab
10
4
Pajares
2013
HPV+
Overall survival
60
10
Lefebvre 2013
76
26
Fayette 2013
120
11
Tang 2014
Total (95% CI)
xxxç xxx
Risk Ratio
M-H, Random, 95% CI
1.64 [0.77,
3.52]plus2008
29 7.7%
6 combinations
The
of radiotherapy
(RT)
chemotherapy (CTRT) with cisplatin or, alternatively, RT plus
cetuximab
(RT
CET), are the
of choice for locally advanced squamous cell carcinoma of the
0.22treatments
[0.10, 0.47] 2011
49 + 7.8%
16
head and neck (HNSCC). We performed a systematic review and meta-analysis of published studies
0.89 [0.54, 1.47] 2011
38 9.5%
18
reporting the efÄ cacy of these 2 combined modality therapies for the treatment of locoregionally
2012 search of PUBMED, EMBASE, Web of Science, SCOPUS,
0.65 [0.44,a 0.97]
25 10.3%
16
advanced
HNSCC.
We performed
systematic
and
Register 0.45
of Controlled
Trials. Meta-analysis was performed using the Ä xed- or ran[0.29, 0.70] 2012
51 9.9%
25 the Cochrane
dom-effects models. The primary endpoints were 2-year overall survival (OS), 2-year progression-free
2013 (LRR), reported as risk ratios (RRs) and 95% conÄ dence
1.17 [0.91, 1.51]relapse
11.1%2-year locoregional
160 and
56
survival
(PFS),
intervals
(CIs).
1.11 [0.70, 1.74] 2013
44 9.9%
19
a 0.28
total[0.10,
of 1808
were analysed. Three of these trials were prospective,
2013
0.83] patients,
5.7%
29 including
17Fifteen trials,
and 12 were retrospective. Overall, for locally advanced HNSCC, concomitant CTRT signiÄ cantly improved
3.200.46ç
[0.44,0.94;
23.28]P =2013
2.6% 95% CI,
8 = 0.66;
1
2-year
OS (RR
0.02), 2-year PFS (RR = 0.68; 95% CI, 0.53ç 0.87; P = 0.002), and
2-year
LRR
(RR
=
0.63;
95%
CI,
0.45ç
0.87; 2013
P = 0.005) compared to RT + CET. For the treatment of locally
0.93 [0.42, 2.07]
56 7.4%
10
advanced HNSCC, platinum-based CTRT is associated with a better OS and PFS compared to RT + CET,
0.63 [0.41, 0.97] 2013
37 10.0%
20
and this is probably attributed to improved locoregional disease control. Thus, platinum-based CTRT
2014
[0.09, until
0.37] equivalence
8.2%
24
12
should remain the standard0.18
of care
with RT + CET can be prospectively demonstrated.
! 2014 Elsevier Ltd. All rights reserved.
1049
550 100.0%
0.66 [0.46, 0.94]
Platin-basierte
Radiochemotherapie
ist der
therapeutischer
Standard beim nicht
resektablen KopfHals Karzinom
216
301
Total events
Heterogeneity: Tau² = 0.29; Chi² = 56.72, df = 11 (P < 0.00001); I² = 81%
Introduction
Test for overall effect: Z = 2.28 (P = 0.02)
0.2 to single
1
5
20 treatment, the addithe aim of cure.0.05
Compared
modality
Favours
RT + CT Favours
RT +tocetuximab
tion of concomitant
chemotherapy
(CT)
RT increases the 5-year
The treatment of choice for locally advanced/inoperable squaoverall survival (OS) rate by 6.5%, especially for patients with oromous cell carcinoma of the Fig.
head2.and
neck (HNSCC)
concomitant
pharynx
and larynx
Meta-analysis
ofis2-year
overall survival
(forest
plots). tumours, according to a meta-analysis of ranplatinum-based chemoradiotherapy (CTRT) because it improves
domised studies [1,2]. Based on National Comprehensive Cancer
locoregional control compared to radiotherapy (RT) alone. ChemoNetwork guidelines, single agent cisplatin (CDDP) at a dose of
Favour
RT Favour
Cetuximab
+ RT
Ratiomg/m2 every 3 weeks Risk
Ratio RT is the systemic agent of
during
radiation moreover is
the CDDP
Ä rst +choice
when
organ preservation
is Risk100
COMPREHENSIVE
CANCER
CENTER
I
UNIVERSITÄTSTUMORZENTRUM
95%preferred
CI
95%CTRT
CI Yearwith CDDPM-H,is Random,
Total Weight M-H, Random,
Events
Total
Events
Study or Subgroup
choice.
also the
combined therapy
19
63.6%) for arm B (P ! .76). The 3-year probabilities for OS were
More treatment-related grade 5 adverse events took place in the
72.9% (95% CI, 68.7% to 77.1%) for arm A and 75.8% (95% CI,
cetuximab arm (10 events in arm B v three events in arm A; P ! .05).
VOLUME 32 ! NUMBER 27 ! SEPTEMBER 20 2014
71.7% to 79.9%) for arm B (P ! .32); the 3-year LRF probabilities
However,
death rates within 30 days of treatment completion were
were 19.9% (95% CI, 16.2% to 23.7%) for arm A and 25.9% (95%
similar between the two arms (2.0% with cetuximab v 1.8% without;
O 21.7%
R I GtoI 30.1%)
N A Lfor R
E BP(PO!R.97);
T and the 3-year DM
J
OURNAL
OF
C
LINICAL
O
NCOLOGY
CI,
arm
P ! .81). Table 2 lists the distribution of worst grade adverse effects.
probabilities were 13.0% (95% CI, 9.9% to 16.2%) for arm A and
The cetuximab arm had significantly higher rates of grade 3 to 4 skin
9.7% (95% CI, 6.9% to 12.6%) for arm B (P ! .08).
reactions (both inside and outside radiation volumes), radiation muTrends were noted toward differential cetuximab treatment efcositis, fatigue, anorexia, and hypokalemia up to 90 days from the start
fects in patients with OPCs with known p16 status. For PFS, the
of therapy. However, no significant differences were observed between
treatment effect HRs were 1.57 for p16-positive OPC and 0.86 for
the arms in rates of adverse effects after 90 days. In arms A and B, rates
Phase
III Trial
of Concurrent
Accelerated
p16-negative
OPC (P for interaction
! .12); imputation and adjustof feeding tube dependency wereRandomized
21.2% (95% CI, 17.2%
to 25.7%)
ment for
prognostic
factors reduced for
these HRs (1.29 v 0.92,
and 18.8% (95% CI, 15.0% to 23.2%)
at 1 year (P Plus
! .47), Cisplatin
13.5% (95% With
Radiation
orknown
Without
Cetuximab
respectively;
P
for
interaction
!
.31).
For
OS,
the corresponding HRs
CI, 10.0% to 17.8%) and 11.9%Stage
(95% CI,III
8.6%
to
15.9%)
at
2
years
to
IV
Head
and
Neck
Carcinoma:
RTOG
0522
were 1.42 for patients with p16-positive OPC and 0.69 for patients
(P ! .56), and 12.1% (95% CI, 8.4% to 16.8%) and 7.0% (95% CI,
K. Kian Ang,† Qiang Zhang, David I. Rosenthal, Phuc Felix Nguyen-Tan, Eric J. Sherman, Randal S. Weber,
with p16-negative OPC (P for interaction ! .13); after imputation and
4.2% to 10.8%) at 3 years (P ! .05),
respectively.
James M. Galvin, James A. Bonner, Jonathan Harris, Adel K. El-Naggar, Maura L. Gillison, Richard C. Jordan,
A
Garden, The 100
University of Texas MD
Anderson Cancer Center, Houston, TX;
Qiang Zhang and Jonathan Harris, Radia-
See accompanying editorial on page 2929
A
B
B
S
Progression-Free
Survival (%)
80
tion Therapy Oncology
Group Statistical
100
T
Overall Survival (%)
K. Kian Ang, David I. Rosenthal, Randal S.
Weber, Adel K. El-Naggar, and Adam S.
Andre A. Konski, Wade L. Thorstad, Andy Trotti, Jonathan J. Beitler, Adam S. Garden, William J. Spanos,†
Sue S. Yom, and Rita S. Axelrod
R
A
C
T
80
Purpose
Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with
60
stage III or IV head and neck carcinoma (HNC). Cetuximab
plus platinum regimens also increase
OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the
York, NY; James A. Bonner, University of
hypothesis that adding cetuximab to the radiation-cisplatin
platform improves progression-free
HR (95% CI) [Arm B/Arm A]
HR (95% CI) [Arm B/Arm A]
40
40
Alabama at Birmingham, Birmingham, AL;
survival (PFS).
1.08 (0.88 to 1.32)
0.95 (0.74 to 1.21)
Center; James M. Galvin and Rita S. Axel-
rod, Thomas Jefferson University Hospital,
60Eric J. Sherman, MemoPhiladelphia, PA;
rial Sloan Kettering Cancer Center, New
Maura L. Gillison, The Ohio
State log-rank
Univer1-sided
P = .76
sity, Columbus, OH; Richard C. Jordan and
Patients and Methods
20
Sue S. Yom, University of California, San
Eligible patients with
RT + cisplatin (Arm A)
1-sided log-rank P = .32
20
stage III or IV HNC were randomly assigned
to receive
and cisplatin
RT + cisplatin
(Arm radiation
A)
Francisco, San Francisco, CA;
A.
RTAndre
+ cisplatin
+ cetuximab
B) A) or with (arm B) cetuximab. Acute and late reactions
RT + cisplatin
+ cetuximab
(Arm B)Common
without(Arm
(arm
were
scored using
Konski, Karmanos Cancer Institute/Wayne
Terminology
Criteria
for
Adverse
Events
(version
3).
Outcomes
were
correlated
with
patient and
State University, Detroit, MI; Wade L.
0
1
Thorstad, Washington University School of
Medicine, St Louis, MO; Andy Trotti, H.
Lee Moffitt Cancer Center and Research
2tumor features
3
4 markers.
5
and
0
Time Since Random
ResultsAssignment (years)
1
2
3
4
5
Time Since Random Assignment (years)
No.
at risk
Of 891 analyzed patients, 630 were alive at
analysis
(median follow-up, 3.8 years). Cetuximab
282
241
118
36 cisplatin-radiation
Arm A alone,
447 resulted
386in more
344
138
plus cisplatin-radiation,
versus
frequent287
interruptions
263
234
108
38
Arm B
444
383
339
295
134
in radiation therapy (26.9% v 15.1%, respectively); similar cisplatin delivery (mean, 185.7
GA; William J. Spanos, University of Louis2
2
ville School of Medicine, Louisville, KY; and
mg/m v 191.1 mg/m , respectively); and more grade 3 to 4 radiation mucositis (43.2% v
Phuc Felix Nguyen-Tan, Centre Hospitalier
33.3%, respectively), rash, fatigue, anorexia,
hypokalemia, but not more late toxicity. No
100
C
D and100
de l’Université de Montréal, RT
Montréal,
+ cisplatin (Arm
A)
RT + cisplatin
(ArmvA)2.0%, respectively;
differences
were found between arms A and B in 30-day mortality
(1.8%
Quebec, Canada.
RT + cisplatin + cetuximab
(Arm3-year
B)
+ cisplatin
+ cetuximab
(Arm B)v 75.8%,
P ! .81),
PFS (61.2% v 58.9%, respectively; P !RT.76),
3-year
OS (72.9%
†Deceased. 80
respectively; P ! .32), locoregional failure (19.9%80
v 25.9%, respectively; P ! .97), or distant
Published online ahead of print at
metastasis
(13.0% v 9.7%, respectively; P ! .08). Patients
with
p16-positive
oropharyngeal
HR (95% CI) [Arm B/Arm
A]
HR (95%
CI) [Arm
B/Arm A]
www.jco.org on August
25,(0.99
2014.to 1.70)
carcinoma (OPC), compared with patients with p16-negative
OPC,
had better 3-year probability
1.30
0.76 (0.51
to 1.13)
60
60
1-sidedatlog-rank
1-sided
log-rank
P = .08
of PFS (72.8% v 49.2%, respectively; P " .001) and OS
(85.6%
v 60.1%,
respectively; P "
Support information appears
the end P = .97
of this article.
.001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome.
No. at risk
Institute, Tampa, FL; Jonathan J. Beitler,
Arm A
447
317
Emory Healthcare, Emory Clinic, Atlanta,
Arm B
444
309
41
43
40
The contents of the article are the sole
COMPREHENSIVEConclusion
CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
responsibility of the authors and do not
ant Metastasis (%)
Locoregional
Failure (%)
Die Hinzunahme von Cetuximab zur platinbasierten Radiochemotherapie
führt nicht zu verlängerten Überleben, noch zu verringerter Rate an
Lokalrezidiven oder Fernmetastasierung
40
Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be
20
Therapiebausteine im Rezidiv/metastasierten
Erkrankungsstadium
Platinderivate
•  Cisplatin
•  Carboplatin
Taxane
•  Docetaxel
•  Paclitaxel
Antimetabolite
•  5 FU
•  MTX
EGFR Antikörper
•  Cetuximab
•  Panitumumab
Platinum–5-FU
doublets
1970
1980
1990
Efficacy of cisplatin
established
Cetuximab + CT
2000
2010
Taxane + cisplatin equal to
5-FU + cisplatin
Combination therapy
(CABO)
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
21
Kombinationsbehandlung vs Single agent in rez/
met HNSCC: Randomized Phase III trials
N
Agents
Response rate
(%)
Jacobs (1992)
249
CisP, 5-FU
CisP
5-FU
32a
17
13
5.5
5.0
6.1
Forastiere (1992)
277
CisP, 5-FU
CarP, 5-FU
M
32b
21
10
6.6
5.0
5.6
Clavel (1994)
382
CisP, MBV
CisP, 5-FU
CisP
34c
31d
15
6.7
6.7
6.7
Gibson (2005)
218
CisP, 5-FU
CisP, Pac
27
26
8.7
8.1
Reference
Median OS,
months
ap=0.035
vs P, p=0.005 vs F; bp<0.001; cp<0.001; dp=0.003.
B=bleomycin; CarP=carboplatin; M=methotrexate; CisP=cisplatin; Pac=paclitaxel; V=vincristine.
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
22
Cetuximab in 1st-line r/m SCCHN
EXTREME: Phase III Studiendesign
r/m SCCHN
Stratified by
•  Prior CT
Cetuximab until PD
CT
•  KPS (<80 vs ≥80)
N=442
CT
Cisplatin (100 mg/m2 IV, day 1) or
Carboplatin (AUC 5, day 1) +
5-FU (1000 mg/m2/day IV, days 1–4)
Every 3 weeks, up to 6 cycles
CT
Cetuximab
Initial dose 400 mg/m2
then 250 mg/m2 weekly
until PD
Primary endpoint: OS
Secondary endpoints include: PFS, RR, safety
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
Vermorken JB, et al. N Engl J Med 2008;359:1116-1127
23
EXTREME
b in Head and Neck Cancer
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
1.0 | | | | |
Hazard ratio (95% CI): 0.80 (0.64ñ 0.99)
|
0.9
|
P=0.04
||
0.8
||
|
0.7
|
0.6
Chemotherapy plus
0.5
|
cetuximab (N=222)
0.4
|
|
| | | ||||
| | |||
0.3
| |
|
Chemotherapy (N=220)
| || | |
|| |||
| ||
|| |
| ||
||
|||
0.2
|| |
|||| | | |
| |||
| | | | || | |
| | |||| ||| |
0.1
Jan B. Vermorken, M.D., Ph.D., Ricard Mesia, M.D., Fernando Rivera, M.D., Ph.D.,
0.0
Eva Remenar,
Andrzej
M.D.,
Ph.D.,21Sylvie
0 M.D.,
3
6
9Kawecki,
12
15
18
24 Rottey, M.D., Ph.D.,
original article
Platinum-Based Chemotherapy
plus Cetuximab in Head and Neck Cancer
Jozsef Erfan, M.D., Dmytro Zabolotnyy,
'%) M.D., Ph.D., Heinz-Roland Kienzer, M.D.,
Didier Cupissol, M.D., Frederic Peyrade, M.D., Marco Benasso, M.D.,
)&
Chemother apy plus Cetuximab in Head and Neck Cancer
Vynnychenko,
Dominique
M.D.,
Chemotherapy Ihor220
173
127 M.D.,
83 Ph.D.,
65
47
19
8De Raucourt,
1
Chemotherapy
184
153M.D.,
118 Armin
82 Schueler,
57
30 M.S.,
15 Nadia
3
Carsten222
Bokemeyer,
Amellal, M.D.,
plus cetuximab
and Ricardo
Hitt,cisplatinñ
M.D., Ph.D.
ceiving
fluorouracil alone could not tol
erate cisplatin and were switched to carboplatin.
1.0
A
bs
t
r
ac
t
Hazard ratio (95% CI): 0.80 (0.64ñ
Of the 413 tumors that were tested by immunohis1.0
0.9
Hazard ratio (95% CI): 0.54 (0.43ñ 0.67)
P=0.04
0.9
P<0.001tochemical analysis, 98% had detectable EGFR,
0.8
Background
0.8
0.7
and more than 80% had 40% or more EGFR-posiis effective in platinum-resistant recurrent or metastatic squamous-cell
Ede- Cetuximab0.7
0.6
tive
cells.
Chemotherapy plus
Hos- carcinoma of
0.6 the head and neck. We investigated the efficacy of cetuximab plus plati0.5
cetuximab (N=222)
um;
0.5
0.4
chemotherapy as first-line treatment in patients with recurrent or metatalet num-based 0.4
Compliance plus
0.3
head and neck.
Chemotherapy (N=220)
pital static squamous-cell carcinoma of the Chemotherapy
0.3
cetuximab
(N=222)
The
median
duration of treatment with cetux0.2
SanMethods 0.2
0.1
bre,
imab was 18 weeks (interquartile range, 8 to 29).
220 of
442 eligible patients with untreated recurrent or meta0.1 assigned
Chemotherapy
(N=220)
agos We randomly
0.0
For
84%
of
the
patients,
the
relative
dose
inten0.0
0
3
6
9
12
15
18
21
and static squamous-cell
carcinoma of the head and neck to receive cisplatin (at a dose of
0
3
6
9 cetuximab
12
15
sity of
(the
amount
given(atover
a speciAn- 100 mg per square
meter of body-surface
area
on
day
1)
or
carboplatin
an
area
'%)
h e n e w e ng l a n d j o u r na l o f m e dic i n e
h in
'%)
fiedTtime
as a proportion of the planned amount)
)&
mo- under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion
was
80%
or
more
aftermeter
the initial
dose
400 mg
)&
Chemotherapy
220
173
127
83
65
47
19
8
.K.); on day 1) plus fluorouracil (at a dose of 1000 mg per
square
per day
for of
4 days)
220
103
29
8
3
1 of 100 patients received
Chemotherapy
222
184
153
118
82
57
30
15
y ofChemotherapy
per
square
meter.
A
total
every 3 weeks222
for a maximum
of726 cycles and
to7receive the same chemoChemotherapy
138 and Survival.*
29 222 patients
12
plus cetuximab
.Z.);Table
2. Responses to Treatment
cetuximab monotherapy during the maintenance
plus cetuximab
umy therapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour
period,
with
a median
duration
of treatment
per
square
meter,
as a 1-hour
intravenous
infu- of oltz- intravenous infusion, then 250 mgCetuximab
plus
Figure 2. Kaplanñ Meier Estimates of Overall Survival and
Progression-free
Re- sion per week) for a maximum of
Platinumñ
Fluorouracil
Platinumñ
Fluorouracil
Alone
Hazard Ratio or Odds Ratio 1.0
11
weeks.
For
82%
of
the
patients,
the
relative
6
cycles.
Patients
with
stable
disease
who
received
Survival According toAUTHOR:
the Treatment
Group.
1st
RETAKE
Vermorken
Hazard ratio (95% CI): 0.54 (0.43ñ
nna
Variable
(N = 222)
(N until
= 220)
P Value
ICM
dose
intensity
of
cetuximab
was
80%
or
more (95% CI)
chemotherapy
plus
cetuximab
continued
to
receive
cetuximab
disease
pro0.9
2nd
P<0.001
marREG F FIGURE: 2 of 4
0.8
3rd
ó moÜor unacceptable toxic effects,
gression
whichever
occurred
first.
during
this maintenance
period. Patients in the
llierSurvival
CASE
Revised
Nice
cetuximab
group received
a median
of five
cy- ratio, 0.80 (0.64ñ 0.99)0.7 0.04á
Results
Line 10.1
4-C
Overall EMail
(8.6ñ 11.2)
7.4 (6.4ñ
8.3)
Hazard
!
Caen
0.6
Efficacy
ARTIST: ts
H/T
H/T of chemotherapy,
cles
and
patients
in the
che- ratio, 0.54 (0.43ñ 0.67)0.5 <0.001á
cetuximab
to platinum-based
chemotherapy
(platinumñ
fluo22p3 with fluorouracil
ion- Adding
Enon
Progression-free
5.6
(5.0ñ
6.0)
3.3
(2.9ñ
4.3)
Hazard
Combo
The median
survival
was
10.1
monthsoverall survival
Italy
rouracil) overall
significantly
prolonged
themotherapy-alone
median
7.4 months
in of
thefour
group from
received
a median
0.4
Chemotherapy plus
%
Best
response
to
therapy
ó
haus
(95%chemotherapy-alone
confidence$%)'#*''#(%)')
interval group
[CI], 8.6
to 11.2)
in the
to 10.1
months
in the group that received chemotherapy
0.3
cycles.
cetuximab (N=222)
.B.);
COMPREHENSIVE
CANCER
CENTER
Overall
36 (29ñ
42)
20
(15ñ
25) 0.64with
Odds ratio, 2.33 (1.50ñ 3.60) 0.2 <0.001ß
)"%"&"
group and(hazard
7.4 months
(95%
CI,
6.4
to
plus
cetuximab
ratio for
death,
0.80;
95%I UNIVERSITÄTSTUMORZENTRUM
confidence
interval,
to 0.99;
The
median
duration of
treatment
cispla)cetuximab
ó
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24
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24
Fallbeispiel 2
•  64 Jahre, männlich, 15 pck yrs
•  Exzessiver Alkoholkonsum vor mehr als 10 Jahren –
seitdem trocken
•  Initial: Zungengrundkarzinom, T3 N2, p16++
•  Initiale Behandlung: Radiochemotherapie
•  Rezidiv 4 Jahre später, p16++
•  Komorbiditäten
–  COPD (ohne Infektkomplikationen seit 2 Jahren)
–  IDDM seit 6 Jahren
–  Niereninsuffiziens seit Radiochemotherapie
(clearance 60 ml/min)
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
25
rT3, rN2, rM1
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
26
Überlegungen zum EXTREME Protokoll
Carboplatin gegenüber Cisplatin gleichwertig?
Cetuximab oder Panitumumab?
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
27
1st line r/m SCCHN: cetuximab increases RR
regardless of which platinum CT used
Cisplatin-based CT
p=0.0035
38.9
Carboplatin-based CT
p=0.0267
30.4
23.0
15.0
Cisplatin/
5-FU
(n=135)
Cisplatin/
5-FU +
Cetuximab
(n=149)
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
Carboplatin/
5-FU
(n=80)
Carboplatin/
5-FU +
Cetuximab
(n=69)
Vermorken JB. Springer Science+Business Media 2011:651–664
28
p16 in r/m SCCHN – SPECTRUM trial
● SPECTRUM trial (panitumumab)
Ø No OS benefit when adding panitumumab to CT
Ø Benefit for panitumumab only in p16- subgroup
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
29
p16 in r/m SCCHN – EXTREME trial
p16− patients
p16+ patients
HR (95% CI) 0.63 (0.30–1.34)
p-value
0.22
1.0
0.9
Overall survival
Overall survival
0.9
HR (95% CI)
p-value
1.0
0.8
0.8
0.7
0.82 (0.65–1.04)
0.11
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
CT + cetuximab (n=18)
CT (n=23)
0.1
CT + cetuximab (n=178)
CT (n=162)
0.1
0.0
0.0
0
3
6
9
12
15
18
21
24
27
0
3
6
9
12
Months
15
18
21
24
27
Months
Number of patients at risk
Number of patients at risk
18
15
12
11
10
8
6
4
1
0
178
150
126
93
61
40
19
10
1
0
23
18
17
12
7
6
3
2
1
0
162
128
92
56
47
33
15
6
0
0
HRs are CT + cetuximab vs CT
COMPREHENSIVE
CI, confidence
interval; HR,CANCER
hazardCENTER
ratio I UNIVERSITÄTSTUMORZENTRUM
30
Behandlungsverlauf
Entscheid für Carboplatin/5FU/Cetuximab
• 
• 
• 
• 
• 
• 
Zyklus 1: Patient berichtet besser schlucken zu können
Zyklus 2: Tumorsymptomatik nicht mehr vorhanden, PR
Hospitalisierung wg Fieber, Diarrhoe und Exsikkose
Supportivmaßnahmen & Antibiose -> Verbesserung
Zyklus 4: sehr gute PR
Hospitalisierung wg Fieber, Diarrhoe und Exsikkose
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
31
Restaging nach 4 Zyklen
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
3232
Cetuximab Erhaltungstherapie
Overall survival (%)
100
90
CT (n=220)
80
Cetuximab + CT (n=222)
HR=0.80 (95% CI: 0.64–0.99)
p=0.04
70
60
10.1 months
50
Duration
of
ChemoTherapy
40
30
20
+ 2.7 months
7.4 months
10
0
0
3
6
9
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
12
Months
15
18
21
24
Vermorken JB, et al. N Engl J Med 2008;359:1116–1127
33
Behandlunsverlauf II
• 
• 
• 
• 
• 
• 
Chemotherapie beendet
Cetuximab Erhaltungstherapie
PR ohne Komplikationen über 2 Jahre
Toxizität Grad 1-2 Hautreaktion
Gute Lebensqualität
Nach 2 Jahren – Auftreten einer einzelnen
Hirnmetastase
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
34
Einzelne Hirnmetastase – wie weiter ?
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
3535
Behandlungsverlauf III
•  Cyberknife Radiotherapie
•  Cetuximab Erhaltungstherapie weiter
•  Erkrankungskontrolle bis heute
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
36
Interdisziplinäre Arbeitsgruppe
Tumoren der Kopf-Hals-Region (IAG-KHT)
in der der deutschen Krebsgesellschaft
Arbeitsgemeinschaft internistischer Onkologen
Arbeitsgruppe Kopf-Hals-Tumoren
cisplatin (P), fluorouracil (F) and cetuximab (C)
alone or with docetaxel (D)
for recurrent/metastatic head and neck cancer
Arm A (DPFC)
HNSCC
1st-line R/M
ECOG 0-1
Cisplatin, 5-FU, Cetuximab + Docetaxel
weekly regimen
Randomization 1:1
Arm B (PFC)
Cisplatin, 5-FU, Cetuximab
3-weekly regimen
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
37
Progression free survival
Median
(months)
95% CI
― Arm A DPFC
5.4
4.6 – 6.0
― Arm B PFC
5.2
4.0 – 6.3
Log-rank p = 0.725
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
38
Overall survival
Median
(months)
95% CI
― Arm A DPFC
9.4
8.2 – 11.4
― Arm B PFC
11.6
7.3 – 15.8
Log-rank p = 0.192
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
39
ADCC: Antikörper vermittelte Zytotoxität
Lysis of antibody-coated
cell
Namboodiri AM & Pandey JP. Clin Exp Immunol 2011;166:361-5
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
40
ADCC – sind anti-EGFR-AB gleich?
?
Antibody
ADCC
Panitumumab
none
Cetuximab
some
Cetugex
yes
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
41
human
GEXMab 52201
CetuGEXTM –
g (NSCLC), and
A new glycooptimized EGFR antibody
based on Cetuximab
© Glycotope GmbH – Confidential Teaser I xx. Monat Jahr
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RESGEX (Glycotope)
Randomised evaluation of efficacy and safety of CetuGEX in rec/met SCCHN
r/m SCCHN (n = 270)
Cisplatin 100 mg/m2 day 1
5-FU 1 g/m2 day 1-4
Cetuximab day 1+8+15
Cisplatin 100 mg/m2 day 1
5-FU 1 g/m2 day 1-4
CetuGEX day 1+8+15
3-week cycles (max 6)
3-week cycles (max 6)
Cetuximab maintenance
CetuGEX maintenance
Follow-up for PFS / OS / Tox / QoL
Rekrutierung für RESGEX läuft,
Global trial, accrual Q1-2014 - Q1-2015
vorrauss. bis Mitte 2015
Major countries Germany, France, Spain, Belgium, U.S.A.
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TPEx:
GORTEC 2008-03 Phase II Studie
Cetuximab + CT: bis zu 4 Zyklen
1 Zyklus
Cetuximab bis zum
Progress
1 Zyklus
Docetaxel
Alle 2 Wochen*
Cisplatin
Cetuximab
Evaluierung nach 2 Zyklen:
Bei ORR oder SD [ 2 zusätzliche Zyklen
•  Primärer Endpunkt: ORR nach 12 Wochen (4 Zyklen)
•  Sekundäre Endpunkte: Best overall response, PFS, OS, Tox, Biomarker
Docetaxel und Cisplatin = 75 mg/m² alle 3 Wochen
Bis zu 4 Zyklen Cetuximab = 400 mg/m² initial, anschließend 250mg/m² wöchentlich
Cetuximab Erhaltungstherapie = 500 mg/m² alle 2 Wochen
G-CSF-Gabe nach jedem Zyklus
* Off-label für Cetuximab
COMPREHENSIVE CANCER CENTER I UNIVERSITÄTSTUMORZENTRUM
Guigay J et al. J Clin Oncol 2012; 30: Abstract 5505.
44
TPExtreme-Studie 2014
Studiendesign
n = 208
Phase II
R/M SCCHN
Erstlinientherapie
n = 416
R
Platin + 5-FU
+ Cetuximab
(bis zu 6 Zyklen)
Cetuximab
bis Progression
n = 208
Platin + Docetaxel
+ Cetuximab
Cetuximab
bis Progression
(bis zu 4 Zyklen)
(alle 2 Wochen)
Primärer Endpunkt:
OS
Sekundäre Endpunkte: PFS, RR, Sicherheit
Multinationale Studie in Frankreich, Spanien und Deutschland
Dosierung:
EXTREME-Arm: Cisplatin 100 mg/m² / Carboplatin AUC 5, 5-FU 4000 mg/m2, Cetuximab initial 400 mg/m², anschließend 250 mg/m² wöchentl.
TPEx-Arm: Cisplatin 75 mg/m² / Carboplatin AUC 5, Docetaxel 75 mg/m², Cetuximab initial 400 mg/m², anschließend 250 mg/m² wöchentl.
Rekrutierung für TPExtreme
beginnt in Deutschland 2 Quartal 2015
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Immuncheckpoint Blockaden
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A Phase Ib Study of Pembrolizumab (MK-3475) in
Patients with HPV-negative and HPV-positive Head
& Neck Cancer
Tanguy Seiwert, Barbara Burtness, Jared Weiss, Iris Gluck, J. Paul Eder, Sara I.
Pai, Marisa Dolled-Filhart, Kenneth Emancipator, Kumudu Pathiraja, Christine
Gause, Robert Iannone, Holly Brown, Jennifer Houp, Jonathan Cheng, Laura Q.
Chow
Presented by:
Tanguy Seiwert, MD
Assistant Professor of Medicine
Associate Director Head and Neck Cancer Program
Fellow, Institute for Genomics and Systems Biology
The University of Chicago
KEYNOTE-012 – Study Design
•  Multi-center, non-randomized Phase Ib HNSCC expansion
cohort
•  Multi-cohort trial* à HNSCC cohort
Recurrent or metastatic
Head and Neck Cancer
- PD-L1 positive
- Investigator assessed
HPV status
HPV(-)
cohort
Pembrolizumab
HPV(+)
cohort
Pembrolizumab
10mg/kg Q2 weeks
10mg/kg Q2 weeks
*
- Treatment beyond initial PD allowed
- Radiation to progressive lesion allowed
*Additional cohorts included: Bladder Cancer, Triple Negative Breast Cancer, Gastric Cancer
Presented by: Tanguy Seiwert
Treat
until
PD*
PD-L1 Screening Results
•  Study Eligible n = 61*
•  HPV (-) n = 36†
•  HPV (+) n = 23†
•  HPV (na) n = 2
PD-L1 negative: 22% (23)
Number of Patients (n)
104 Patients screened:
PD-L1 positive: 78% (81)
Distribution of PD-L1 Positive Results
in Enrolled Patients:
16
14
HPV (-)
HPV (+)
12
10
8
*3 Pts with tumor (-)
but stroma (+) IHC
6
4
2
0
†Central
confirmation
of HPV status pending.
0
1
2
5
10
20
30
50
60
70
80
90 100
Tumor Cell Staining (%)
PD-L1 Staining in Tumors of Screened Patients (N = 104)
Staining (%)
0
n
26*
Presented by:
1-10 11-20 21-30 31-40 41-50 51-60 61-70
24
8
9
3
2
2
4
71-80 81-90 91-100
3
2
21
Efficacy: Waterfall Plot*
100
HPV (+)
HPV (-)
Change From Baseline, %
80
60
40
20
0
–20
–40
–60
51% (26/51) of patients had decreased tumor burden
–80
–100
Subjects
à  Best percent change from baseline in target lesions (site assessment) delineated by HPV status
*as of May 23, 2014; Includes only patients with RECIST measurable lesions at baseline and at least 1 follow-up scan
(n=51)
Presented by: Tanguy Seiwert
Best Overall Response*
56 pts evaluable for
Response
Response Evaluation
Total Head/neck
N=56†
HPV (+)
N=20
HPV (-)
N=36§
n (%)
1 (1.8)
95% CI†
(0.0, 9.6)
n (%)
95% CI†
n (%)
95% CI†
1 (5.0)
(0.1, 24.9)
0 (0.0)
(0.0, 9.7)
Partial Response
10 (17.9)
(8.9, 30.4)
3 (15.0)
(3.2, 37.9)
7 (19.4)
(8.2, 36.0)
Best Overall Response
(Complete + Partial)‡
11 (19.6)
(10.2, 32.4)
4 (20.0)
(5.7, 43.7)
7 (19.4)
(8.2, 36.0)
Stable Disease
16 (28.6)
(17.3, 42.2)
8 (40.0)
(19.1, 63.9)
8 (22.2)
(10.1, 39.2)
Progressive Disease
25 (44.6)
(31.3, 58.5)
7 (35.0)
(15.4, 59.2)
18 (50.0)
(32.9, 67.1)
4 (7.1)
(2.0, 17.3)
1 (5.0)
(0.1, 24.9)
3 (8.3)
(1.8, 22.5)
Complete Response
No Assessment
Based on RECIST 1.1 Per site assessment; includes confirmed and unconfirmed responses
†61 patients eligible for treatment; 60 patients dosed; 56 patients eligible for pre-defined full analysis set.
‡A
single patient with PD followed by PR on treatment was classified as PR.
§Includes
† Based
2 patients for whom HPV data unavailable.
on binomial exact confidence interval method.
•  PD-L1 expression correlates with Response
•  Using a Youden-Index derived, preliminary PD-L1 cut point:
Ø  Above cutpoint: 45.5% (5/11) RR
Ø  Below cutpoint: 11.4% (5/44) RR
*as of May 23, 2014
Presented by: Tanguy Seiwert
Subjects
Time on treatment and disposition*
Complete Response
Partial Response
Treatment Ongoing
0
4
8
12
16
20
24
28
32
Treatment Exposure, weeks
36
40
44
48
Swimmer plot of all patients who experienced CR or PR.
à 8 additional patients had SD >6 months, of which 7/8 remain on treatment.
*as of May 23, 2014
Presented by: Tanguy Seiwert
Zusammenfassung
Notwendigkeit der Definition molekularer Marker zur Therapiestratifizierung
Chirurgie / platinbasierte Radiochemotherapie sind therapeutischer Standard
im frühen Stadium der Erkrankung
Induktionschemotherapie ist kein Therapiestandard
Im Rezidiv ist das EXTREME Schema Standard ABER weitere Verbesserung
ist notwendig, um Toxizitäten zu vermindern und Effektivität zu steigern
PD-L1/ PD1 Checkpointinhibitoren werden gegenwärtig beim HNSCC evaluiert
– Aufgabe wird sein geeignete Partner zu definieren
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Vielen Dank für Ihre Aufmerksamkeit
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