1. The International Federation
of Head and Neck Oncologic Societies
Current Concepts in Head and Neck Surgery and Oncology 2012
Molecular Therapeutics
with Chemotherapy in SCCHN
Jan B. Vermorken

2. Outline
Innovations in the treatment of head & neck cancer
Locoregionally advanced disease
• Research directions with targeted therapy (TT)
Recurrent/metastatic disease
• Studies with cetuximab
• Non cetuximab-containing randomized trials with
anti-EGFR therapies
• Novel targeted agents
Conclusions
2012

3. Innovations in Treatment of HNC
Surgery - reconstructive surgery
- organ sparing techniques
Radiotherapy - altered fractionation schedules
- chemoradiation, IMRT
- bioradiation
Chemotherapy - introduction of taxanes (TPF induction)
2012
- molecular targeted therapies

4. Locoregionally Advanced SCCHN
What do we know?
1. CT-RT is an important standard therapy for resectable and
unresectable SCCHN and for organ preservation. It induces
8% survival benefit at 5-yrs in MACH-NC (Lancet, 2000)
2. Major drawback of this approach: acute and late side effects
(JCO, 2008)
3. RT + EGFRI (cetuximab) is superior to RT alone, but
without additional toxic effects to the mucosa or increased
late side effects (NEJM, 2006)
4. CT-RT and RT – EGFRI (cetuximab) generally do not reduce
2012
distant metastasis

5. Locoregionally Advanced SCCHN
What do we know?
5. PF induction induces 5% survival benefit at 5-yrs in MACH-NC
and is effective in organ preservation in patients with larynx
and hypopharynx cancer (Ann Oncol, 2002)
6. TPF is the new standard ICT, with less toxicity and with better
QoL than with PF (NEJM, 2007)
7. TPF is superior to PF with respect to larynx preservation
(JNCI, 2009)
8. There is an increasing incidence of HPV-associated
oropharynx cancers, that seem to respond differently to
induction chemotherapy and RT and carry a better prognosis
(JNCI, 2008)
2012

6. What are the Challenges?
• To find ways to minimize toxicity and maximize
efficacy (less LRR, DM, SPT)
• To better predict those who need more aggressive
treatment vs those who need less
• To find ways to adapt treatment in individual cases
2012

7. Targets for Next-Generation Therapy
Tumor cell
1. Growth factors and 3. Signal transduction pathways
growth-factor receptors 1
Ras, raf, MAPK, MEK, ERK, AKT
HER family, c-kit/SCFR protein kinase C, PI3K
3
2
Nucleus
2. Extracellular matrix/ 4
angiogenic pathways
5
4. Cell-survival pathways
VEGFR, integrins, MMPs
Cyclin-dependent kinases,
mTOR, cGMP, COX-2, p53, Bcl-2
2012 5. Protein production
Proteasome

8. EGFR Expression in Human Tumors
EGFR Expression: High Expression Generally
Associated with:
• NSCLC 40-80%
• Prostate 40-80%
• Head & Neck 90-100% • Invasion
• Gastric 33-74% • Metastasis
• Late-stage disease
• Breast 14-91%
• Chemotherapy resistance
• Colorectal 75-89%
• Pancreatic 30-95% • Poor outcome
• Ovarian 35-77%
• Bladder 31-72%
• Glioma 40-63%
2012

9. EGFR-targeting Agents under Clinical
Investigation in SCCHN
Monoclonal Antibodies Toxicity
Cetuximab IMC225 chimeric human/murine IgG1 skin
Matuzumab EMD72000 humanized mouse IgG1 skin
Nimotuzumab h-R3 humanized mouse IgG1 systemic/hemodynamic
Zalutumumab 2F8 human IgG1 skin
Panitumumab ABX-EGF human IgG2 skin
Tyrosine Kinase Inhibitors
Gefitinib ZD1839 reversible EGFR skin/gastrointestinal (GI)
Erlotinib OSI-774 reversible EGFR skin/GI
Lapatinib GW-572016 reversible EGFR/erbB2 skin/GI/systemic
Afatinib BIBW-2992 irreversible EGFR/erbB2 skin/GI/systemic
Canertinib CI-0033 irreversible EGFR skin/oral/GI/systemic
2012

10. Cetuximab: Properties and Mechanism
of Action
• IgG1 monoclonal antibody
• Specifically binds to the EGFR with
higher affinity than its natural
ligands (TGFα, EGF), thus
competitively inhibiting their
binding
• High affinity: Kd = 0.39 nM
• Induces apoptosis and ADCC1
• Preclinical synergistic activity
2012 in combination with chemotherapy ADCC = antibody-dependent cellular cytotoxicity
and radiotherapy

11. Background & Rationale - Preclinical Studies
Cetuximab Enhances Tumor Response to
Cisplatin or Radiation A431 Tumor
Cetuximab Control
Cetuximab x 3
14
Cisplatin
4
Tumor Size (cm3)
Tumor Size (mm)
Control (PBS) 12
18 Gy
3
Cetuximab 10 Cetuximab x3
+ 18 Gy
2
8
Cisplatin
1 A43 Cetuximab
6 A43
1 + Cisplatin
Cetuxima 1
0 4 b
0 5 10 15 20 25 30 35 0 8 16 24 32 40 48 56 64 72 80
Time (days) Days After Initial Treatment
2012
Fan (Mendelsohn), Cancer Res 53:4637, 1993
Courtesy Dr. Ang
Milas (Fan), Clin Cancer Res 6:701, 2000

12. Background & Rationale – Clinical Studies
Phase III Trials of Cetuximab with Radiotherapy or
Platinum-Based Chemotherapy Improves Survival
1.0 |
Overall Survival
0.9
0.8 Locally Advanced HNSCC
Bonner et al, NEJM, 2006
Proportion Alive
0.7 HR: 0.73 (0.56, 0.95), P= 0.02
0.6 RT + Cetuximab
(≤8 doses)
0.5
Δ 2.7 Months 20 Months
0.4 10%
0.3 Chemotherapy ≤6 cycles + RT Alone
Cetuximab (Med: 29 doses)
0.2
Recurrent/Metastatic HNSCC
0.1 Vermorken et al, NEJM, 2008
Chemo Alone
HR: 0.80 (0.64, 0.99), P= 0.04
0.0
2012 0 10 20 30 40 50 60 70
Months
Courtesy Dr. Ang

13. MACH-NC
Meta-Analysis of Chemotherapy
in Head & Neck Cancer
Taxane-Cisplatin-5-Fluorouracil as
Induction Chemotherapy in Locally
Advanced Head and Neck Squamous Cell
Carcinoma: an Individual Patient Data
Meta-analysis of the MACH-NC Group
2012 Pierre Blanchard, Abderrahmane Bourredjem, Jean Bourhis, Ricardo Hitt, Marshall R. Posner, Jan B.
Vermorken, Gilles Calais, Adriano Paccagnella, Jean Pierre Pignon
on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) Collaborative
Group

15. Randomized Trials of Sequential Therapy
versus Concurrent Chemoradiation Only
Group Regimen
TPF (or PF) x 3 → CRT (cisplatin)
TTCC (Sp)
CRT (cisplatin)
TPF x 3 → CRT (carboplatin)
Boston (US)
CRT (cisplatin)
TPF x 2 → THFX
Chicago (US)
THFX
XRT (cetuximab)
2012
TPF x 3 XRT (PF)
GCTCC (It) XRT (cetuximab)
XRT (PF)

16. Induction Chemotherapy (ICT) and
Targeted Therapy
Superior to standard ICT?
Induction Concurrent
D P F E C T P E C T
Wanebo
200 2 90 200 1 30
2010
Ferris
75 75 250 30 250
2010
Argiris
75 75 250 30 250
2010
Posner
75 100 1000 x5 1.5
2007
2012
D=docetaxel; P=cisplatin; F=5-FU; E=cetuximab (Erbitux® ); C=carboplatin; T: paclitaxel (Taxol®)

17. Induction Chemotherapy (ICT) and
Targeted Therapy
Superior to standard ICT?
Wanebo Ferris Argiris Posner
No. of pt 63 39 39 255
Stage IV (%) 64 92 92 84
OPC (%) 61 59 59 52
HPV + - 65 68 29
PFS (%) 66 (2yr) 70 (3yr) 70 (3yr) 52 (3yr)
OS 82 (2yr) 74 (3yr) 74 (3 yr) 62 (3yr)
ICT-resp (%) 74 86 86 72
2012

18. Conclusions on Adding Cetuximab to TPF
• Difficult with full dose TPF (EORTC 24061:
EHNS 2012)
• Feasible in combination with 2 drug
regimens (as in R/M disease)
• Superiority of ICT + cetuximab over ICT
alone difficult to detect in nonrandomized
trials (patient and tumor characteristics)
2012
• Randomized trials are needed

19. Recurrent and/or Metastatic SCCHN
Introduction
• Over 50% of newly diagnosed cases are not cured and
will relapse locally or at distant sites
• 10% of newly diagnosed cases present with distant
metastases
• Treatment options: - Chemotherapy (CT)
10-15% of
- Re-irradiation localized
- Salvage surgery recurrences
- Best supportive care (BSC)
2012
• Cisplatin-based CT: - Response rate: 30%
- Overall survival: 6–9 months

20. Platinum-Refractory R/M SCCHN
Therapeutic options
• Best supportive care (BSC)
Chemotherapy (CT)
Radiation therapy (RT)
Other local therapies
• In a retrospective analysis of 151 patients with platinum-
refractory disease 45% received BSC, and 55% any form of
treatment (Leon et al, Clin Oncol 2005; 17: 418-424)
• Overall response rate was 2.6%, the clinical benefit rate 15.2%,
2012 and survival 103 days.
(for patients receiving BSC 56.5 days, CT 107 days)

21. EGFR Inhibitor Response Rates in SCCHN
Drug Phase/ prior CT Reference Resp Rate, %
Cetuximab II Pt- refract Vermorken, JCO, 2007 10-13
Erlotinib II 0-1 lines Soulieres, JCO, 2004 4
Gefitinib II 0-1 lines Cohen, JCO, 2003 11
II 0-5 lines Cohen, CCR, 2005 2
II 0-1 lines Kirby, BJC, 2006 9
III Pt + (A) Stewart, JCO, 2009 3-8
Lapatinib II unclear Abidoye, ASCO 2006 0
Cetuximab II prior Pt Seiwert, THNO 2011 7
Afatinib II prior Pt Seiwert, THNO 2011 16
2012
Prior CT= for recurrent/metastatic disease

22. CT plus Cetuximab in 1st-Line SCCHN:
Consistent Efficacy Regardless of CT Type
ORR Median PFS Median OS
Author Phase N Regimen (%) (months) (months)
Vermorken PF 20 3.3 7.4
III 442
2008 PF + cetuximab 36* 5.6* 10.1*
Burtness Cis + Placebo 10 2.7 8.0
III 117
2005 Cis + cetuximab 26* 4.2 9.2
Bourhis
I/II 53 PF + cetuximab 36 5.1** 9.8
2006
Hitt
II 46 Pacli + cetuximab 54 4.2 8.1
2011
Buentzel Pacli/Carbo +
II 23 56 5.0**
2007 cetuximab 8.0
2012
*Significant; **TTP
Vermorken et al. NEJM 2008; Burtness et al. JCO 2005;
Bourhis et al. JCO 2006; Hitt et al. Ann Oncol 2011; Buentzel et al. ASCO 2007

23. Grade 3/4 AEs (%)
A
0
5
10
15
20
25
2012
ne
m
N ia
eu
Th tr
ro op
m en
bo ia
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to
pe
ni
H a
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ok
H al
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om ia
ag
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ar ia
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ac
ev
en
ts
Vo
m
iti
ng
A
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he
ni
a
Se
Sk ps
in is
re
ac
In tio
fu ns
si
on
(n=219)
re
ac
tio
CT (n=215)
n
EXTREME: Safety Profile
CT + cetuximab
Vermorken et al. NEJM 2008

24. EXTREME: Symptom Control
Improving
-20
CT CT + cetuximab symptoms
-15
Mean change from baseline to
-9.99 -9.98
-9.17
worst post-baseline score
-10 -7.81
-5 -2.64 -2.55
-2.60
-0.43
0
+0.24
+1.33
5 +3.51 +4.42
+5.21 +4.37
10 p=0.0027 p=0.0162 p=0.5702 p=0.0787 p=0.0694 p=0.7732 p=0.2237
15 Worsening
symptoms
20
Pain Swallowing Sense Speech Social eating Problems Problems
problems problems problems problems with social with
contact reduced
2012
sexuality
QLQ-H&N35 module
Modified from Mesía et al. Ann Oncol 2010

25. EXTREME: Quality of Life
Global health status/QoL
100 CT
CT + cetuximab
80
60 <50% of patients
completed a baseline
Score
questionnaire;
40
=95% CIs for
difference in treatment
20 groups
0
-20
Baseline Cycle 3 6 months
CT: n=94 n=63 n=20
CT + cetuximab: n=109 n=80 n=45
2012
EORTC QLQ-C30
Mesía et al. Ann Oncol 2010

26. The Role of Cetuximab in First-Line
R/M - SCCHN
Adding cetuximab to platinum/5-fluorouracil:
• significantly improves overall survival1
• significantly increases PFS1
• almost doubles the response rate1
• is feasible with an acceptable side-effect profile1
• significantly reduces pain and swallowing problems2
• has no negative effect on quality of life2
First regimen to show survival benefit in 30 years
Is a new standard regimen for R/M-SCCHN3,4
2012 1Vermorken et al, N Engl J Med 2008; 359: 1116-1127
2Mesia et al, Ann Oncol 2010 (doi 10,1093/annonc/mdq077)
3Licitra L and Felip E, Ann Oncol 2009; 20 (suppl 4): 121-122
4Petrelli et al, J Clin Oncol 2009; 27: 6052-6069

27. Cetuximab and Beyond
Where do we go from here?
2012

28. Non-Cetuximab Containing Randomized
Trials in Recurrent/Metastatic SCCHN
Anti-EGFR therapies
Study/Reference N Regimen RR (%) PFS (mo) OS (mo)
SPECTRUM/ 657 PF2 + panitumumab 36* 5.8** 11.1
Vermorken et al 2010 PF2 4.6** 9.0
25*
ZALUTE 286 Z + BSC (-MTX) 6 2.3… 6.7°
Machiels et al, 2010 BSC (optional MTX)a 1.9… 5.2°
1
IMEX 486 Gefitinib (250 mg) 2.7 ND 5.6
Stewart et al, 2009 Gefitinib (500 mg) 7.6 ND 6.0
Methotrexate ND 6.7
3.9
ECOG 1302 270 D + Gefitinib 12 3.3 6.8
Argiris et al, 2009 D + placebo 2.2 6.2
2012 6
a87% received MTX
*p=0.007; **p=0.004; …p=0.001; °p=0.0648

29. The Problem of Resistance
EGFR is a validated therapeutic target in SCCHN
Discordance between EGFR expression and response
Possible mechanisms of resistance
EGFR mutations
Increased EGFR internalization
Parallel signaling pathways
• IGF-1R, MET, erbB2
• PI3K/AKT mutations
• Cycline D1 amplification
2012

30. Other Novel Targeted Agents in SCCHN
Anti-angiogenesis
• VEGF
• VEGFR
Integrin inhibitors
Histone deacetylase inhibitors
PI3K/Akt/mTOR
Proteasome inhibitors
IGFR inhibitors
2012
SRC inhibitors
No phase III data!

31. VEGF Ligand Targeted Therapy in
R/M SCCHN
Drugs N RR (%) SD (%) Reference
Bevacizumab 15 mg/kg q. 21d 37 30 (5)* 57 Argiris+
+ pemetrexed 500 mg/m² q. 21d (2011)
Bevacizumab 15 mg/kg q. 21d 48 15 (8)* 30 Cohen
+ erlotinib 150 mg/day (2009)
Bevacizumab+ 15 mg/kg q. 21d 46 18 (0)* 55 Argiris°
cetuximab 250 mg/m²/wk (2011)
2012 *( ) = percentage CR; +Median TTP 5 months, median OS 11.3 months
°PFS 2.8 months, median OS 7.6 months

32. Phase III Randomized Trial of Cisplatin-
Based Chemotherapy with or without
Bevacizumab in SCCHN (E1305)
R
A Cisplatin doublet*
Recurrent/ N Every 21 days
metastatic D
SCCHN O Endpoint: survival
PS 0-1 N=400
M Cisplatin doublet*
No prior I + Bevacizumab 15 mg/kg
chemo Z
E Every 21 days
2012
* Cisplatin/docetaxel or cisplatin/5-FU
Study Chair: A. Argiris

33. Anti-Angiogenic Agents in Recurrent or
Metastatic SCCHN: Conclusions
Sorafenib and sunitinib cannot be recommended for
further study as monotherapy (combination
regimens?)
Bevacizumab added to pemetrexed or cetuximab had
promising preliminary activity in 2 ongoing trials
Bevacizumab will be evaluated in a phase III
2012
randomized trial in rec/met SCCHN

34. Novel Agents not Targeting EGFR in
Recurrent or Metastatic SCCHN
Target Single agent Combination
Bevacizumab Angiogenesis No data Promising/ongoing
Low/mod
Sorafenib Angiogenesis Ongoing
activity
Sunitinib Angiogenesis Low activity -
Dasatinib Src, others Low activity Ongoing
Bortezomib Proteasome Low activity Low activity
Vorinostat HDAC Low activity -
Figitumumab IGF-1R Low activity -
2012 Cixutumumab IGF-1R Ongoing Ongoing
Everolimus mTOR Ongoing Ongoing

35. Targeted Therapies: Combinations*
Drug combinations with cetuximab Phase II Sample Size Target
Bevacizumab + cetuximab II 48 VEGF
Dasatinib + cetuximab I 30 Scr
Cilengitide + cetuximab (+ PF) I/II 194 Integrins
Cixutumumab ± cetuximab II 90 IGF-1R
Cetuximab ± EMD1201081 II 104 TLR9
Raf, VEGF1,2,3, Flt3,
Cetuximab ± sorafinib II 88
PDGFß, c-KIT, RET
Temsirolimus ± cetuximab II 80 mTOR
*Available on clinicaltrials.gov
2012

36. Conclusions
Better understanding of the biology of SCCHN has led to change in
treatment approaches, which may end up with improved outcome
and less toxicity
The interaction between targeted therapies and cytotoxic
chemotherapy is promising → survival benefit in R/M SCCHN, but
improvement with ICT still uncertain.
In R/M SCCHN regimens with less toxicity need to be further explored
A plethora of new targeted therapies are in various stages of
preclinical and clinical development: how to integrate the active
ones is an important goal.
2012