Target Audience This activity has been designed to meet the educational needs of medical oncologists, radiation oncologists, surgical oncologists, APNs, RNs, pharmacists, managed care pharmacy directors, pathologists, medical directors, allied health professionals, and other physicians affiliated with medical facilities treating patients with head and neck cancers (HNC). HNC are challenging to treat due to the complex and aggressive nature of these cancers. Timely diagnosis and referral to the appropriate specialist is imperative as early diagnosis can lead to reduced mortality. Clinical advances are evolving regarding the use of molecularly targeted therapies such as EGFR inhibitors and anti-angiogenic agents into the multidisciplinary treatment of HNC. Optimal disease management, rehabilitation, and survivorship care depend on access to a multidisciplinary team comprised of a spectrum of specialists and support services. As research advances, clinicians need to remain aware of this new evidence to understand the multidisciplinary clinical practice implications that can affect patient care. This series of live grand rounds, webinars, and enduring curriculum include a didactic presentation, case illustrations, and clinical resources and tools.

2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of April 2012. All materials contained herein reflect the views of the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
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3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. PIM and IMER do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not
necessarily represent the views of PIM and IMER. Please refer to the official
prescribing information for each product for discussion of approved indications,
contraindications, and warnings.

4. Disclosure of Conflicts of Interest
Marshall R. Posner, MD
Reported a financial interest/relationship or
affiliation in the form of: Consultant, Eisai, Inc.,
GlaxoSmithKline plc., Novartis Pharmaceuticals
Corporation, Oxigene, Inc.

5. Learning Objectives
L
Upon completion of this activity,
participants should be better able to:
 Review the clinical, pathologic, and molecular characteristics of
patients with HNC
 Appraise the importance of multidisciplinary collaboration in early
screening and detection
 Enumerate the role of HPV status in optimal treatment selection
 Review current guidelines and emerging chemotherapy-based
curative treatments, including combination therapies
 Evaluate the impact of targeted therapies in the treatment of
metastatic HNC
 Integrate effective multidisciplinary rehabilitation therapy and
survivorship care for patients with HNC
 Provide accurate and appropriate counsel as part of the treatment
team

6. Activity Agenda
 Activity Overview (5 minutes)
 Molecular and Biological Considerations (10 minutes)
 Chemotherapy-Based Curative Treatment (10 minutes)
 Individualized Treatment: Rationale for Emerging
Targets (30 minutes)
 Questions & Answers (5 minutes)

7. Molecular and Biological
Considerations

8. Molecular and Biological Events in
Head and Neck Cancer (HNC)
HNC Can Now Be Divided Into 2 Large and Distinct Subtypes
HPV-Related Cancers Environment-Related Cancers
 Caused by high-risk HPV  Caused by environmental
– HPV 16 mutagens
– Driven by viral oncogenes – Smoking, alcohol
 Restricted to oropharynx  Throughout oral mucosa
 Distinct molecular markers  Distinct molecular markers
 “Good” prognosis  “Poor” prognosis, comorbidity
 Young, good general health  Second cancers
HPV = human papillomavirus.
Goon et al, 2009; Rodriguez et al, 2010.

9. Change in HPV Rates and Incidence
Over Time: United States
Chaturvedi et al, 2011.

10. Human Papillomavirus (HPV)
HPV-Associated Cancers
> 99% of Cervical Carcinoma
~ 90% Anal Carcinomas
~ 40% Vulvar and Vaginal Carcinomas
~ 60% of Oropharynx Cancers
HPV GENOME INTEGRATION
LCR E6 E7
Frequent Event During Malignant Progression
Terminates Viral Life Cycle
Circular 8 kB dsDNA Genomes
Expression of E6 and E7 Is Retained
Only One Coding Strand
Infect Epithelial Cells HPV E6/E7 Oncoproteins
~ 200 HPV types
Small, Non-Enzymatic Proteins
~ 30 Mucosal HPVs
(~ 150aa E6; ~ 100aa E7)
Low-Risk: Genital Warts Associate With and Functionally Modify
High-Risk: Lesions That Progress to Cancer Host Cellular Protein Complexes
Münger et al, 2004.

11. Mechanisms of HPV-Associated
Carcinogenesis
HPV E6 And E7 Oncoproteins Associate With and Reprogram Cellular Enzymes
E2 S Ub
Rbx1
S Ub
NEDD8
E6-AP Cul2
pRB Ubn
E6 Ubn E7
p53 EloC
EloB
HPV16 E6 Retargets the Cellular HPV16 E7 Retargets the Cellular
Ubiquitin Ligase E6AP to the P53 Cullin 2 Ubiquitin Ligase Complex
Tumor Suppressor Protein to the Retinoblastoma Tumor
Suppressor Protein, pRB
HPV E6 and E7 Oncoproteins Target Associated
Cellular Tumor Suppressors for Degradation
Münger et al, 2004.

12. RTOG 0129: A Randomized Phase III Trial
of Chemoradiotherapy With 2 Schedules
P: 100 mg/m2
R
A XRT
N
D Trial Completed Accrual in 6/05
O
M P: 100 mg/m2
I
Z XRT
E
743 Patients
Randomized
P = platinum; XRT = fractionated radiotherapy.
Ang et al, 2010.

13. Results of HPV Analysis: RTOG 0129
 433/721 (60%) Oropharynx Primary
 323/433 (75%) HPV Determination
 206/323 (64%) HPV+
 198/206 (96%) HPV16+
P16+ P16–
HPV+ 192 (96%) 7 (4%)*
HPV– 22 (19%)* 94 (81%)
Kappa = 0.80: 95% CI 0.73–0.87
CI = confidence interval.
Gillison et al, 2009.

14. Sequential Combined Modality Therapy
A Phase III Study: TAX 324 TPF Vs. PF
Followed by Chemoradiotherapy
R T
A P Carboplatinum: AUC 1.5 Wkly
N
D F
O EUA Surgery
M
P Daily Radiotherapy
I
Z
F
E
TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1,000 CI: D1–4 q3wks x 3
PF: Cisplatin 100 D1 + 5-FU 1,000 CI: D1–5 q3wks x 3
AUC = area under the curve; EUA = examination under anesthesia.
Posner et al, 2007.

15. TAX 324: Demographics by HPV Status
HPV+ HPV–
N = 56 (50%) N = 55 (50%) p Value
Treatment
TPF 28 (50%) 26 (47%) .85
PF 28 (50%) 29 (53%)
Age Yrs
Median (Range) 54 (39–71) 58 (41–78) .02
Nodal Stage
N0–N1 13 (23%) 18 (33%) .30
N2–N3 43 (77%) 37 (67%)
T stage
T1–T2 28 (50%) 11 (20%) .001
T3–T4 28 (50%) 44 (80%)
PS WHO
0 43 (77%) 27 (49%) .003
1 13 (23%) 28 (51%)
PS = performance status; WHO = World Health Organization.
Posner et al, 2011.

16. TAX 324: Survival and HPV Status
Survival Oropharynx Cancer p < .0001
HPV+
HPV–
Posner et al, 2011.

17. TAX 324: Survival, PFS, and Site
of Failure By HPV Status
HPV+ HPV– p Value
N = 56 N = 55
Median Follow-Up
Months (95% CI) 83 (77–93) 82 (68–86) NS
Survival Status
– Alive 44 (79%) 17 (31%) < .0001
– Dead 12 (21%) 38 (69%)
PFS Status
– No Progression/Death 41 (73%) 16 (29%) < .0001
– Progression/Death 15 (27%) 39 (71%)
Local-Regional Failure 7 (13%) 23 (42%) .0006
Distant Metastases 3 (5%) 6 (11%) NS
Both 1 (2%) 2 (4%) NS
Total Disease Failures 9 (16%) 27 (49%) .0002
Died Without Recurrence 5 (9%) 12 (22%) .07
PFS = progression-free survival; NS = not significant.
Posner et al, 2011.

18. RTOG 1016: A Randomized Phase III Trial of
Chemoradiotherapy With Cisplatinum or Cetuximab
in P16+ Oropharynx Cancer
R Cisplatin
A 100 mg/m2/q21d
ELIGIBILITY
N IMRT
Stage
D 70Gy/35 fxs
III, IVA, B
O
Resectable
M
P16+
I Cetuximab
Oropharynx 400/250
Z mg/m2 qwk
Cancer E
IMRT 70Gy/35 fxs
Stratify: HPV, smoking, stage
Cetuximab loading dose = 400 mg/m2 on Day 1 of Cycle1 with induction
IMRT = intensity-modulated radiation therapy.
ClinicalTrials.gov.

19. ECOG 1308: P16+ Oropharynx Phase II:
Reduced Dose CRT for Resectable Oropharynx
E
Paclitaxel CLINICAL
PR/CR
Cisplatin
Daily Radiotherapy 5400 cGy
Cetuximab Assess
Response
9 wks
CLINICAL NR
SURGERY AND CRT
Trial Accrual Completed
CRT = chemoradiotherapy; PR = partial response; CR = complete response; NR = no response.
ClinicalTrials.gov.

20. HPV+ Oropharynx Phase III:
Reduced Dose Chemoradiotherapy for Induction PR/CR
The Quarterback Trial
C/E
Docetaxel
CLINICAL and PET
PR/CR
Randomize
Cisplatin 2:1
Daily Radiotherapy 5600 cGy
Reduced
Assess 20%
5-FU Reduced 25% Response
3 Cycles C
CLINICAL and PET
Primary End Points SD/NR
1. 3-yr LRC, PFS
2. Toxicity/Function Daily Radiotherapy 7000 cGy
3. Patterns of Failure
Stage IV, HPV 16, P16+
Stratify: < 20 pack yrs smoking
SD = stable disease; LRC = local-regional control.

21. HPV+ Oropharynx Cancer in 2012:
Summary
 HPV+ oropharynx cancer is increasing rapidly in North
America and Europe
– > 20,000 cases/yr in 2015
 The population is different
– More non-smokers, younger, healthier
 The prognosis is better in advanced disease
– > 75% patients alive at 3 yrs
– Surgery, radiotherapy, and chemotherapy are all effective
 HPV+ oropharynx patients will survive for decades
– Morbidity from therapy is considerable and studies to reduce
morbidity are under way using surgery and chemotherapy to
reduce radiotherapy impact

22. Molecular and Biological Events in HNC
Molecular Changes in HNC Are Organized Into Categories
Based on Systems Biology Approach
There Are Distinct Pathways That Are Altered in HNC
 Genetic integrity  Proliferation
– p53 pathway – Rb, p16 Pathway
 Survival, metabolism – MET
– PI3K pathway (AKT, mTor, PTEN)  Differentiation
– EGFr, MET – Notch, p63 pathway

23. Signaling Pathways in HNC
Image courtesy of Aaron Tward, MD, PhD.

24. Molecular and Biological Events in HNC
Drivers Vs. Suppressors
 Many genetic alterations in cancer are divided into driver
(oncogene addiction) or loss of suppressor events
– Drivers: Activating mutations – creates critical drug targets
• NSCLC: EGFR, ALK-4; Melanoma: BRAF
• HNC: MET, PI3K
– Suppressors: Releasing mutations – loss of function – down stream
targets
• How do you restore function?
• HNC: p53 (50%), p16 (60%), PTEN
NSCLC = non-small cell lung cancer; EGFR = epidermal growth factor receptor.

25. The Multi-Fold Impact of Inactivating Suppressor Genes
p53
Image courtesy of Christine Chung, MD.

26. Key Takeaways
Molecular and Biological Events in HNC
 Themost important molecular biomarker in
HNC is HPV status
 Single-gene driver mutations are rare in HNC
and loss of suppressor events are common
 Single-agent targeted therapy is challenging
in HNC
 Multipletargets within signaling pathways are
being identified

27. Chemotherapy and Surgery-Based
Curative Treatment

28. The Current State of Curative Therapy
 Multidisciplinary decision making prior to
definitive care is key
– Working together to establish and coordinate the
combined modality treatment plan
• Determine stage/extent
• Establish prognostic/predictive factors
• Identify and coordinate a complex treatment plan
• Monitor response and toxicity: Modify therapy based on
response/prognosis
• Long-term follow-up for toxicity, recurrence, and second
primary

29. The Current State of Curative
Therapy (cont.)
 Surgery
 Postoperative chemoradiotherapy
 Concurrent chemoradiotherapy
 Sequential therapy

30. Surgical Technology Has Changed
Significantly in the Last Decade
 Transoral approaches
– Transoral Laser Microsurgical (TLM) resection
– TransOral Robotic Surgery (TORS)
– Much better exposure
 Lessened morbidity
– Much less bystander tissue damage, trauma
– Quick recovery
– More tumors resectable – oropharynx, larynx, pyriform
 Who is a candidate?
– Is surgery biologically rational? Does it improve function, reduce late
morbidity, impact on subsequent therapy
– HPV+ oropharynx

31. Transoral Robotic Surgery (TORS)
Images courtesy of Marshall Posner, MD.

32. Surgical Technology Has Changed
Significantly in the Last Decade (cont.)
 Who is a candidate?
– Is surgery biologically rational?
– Does it improve function, reduce late morbidity?
– Does surgery impact on subsequent therapy?
 HPV+ oropharynx
– Can we eliminate or reduce post-operative
radiotherapy?

33. E3311 Trial Design
 Phase II trial of HPV+ (P16+) OPSCC patients will be randomized to
either low-dose (50 Gy) or standard-dose RT (60 Gy)
 Patients with T1-T2N0-N1 will be observed (Arm A)
 Patients with clear/close margins, ≤ 1 mm ECS, PNI/LVI, and/or 2–3
metastatic LN will be randomized to 50 Gy vs. 60 Gy (Arms B & C)
 Patients with positive margins, ≥ 4 metastatic LN, and/or > 1 mm
ECS will be treated with standard-dose RT + cisplatin (Arm D)
 Primary objective is to evaluate the 2-yr PFS in HPV+ SCC
patients treated with cetuximab plus low-dose RT (assume 85% per
arm)
 Secondary end points: Early & late toxicities, swallowing function,
QOL, OS, and serum/tissue biomarkers in predicting clinical
outcomes
 Stopping rules for excessive recurrence or bleeding
RT = radiotherapy; QOL = quality of life; OS = overall survival.

34. ECOG 3311 P16+ Trial – Low Risk OPSCC:
Personalized Adjuvant Therapy Based on Pathologic
Staging of Surgically Excised HPV+ Oropharynx Cancer
LOW RISK:
T1-T2N0-N1 Observation
Assess negative margins
Eligibility:
HPV (p16)+ Radiation Therapy
SCC IMRT 50Gy/25 Fx
oropharynx R
A
N INTERMEDIATE:
Stage III-IV: Transoral Resection D Clear margins Evaluate for 2-yr PFS
cT1-3, N1-2b (any approach) ≤ 1 mm ECS Local-Regional
O
(no T1N1) with neck dissection 2–3 metastatic LN Recurrence, Functional
M
PNI Outcomes/QOL
I
Baseline Z LVI
Functional/ E
Radiation Therapy
QOL IMRT 60 Gy/30 Fx +
Assessment HIGH RISK:
Positive Margins
> 1 mm ECS or Radiation Therapy
≥ 4 metastatic LN IMRT 66 Gy/33 Fx +
CDDP 40 mg/m2 wkly

35. Postoperative Chemoradiotherapy
RTOG 95-01
459 patients
R XRT
S
A EORTC (66 Gy over 6 ½ wks)
U RTOG (60–66 Gy over 6-6 ½ wks)
N
R
D
G
O
E
M Cisplatin
R 100 mg/m2 d 1, 22, 43
I
Y
Z XRT
EORTC 22931 E
334 patients
Cooper et al, 2004; Bernier et al, 2004.

36. Survival/Local Regional Control RTOG:
95-01 Median Follow-Up 9.4 Yrs
100 100
75 75
p = 0.31
Local-Regional Control (%)
p = 0.10
Overall Survival (%)
50 50
25 25
RT RT
0 RT+CT 0 RT+CT
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Years after Randomization Years after Randomization
Patients at Risk Risk
Patients at Patients at Risk Risk
Patients at
RT 208 170 119 92 75 68 60 53 44 33 26 RT 208 142 106 84 71 66 57 51 44 33 26
RT+CT 208 170 202 119
RT 158 129
92 111
75 95
68 85 7553 64 44 55
60 33 48 26 RT+CT 208
37 RT 142 202 106146 84 121 108
71 6691 83
57 74 6344 54 33 47 26 36
51
RT 202 158 129 111 95 85 75 64 55 48 37 RT 202 146 121 108 91 83 74 63 54 47 36
+ +
CT CT
Images courtesy of Jay Cooper, MD.

37. Survival/Local Regional Control RTOG:
95-01 ECE or Positive Margin Median Follow-Up 9.4 Yrs
100 100
75 75
Local-Regional Control (%)
Overall Survival (%)
50 p = 0.07 50
p = 0.02
25 25
RT RT
0 RT+CT 0 RT+CT
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Years after Randomization Years after Randomization
Patients at Risk Risk
Patients at Patientsatat Risk
Patients Risk
RT 115 88 53 37 31 28 23 21 16 13 11 RT 115 71 48 34 29 27 21 20 16 13 11
RT+CT 115 88 12753 9737 77 31 65
RT 28 52 23 48 2145 37
16 32
13 28
11 23 RT+CT 115 71
RT 127 9334 72 29 64
48 27 50 47
21 45
20 37 3213 28 11 23
16
RT 127 97 77 65 52 48 45 37 32 28 23 RT 127 93 72 64 50 47 45 37 32 28 23
+ +
CT CT
Images courtesy of Jay Cooper, MD.

38. Postoperative Chemoradiotherapy
 Indicated for ECE, positive margin
– Relative indication for LVI, PNI
 Cisplatin bolus therapy
– Replace with weekly cisplatin 40 mg/m2 based on
data from nasopharynx cancer trials
 No indication for weekly cetuximab or
extended therapy as adjuvant
 Multiple adjuvant trials ongoing
– Lapatinib, afatinib

39. Concurrent Chemoradiotherapy
RTOG 0129: A Phase III Trial Comparing
Acerbated Therapy to Standard Radiotherapy
P: 100 mg/m2
R
A XRT
N
D Trial Completed Accrual in 6/05
O
M P: 100 mg/m2
I
Z XRT
E 743 Patients
Randomized
Ang et al, 2010.

40. RTOG 0129: Outcome End Points
Ang et al, 2010.

41. RTOG 0129: Secondary Analyses
Multivariate Analysis With Therapy Variables
Parameters HR (95% CI)
OS PF Survival LR Relapse Distant
Metastasis
HPV (ISH- vs. ISH+) 2.7 (1.90–3.92) 2.3 (1.68–3.08) 2.6 (1.72–3.84) 2.0 (1.19–3.49)
Smoking (> 10 vs. ≤ 10 PY) 1.8 (1.28–2.65) 2.0 (1.43–2.74) 2.0 (1.34–3.08) 1.6 (0.94–2.85)
T-Stage (T4 vs. T2-3) 1.6 (1.23–2.08) 1.3 (1.00–1.62) 1.4 (1.07–1.95) 1.0 (0.60–1.56)
N-Stage (N2b-3 vs. N0-2a) 1.6 (1.20–2.02) 1.5 (1.20–1.92) 1.3 (0.98–1.77) 2.2 (1.37–3.46)
Zubrod PS (1 vs. 0) 1.6 (1.21–2.03) 1.6 (1.25–1.99) 1.6 (1.20–2.17) 1.4 (0.92–2.19)
Cisplatin Cycles (1 vs. 3) 2.1 (1.35–3.32) 1.8 (1.19–2.82) 1.9 (1.07–3.34) 1.5 (0.67–3.41)
Cisplatin Cycles (2 vs. 3) 1.2 (0.84–1.59) 1.3 (0.98–1.76) 1.7 (1.20–2.54) 1.0 (0.57–1.66)
RT Dose (64-76 Gy, cont.) 1.08 (0.99–1.19) 1.03 (0.94–1.12) 1.02 (0.92–1.14) 1.04 (0.88–1.23)
RT Wks (7 vs. 6) 1.4 (0.88–2.15) 0.9 (0.64–1.32) 0.9 (0.55–1.35) 1.3 (0.59–2.62)
RT Wks (8–9 vs. 6–7) 2.2 (1.33–3.46) 1.4 (0.94–2.06) 1.5 (0.89–2.34) 1.7 (0.76–3.76)
HR = hazard ratio.
Ang et al, 2010.

42. Concurrent Chemoradiotherapy
RTOG 0522: A Phase III Trial of Cisplatin CRT
With or Without Cetuximab
R P: 100 mg/m2
A
N XRT
D
O Cetuximab 400/250 mg
M
I P: 100 mg/m2
Z
E XRT
Stratify: XRT as
Standard or IMRT on
DAHANCA
Ang et al, 2011.

43. GORTEC 99-02: Chemoradiotherapy Vs. Accelerated
Radiotherapy With or Without Chemotherapy
Carboplatin/5-FU
R
A XRT
N
D
O Carboplatin/5-FU
M
XRT
I
Z
E
XRT
Bourhis et al, 2012.

44. GORTEC 99-02
 Standard
chemoradiotherapy was
better in all parameters
compared to
accelerated therapy
 There was a trend for
standard fraction CRT
to be better than ACB
CRT in all parameters
Bourhis et al, 2012.

45. The Cetuximab/Radiotherapy Phase III Trial
Stratify by R
XRT Surgery
 Karnofsky score: A
90–100 vs. 60–80
N
 Regional Nodes:
D QD, BID or
Negative
vs. Positive O ACB Allowed
 Tumor stage: M
AJCC T1–3 vs. T4 I
 RT fractionation: Z ERB
Concomitant boost
vs. once daily E XRT Surgery
vs. twice daily
Bonner et al, 2006.

46. OS By Treatment:
Median Follow-Up 60 Months
1.0
0.9
0.8
0.7
OS (%)
0.6
0.5
0.4
0.3
0.2
Stratified Log Rank p = .018, HR = 0.73 (0.56–
0.1 0.95)
0.0
0 10 20 30 40 50 60 70
Time (months)
Treatment Total Death Alive Median
Radiation Alone 213 130 83 29.3
RT + Cetuximab 211 110 101 49.0
Bonner et al, 2006.

47. Chemoradiotherapy for Locally
Advanced HNC
 Chemoradiotherapy improves survival compared to
radiotherapy alone for locally advanced HNC
 Standard fraction CRT is preferred over ACB CRT with
reduced chemotherapy
 There is no role for reducing chemotherapy during CRT
– 3 doses of cisplatin are better then 2 doses (RT0G 01-29,
GORTEC 99-02)
 CRT with platinum containing regimens remains the
standard for CRT – carboplatin/FU or cisplatin

48. TAX 323: TPF VS. PF Followed by Radiotherapy
A Phase III Study in Unresectable SCCHN
R
T
A
N P
D F
O
EUA Surgery
M
I P Daily Radiotherapy
Z
E F
TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI: D1–5 q3wks x4
PF: Cisplatin 100D1 + 5-FU 1000CI: D1–5 q3wks x 4
Vermorken et al, 2007.

49. TAX 323 Update: 2011
PF TPF
Median PFS 14.5 m 18.8 m
OS Rate: 5 Yrs 19% 28%
HR 0.75 [0.60;0.95]
Adjusted p Value .015
Vermorken et al, 2011.

50. Sequential Combined Modality Therapy
A Phase III Study: TAX 324 TPF Vs. PF
Followed by Chemoradiotherapy
T
Carboplatinum: AUC 1.5 Wkly
R P
A
N F
D EUA Surgery
O
P Daily Radiotherapy
M
IZ F
E
TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI: D1–4 q3wks x 3
PF: Cisplatin 100D1 + 5-FU 1000CI: D1–5 q3wks x 3
Posner et al, 2007.

51. TAX 324: 5-Yr Follow-Up – OS
HR 0.74 (.058–.094)
p = .013
TPF 52%
PF 42%
Sustained Survival Advantage At 5 Yrs For Patients Receiving TPF Vs. PF
Median OS 71 Vs. 30 Mos (HR 0.74, p = .0129)
Lorch et al, 2011.

52. Sequential Chemotherapy
 Induction chemotherapy and sequential therapy improve local
regional control and OS
 Sequential therapy is a standard curative treatment for advanced
disease and organ preservation
 Sequential therapy requires and experienced team
Study Primary Significant
Population N End Point Regimen Outcomes
TAX 323 Inoperable 358 PFS PF vs. TPF Better PFS, OS
p < .01
TAX 324 Locally Advanced 501 Survival PF/CRT vs. Better
TPF/CRT PFS, OS, LFS
p = 0.01 and 0.3
GORTEC 2000-01 213 Larynx PF vs. TPF Better LFS
Resectable Preservation p < .04
Larynx/Hypopharynx
LFS = laryngectomy-free survival.
Vermorken et al, 2007; Lorch et al, 2011; Pointreau et al, 2010.

53. Individualized Treatment:
Rationale for Emerging Targets

54. New Targets and Therapies in HNC
 Small Molecules  Complex Biologics
– EGFR – Virolytics
• Afatinib, Lapatinib • Rheovirus
– Met – Vaccines
• ARQ 197, XL 184, XL 880 • Dendritic Cell
– PI3K Pathway • Long HPV Peptides
• BKM120 – Immune Modulators
– mTOR • Ipilimumab, PD-1
• Everolimus
– VEGFR
• Bevacizumab

55. The EXTREME Trial
Randomized
Group A Group B
Cetuximab 400 mg/m2 initial dose EITHER carboplatin (AUC 5, D1)
then 250 mg/m2 wkly + OR cisplatin (100 mg/m2 IV, D1)
EITHER carboplatin (AUC 5, D1) + 5-FU (1,000 mg/m2 IV, D1–4):
OR cisplatin (100 mg/m2 IV, D1) 3-wk cycles
+ 5-FU (1,000 mg/m2 IV, D1–4):
3-wk cycles
6 Chemotherapy Cycles Maximum
Cetuximab No Treatment
Progressive Disease or Unacceptable Toxicity
Vermorken et al, 2008.

56. EXTREME Trial: OS
~ 10%
10.1 months
7.4 months
Survival Time, Months
Vermorken et al, 2008.

57. Afatinib: An ErbB Family SMI
 Has demonstrated
preclinical activity on Erbb1
(EGFR/HER1), Erbb2
(HER2), and Erbb4 (HER4)
 Has shown clinical activity
in solid tumors (eg, lung
and breast cancer)
In vitro Molecular Potency
 Side effects associated with
nM
afatinib treatment are
ErbB1 0.5
manageable and reversible
ErbB2 14
ErbB4 1
Eskens et al, 2008; Li et al, 2008; Yamamoto et al, 2011.
Image courtesy of Marshall Posner, MD.

58. Afatinib Randomized Phase II
Afatinib
Afatinib Cetuximab
Cetuximab
R
50 mg 400/250
A
N
po mg/m2 IV wkly
Metastatic daily Continue Continue
D
recurrent O until PD or undue until PD or undue
AEs AEs
HNSCC M
I
N = 124 Z
E
(62 per arm)
Cetuximab
Cetuximab Afatinib
Afatinib
400/250 mg/m2 50 mg po
IV wkly daily
Stratum: No. Prior
Chemotherapies for R/M
Disease (0 or 1)
Stage 1 Stage 2
CT/MRI q8wks
HNSCC = head and neck squamous cell carcinoma; IV = intravenous; PD = progressive disease;
CT = computed tomography scan; MRI = magnetic resonance imaging; R/M = recurrent/metastatic.

59. Response to Therapy (Randomized Set)
Afatinib Cetuximab
Total randomized, n (%) 62 (100.0) 62 (100.0)
Disease control (CR, PR, SD), n (%) 31 (50.0) 35 (56.5)
95% CI 37.0%, 63.0% 43.3%, 69.0%
p Value 0.48
Objective response (CR, PR), n (%)
10 (16.1) 4 (6.5)
(confirmed in randomized patients)
95% CI 8.0%, 27.7% 1.8%, 15.7%
p Value 0.09
Objective response (CR, PR), %
19.2 7.3
(confirmed in evaluable patients)
Partial response, n (%) 10 (16.1) 2 (3.2)
Stable disease, n (%) 21 (33.9) 31 (50.0)
Confirmation was made per protocol after 8 wks.
Evaluable patients are those with at least 1 post-baseline image (afatinib = 52 and cetuximab = 57).
Seiwert et al, 2012.

60. All Adverse Events in ≥ 5% (All Grades)
Afatinib
Cetuximab
*Rash, dermatitis acneiforem, dry skin, skin fissures, acne, dermatitis, nail disorders, hand-foot-syndrome, pruritus, skin reaction, xerodema.
Safety data includes treated patients only (1 randomized patient in the afatinib group and 2 randomized patients in the cetuximab group were
not treated).
Image courtesy of Seiwert et al, 2012.

61. LUX: HNC 1 (1200.43) Afatinib Vs.
MTX in Second-Line R/M HNSCC
Trial Design End Points Study Sites
Phase III, Randomized, Primary: PFS Global
Open-Label Key Secondary: OS; HR 0.73
R Afatinib 40 mg qd
A N = 316
R/M SCC N 2
• Failing Platinum-Based CT for R/M
D
• Documented PD Treatment
O
• PS = 0–1 Until PD
M
• Max 1 CT Regimen for R/M HNSCC 1
I
• No Prior EGFR TKIs MTX, 40 mg/m2/qw
Z
E N = 158

62. LUX: HNC 2 (1200.131) Adjuvant Afatinib
in Locally Advanced HNSCC
Trial Design End Points Study Sites
Phase III, Primary: DFS HR 0.72 Global
Randomized, Placebo Controlled Secondary: DFS Rate 2 Yrs, OS, Safety
R Afatinib 40 mg qd
Locally Advanced HNSCC A N = 446
• Unresected N 2
• Stage III–IVb D Treatment for
• Previous CRT O 18 months/
• Exclude non-smokers with OP cancer M recurrence
• PS 0–1 I 1
• NED After CRT Z Placebo qd
E N = 223
NED = no evidence of disease.

63. The PI3K/mTOR Pathway
Clarke et al, 2011.

64. BKM120: A Potent Oral Pan-PI3K
Inhibitor
 BKM120 is a potent oral pan-class I PI3K inhibitor that selectively inhibits all
four class I PI3K isoforms (α,β,γ,δ)
 BKM120 demonstrates
anti-proliferative activity in a
variety of human tumor cell
lines with dysregulated PI3K
pathways
 BKM120 has shown potent
anti-tumor activity in tumor
xenograft models
 The MTD of oral BKM120 on a
continuous daily schedule was
determined as 100 mg
 BKM120 is now in phase II
development
MTD = maximum tolerated dose.
Voliva et al, 2010; Maira et al, 2010; Bendell et al, 2011; Graña-Suárez et al, 2011.

65. Treatment Schema: Cetuximab
Plus Bevacizumab
Recurrent or
Metastatic SCCHN
ECOG PS 0–2
Cetuximab 250 mg/m2 IV wkly
No Previous EGFR (after loading dose of 400 mg/m2)
or VEGF Inhibitors
Up to 1 Regimen Bevacizumab 15 mg/kg IV, q3wks
for Recurrent or
Metastatic Disease
1 Prior Curative
Regimen Is Also
Allowed

66. Efficacy Results:
Best Objective Response (RECIST)
Best Response N = 45
PR 8 (18%)
SD 25 (55%)
DCR (CR/PR/SD) 33 (73%)
Progression 12 (27%)
Argiris et al, 2011.

67. Cet/Bev Grade 3/4 Toxicities (n = 46)
Toxicity Grade No. Patients (%)
Proteinuria 4 1 (2%)
Cardiac ischemia 4 1 (2%)
Hyponatremia 3 3 (7%)
Dysphagia 3 4 (9%)
Rash 3 4 (9%)
Fatigue 3 3 (7%)
Pain 3 4 (9%)
Hypertension 3 3 (7%)
Infection 3 3 (7%)
Hemorrhage 3 2 (4%)
*Grade 2 hemorrhage was reported in 4 patients and grade 1 in 6.
Two patients died of aspiration pneumonia, one with associated cardiac ischemia and
another with acute renal failure; these events were considered unrelated to study drugs.
Argiris et al, 2011.

68. E1305 Schema
Physician’s choice of Cisplatin + Docetaxel
chemotherapy regimen Cisplatin + 5-FU
RANDOMIZATION
ARM A ARM B
Cisplatin-doublet Cisplatin-doublet plus
q21days until bevacizumab q21days
progression until progression
Option to discontinue Option to discontinue
chemotherapy after 6 cycles if chemotherapy after 6 cycles if
maximum response reached maximum response reached.
Bevacizumab will continue until
progression.
ClinicalTrials.gov

69. Clinical Trial Design
 Neoadjuvant bevacizumab dose flanked by novel imaging
studies and tissue biopsy
 Bevacizumab dose escalated with concurrent CRT
ClinicalTrials.gov

70. c-MET Signaling Pathway
Motility Proliferation
Progression
Survival Angiogenesis
Shinomiya et al, 2003.

71. What Can Activate MET?
 Amplification
 Mutation
 HGF
 Non-amplified
overexpression
– Secondary induction of
transcription
– Secondary activation
– Promotor mutation
– Altered degradation

72. Expression: MET IHC
“Normal”
(Adjacent Tissue) Dysplasia Cancer
Normal tissue - N=24 Dysplasia - N=10 Cancer - N=97
0% 0% 1%
20% 15%
21% 21% 20%
30%
58% 50% 64%
0+ 1+ 2+ 3+ 0+ 1+ 2+ 3+ 0+ 1+ 2+ 3+
Seiwert et al, 2009.

73. Expression: HGF IHC
Seiwert et al, 2009.

74. Anti-MET/HGF Compounds
Compound Company Mechanism Phase
AMG102 Amgen Anti-HGF Ab I/II
ARQ197 Arqule MET inhibitor I / II (HNSCC)
BMS-777607 BMS MET inhibitor I / II
INCB-28060 Incyte MET inhibitor I
JNJ-38877605 Johnson & Johnson MET inhibitor I
MetMAb Genentech Anti-MET Ab I / II
MGCD-265 Methylgene MET, Ron, Tek, VEGFR1/2/3 I
MK-2461 Merck MET inhibitor I / II
PF02341066 Pfizer MET, ALK I
PF4217903 Pfizer MET inhibitor I
SGX523 SGX MET inhibitor Discontinued
XL184 Exelixis / BMS MET, VEGFR2, RET I / II
XL880 (GSK1363089) Exelixis / GSK MET, VEGFR2 I / II (HNSCC)

75. Phase II Study of XL880 (Foretinib) in HNSCC
 Failed to meet primary end point (trial did not proceed to stage II)
Evidence of minor activity; more specific anti-MET agents in clinical testing for HNC
Seiwert et al, Epub.

76. Blocking Inhibitory Receptors to
Reactivate Cancer Cells
PD-1 (Programmed Death-1) and CTLA-4
Anti-CTLA-4 mAb (MDX-010, IgG1)
*
CTLA-4 Anti-PD-1 mAb (MDX-1106, IgG4)
(CD152)
(*PD-Ligand are expressed on cancer cells)
Adapted from Keir et al, 2008.

77. Phase Ib/II Trial of Concurrent Cetuximab/IMRT With
Ipilimumab, Plus Biomarker Correlatives, in Locally
Advanced P16+ (HPV+) Oropharynx Cancer
SCHEMA
R
Stage a
III–IVA n Arm A: Cetuximab/Radiotherapy Plus Low-Dose Ipilimumab
OPSCC d RT 66 Gy with 200 cGy daily fractions in 6.5 wks
Tumor/ o Cetuximab wkly at a dose of 250 mg/m2 during radiation*
Blood m Ipilimumab 3 mg/kg q21days
Collection i
P16 IHC z *After loading dose of 400 mg/m2 on Cycle 1, Day 1
e Ipilumumab will be continued at indicated dose for additional 2 cycles
Hodi et al, 2010; Robert et al, 2011.

78. New Targets and Therapies in HNC
 There are many new agents directed at important
signaling pathways in HNC
– Survival, metabolism: EGFR, MET
– Cell death: PI3K, PTEN, MTOR
– Vascular support: Bevacizumab
– Differentiation?
 Biomarkers are potentially available for some agents, but
aside from HPV as a prognostic marker, predictive
markers are not ready for prime time
 Personalized cancer therapeutics are close to becoming
a reality in HNC

79. Case Study 1: HPV16+ Oropharynx Cancer
 A 72-yr-old retired man, executive notes a lump in his
right neck
– Asymptomatic, non-smoker, single glass of wine on weekend
nights, no exposures
– No significant comorbidities
– CT reveals base of tongue mass and pathologic lymph node
– FNA of lymph node: SCC, P16+, HPV16+
– EUA reveals infitrative mass in the base of tongue, approaching
midline
– A PET scan was performed

80. Case Study 1: HPV16+ Oropharynx Cancer
Clinical Implications of T2N1 or T2N2b

81. Case Study 1: Clinical Decision
Question 1
What is your choice of therapy?
1) Surgery plus post-operative chemoradiotherapy
2) Chemoradiotherapy
3) Sequential therapy
4) A diagnostic procedure

82. Case Study 1: HPV16+ Oropharynx Cancer
Clinical Implications of T2N1 or T2N2b
 Your choices are:
– Surgery plus post-operative chemoradiotherapy
• No change in therapy, bilateral neck irradiation, margins
• Proper staging
– Chemoradiotherapy
• Long-term sequelae, extent of fields (lower neck)
– Sequential therapy
• Only indicated if lower neck node positive
– A diagnostic procedure
• Lower, lymph node biopsy/FNA or neck dissection

83. Case Study 1: HPV16+ Oropharynx Cancer
 Lower, lymph node biopsy/FNA
– Negative
Case Study 1: Clinical Decision Question 2
 What is your treatment choice now?
1) Surgery plus PORT
2) CRT
3) Sequential therapy

84. Case Study 2: HPV – Base of Tongue Cancer
 A 57-yr-old man presents
with dysarthria and
bilateral neck masses
– No alcohol, smoked
2–3 ppd for 20 yrs, Primary
quit 20 yrs ago Tumor
– No comorbidities
 FNA and biopsy positive
for SCC
– T4 right base of tongue,
bilateral extensive
adenopathy staged
T4N2c, stage 4a
– P16-, HPV-

85. Case Study 2: Clinical Decision Question
 What is your choice of therapy?
1) Surgery plus post-operative chemoradiotherapy
2) Chemoradiotherapy
3) Sequential therapy
4) Palliative therapy

86. Case Study 2:
HPV16- Oropharynx Cancer: T4N2c, Stage 4a
 Your choices are:
– Surgery plus post-operative chemoradiotherapy
• Total glossopharyngectomy and reconstruction
– Chemoradiotherapy
• Bolus cisplatin or carboplatin/5-FU
• Cetuximab
– Sequential therapy
• TPF followed by CRT
– Palliative therapy
• Afatinib randomized trial, MET+ cetuximab, etc.