1. RTP ON DEMAND: Thyroid Cancer Ezra W Cohen
University of California, San Diego 1

2. Thyroid Cancer Newly Detected 2015 (n = 62,450)
Hürthle
Cancer Facts & Figures 2015.

3. Cumulative incidence of death resulting from thyroid cancer
Five- and 10-Year Cumulative Incidences of Death Among Patients with Thyroid Cancer
Characteristic
Cumulative incidence of death resulting from thyroid cancer
5 years (%)
10 years (%)
p-value*
All patients
1.9
3.0 —
Age at diagnosis, years
<0.001
<45
0.3
0.5
45-64
3.5
65-74
6.8
10.3
≥75
12.2
16.0
Histologic subtype
Papillary
1.3
2.2
Follicular
2.6
4.8
Medullary
9.3
Anaplastic
77.8
78.9
Other
27.4
29.3
* Gray's test
Yang L et al. J Clin Oncol 2013;31(4):

4. Cumulative incidence of death resulting from thyroid cancer
Five- and 10-Year Cumulative Incidences of Death Among Patients with Thyroid Cancer by Age
Characteristic
Cumulative incidence of death resulting from thyroid cancer
5 years (%)
10 years (%)
p-value*
All patients
1.9
3.0 —
Age at diagnosis, years
<0.001
<45
0.3
0.5
45-64
3.5
65-74
6.8
10.3
≥75
12.2
16.0
Other
27.4
29.3
Yang L et al. J Clin Oncol 2013;31(4):

5. Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Molecular Pathways and Drug Targets
Adapted from Dadu R, Cabanillas ME. Minerva Endocrinol 2012;37(4):

6. Selected Agents in Thyroid Cancer and Some of Their Kinase Targets — Are These “Actionable”?
FGFR
VEGFR
PDGFR
BRAF
CKIT
FLT3
CMET
TIE2
EGFR
RET
Sorafenib X
Sunitinib
Cabozantinib
Vandetanib
Lenvatinib
Lenalidomide
Axitinib
Motesanib
Pazopanib
Vemurafenib
Colevas AD et al. Proc ASCO 2014;Discussant.

7. VEGFRi in Thyroid Cancer — Phase II Trials
Agent
ORR (RECIST)
mPFS
Axitinib1,2
30%-35%
months
Lenvatinib3
50%
12.6 months
Motesanib4
14%
40 weeks
Pazopanib5
49%
11.7 months
Sorafenib6,7,8
15%-23%
16 months – not reached
Sunitinib9,10
18%-31%
12.8 months – not reached
1 Cohen EE et al. J Clin Oncol 2008;26(29): ; 2 Locati LD et al. Cancer 2014;120(17): ; 3 Sherman SI et al. ASCO 2011;Abstract 5503; 4 Sherman SI et al. N Engl J Med 2008;359(1):31-42; 5 Bible KC et al. Lancet Oncol 2010;11(10):962-72; 6 Gupta-Abramson V et al. J Clin Oncol 2008;26(29):4714-9; 7 Kloos RT et al. J Clin Oncol 2009;27(10): ; 8 Ahmed M et al. Eur J Endocrinol 2011;165(2):315-22; 9 Carr LL et al. Clin Cancer Res 2010;16(21):5260-8; 10 Cohen EE et al. WCTC 2011.

8. Investigator-Assessed Response to Treatment in a Phase II Study of Axitinib
Response (n = 60)
No. %
Complete response
Partial response 18 30
Stable disease 23 38
Progressive disease 4 7
Indeterminate* 8 13
Missing 12
Objective response rate
95% CI
18.9 to 43.2
Cohen EE et al. J Clin Oncol 2008;26(29):
CI = confidence interval
* Includes 8 patients who did not meet any response criteria and 7 patients without postbaseline scans 8

9. Efficacy of Pazopanib in a Phase II Study in Progressive, Radioiodine-Refractory, Metastatic Differentiated Thyroid Cancer
Response (n = 37 evaluable patients)
No. (%)
Complete response
0 (0)
Partial response
18 (49)
Follicular (n = 11)
8 (73)
Hürthle cell (n = 11)
5 (45)
Papillary (n = 15)
5 (33)
Bible KC et al. Lancet Oncol 2010;11(10):   9

10. Vandetanib in Locally Advanced or Metastatic Differentiated Thyroid Cancer: Progression-Free Survival in a Randomised, Double-Blind, Phase II Trial
Vandetanib
(n = 72)
Placebo
(n = 73)
Hazard ratio
(95% CI)
p-value
Median progression-free survival
11.1 mo
5.9 mo
0.63 ( )
0.008
CI = confidence interval
Leboulleux S et al. Lancet Oncol 2012;13(9):

11. Phase III Trials of Lenvatinib and Sorafenib in Radioiodine-Refractory Differentiated Thyroid Cancer
SELECT1
DECISION2
Endpoint
Lenvatinib
(n = 261)
Placebo
(n = 131)
Sorafenib
(n = 207)
(n = 210)
Response rate
64.8%
1.5%
12.2%
0.5%
Median PFS
18.3 mo
3.6 mo
10.8 mo
5.8 mo
1 Schlumberger M et al. N Engl J Med 2015;372(7):621-30; 2 Brose MS et al. Lancet 2014;384(9940):

12. Phase III DECISION Study Design
417 patients
Locally advanced or metastatic RAI- refractory DTC
Progression (RECIST) within the previous 14 months
No prior chemotherapy, targeted therapy or thalidomide
Sorafenib
400 mg orally twice daily R
Primary endpoint
Progression-free survival
Randomization 1:1
Placebo
Orally twice daily
Stratified by
Geographical region (North America or Europe or Asia)
Age (<60 or 60 years) 
Progression assessed every 8 weeks (independent central review)
Patients were allowed to receive open-label sorafenib after progression
Secondary endpoints:
Overall survival
Response rate
Safety
Time to progression
Disease control rate
Duration of response
Sorafenib exposure (AUC 0-12 hours)
Brose MS et al. BMC Cancer 2011;11:349; NCT

13. DECISION Study: Response, Survival and AEs
Endpoint
Sorafenib
(n = 207)
Placebo
(n = 210)
Hazard ratio
p-value
Median PFS
10.8 mo
5.8 mo
0.59
<0.0001
Median TTP
11.1 mo
5.7 mo
0.56
Median OS* NR
0.80
0.14
Median OS corrected for crossover† —
0.69
ORR
12.2%
0.5%
Disease control rate
54.1%
33.8%
* 71.4% of patients receiving placebo crossed over at progression
Most AEs were Grade 1 or 2
Most frequent sorafenib-associated AEs
Hand-foot skin reaction: 76.3%
Diarrhea: %
Alopecia: %
Rash or desquamation: 50.2%
Brose MS et al. Lancet 2014;384(9940):319-28; † Brose MS et al. Proc ASCO 2014;Abstract 6060.

14. Treatment until disease progression confirmed by IRR (RECIST v1.1)
SELECT: Phase III Trial of Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer
Patients with DTC (N = 392)
IRR evidence of progression within previous 13 months
131I-refractory disease
Measurable disease
Up to 1 prior VEGF- or VEGFR- targeted therapy
Primary endpoint
PFS 
Secondary endpoints
ORR OS
Safety
Lenvatinib (n = 261)
24 mg daily PO
Stratification
Geographic region (Europe, North America, other)
Prior VEGF/VEGFR- targeted therapy (0, 1)
Age (≤65 years, >65 years)
Treatment until disease progression confirmed by IRR (RECIST v1.1) R
2:1
Lenvatinib
(optional, open label)
Placebo (n = 131)
24 mg daily PO
Schlumberger M et al. N Engl J Med 2015;372(7):

15. SELECT: Patient Characteristics
Variable
Lenvatinib (N = 261)
Placebo (N = 131)
Median age — y 64 61
Male sex — no. (%)
125 (47.9)
75 (57.3)
Region — no. (%)
Europe North America Other
131 (50.2) 77 (29.5) 53 (20.3)
64 (48.9) 39 (29.8) 28 (21.4)
ECOG performance status — no. (%)
0 or or 3
248 (95.0) 13 (5.0)
129 (98.5) 2 (1.5)
One prior treatment regimen with a tyrosine kinase inhibitor — no. (%)
66 (25.3)
27 (20.6)
Histologic subtype of differentiated thyroid cancer — no. (%)
Papillary
Poorly differentiated
Follicular, not Hürthle cell
Hürthle cell
132 (50.6) 28 (10.7) 53 (20.3) 48 (18.4)
68 (51.9) 19 (14.5) 22 (16.8) 22 (16.8)
Metastatic lesions — no. (%)
With bony metastases With pulmonary metastases
104 (39.8) 226 (86.6)
48 (36.6) 124 (94.7)
Schlumberger M et al. N Engl J Med 2015;372(7):

16. SELECT: Kaplan-Meier Estimate of PFS
From The New England Journal of Medicine, Martin Schlumberger, Makoto Tahara, Lori J Wirth, et al, Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer, 372, Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

17. SELECT: Progression-Free Survival by Previous VEGF-Targeted Therapy
Median progression-free survival 
Lenvatinib
Placebo
Hazard ratio
(95% CI)
p-value
TKI naïve (n = 299)
 18.7 mo
 3.6 mo
 0.20
( )
<0.0001
One prior TKI regimen (n = 93)
15.1 mo
3.6 mo
0.22
( )
CI = confidence interval
Schlumberger M et al. N Engl J Med 2015;372(7):

18. SELECT: Progression-Free Survival Subgroup Analysis
Events/N
Median (months)
Lenvatinib
Placebo
HR (95% CI)
Target tumor size at baseline (mm)
≤35
14/65
21/28
0.14 (0.06, 0.33) NE
5.6
35-60
31/72
31/32
0.19 (0.10, 0.36)
16.4
3.7
61-92
31/63
31/34
0.24 (0.13, 0.43)
14.8
3.6
>92
31/61
30/37
0.21 (0.11, 0.42)
13.9
2.4
Histology
Papillary
58/132
58/68
0.30 (0.20, 0.44)
3.5
Poorly differentiated
14/28
18/19
0.21 (0.08, 0.56)
2.1
Follicular
20/53
20/22
0.07 (0.03, 0.21)
18.8
Hürthle cell
15/48
17/22
0.22 (0.10, 0.51)
5.3
Bone metastasis No
60/157
74/83
0.18 (0.12, 0.27)
20.2
Yes
47/104
39/48
0.26 (0.16, 0.42)
Lung metastasis
17/35
7/7
0.24 (0.08, 0.77)
90/226
106/124
0.21 (0.15, 0.29)
18.7
NE = not evaluable/estimable (not reached)
Schlumberger M et al. N Engl J Med 2015;372(7):

19. SELECT: Response Rates
Lenvatinib (N = 261)
Placebo
(N = 131)
Odds ratio (95% CI)
Response rate — no. (%)*
169 (64.8)
2 (1.5)
(12.46–66.86)†
Complete response
4 (1.5)
Partial response
165 (63.2)
Stable disease
60 (23.0)
71 (54.2)
Durable stable disease ≥23 wk
40 (15.3)
39 (29.8)
Progressive disease
18 (6.9)
52 (39.7)
Could not be evaluated
14 (5.4)
6 (4.6)
Median time to first objective response — mo (95% CI)
2.0 (1.9–3.5)
5.6 (1.8–9.4)
* Tumor responses were assessed with the use of Response Criteria in Solid Tumors (RECIST), version 1.1, and were confirmed by independent centralized radiologic review.
† p < for the comparison between the two groups
Schlumberger M et al. N Engl J Med 2015;372(7):

20. SELECT: Best Tumor Response
Treatment group: Lenvatinib
Percent Change From Baseline at Nadir
Best Overall Response (n = 245)
CR (n = 4)
PR (n = 165)
SD (n = 60)
PD (n = 16)
Treatment group: Placebo
Percent Change From Baseline at Nadir
Best Overall Response (n = 126)
PR (n = 2)
SD (n = 71)
PD (n = 51)
NE (n = 2)
CR = complete response; NE = not evaluable/estimable (ie, not reached); PD = progressive disease; PR = partial response; SD = stable disease
From The New England Journal of Medicine, Martin Schlumberger, Makoto Tahara, Lori J Wirth, et al, Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer, 372, Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

21. SELECT: Overall Survival, ITT Population
Lenvatinib
(n = 261)
Placebo
(n = 131)
Hazard ratio
(95% CI)
p-value
Median overall survival NR
0.73
( )
0.1032
No significant difference was observed in RPSFT-adjusted overall survival (p = 0.051), which was used to correct for a potential crossover effect in the placebo arm.
Schlumberger M et al. N Engl J Med 2015;372(7):

22. SELECT: Effect of Age and Lenvatinib Treatment on Overall Survival
Patients stratified by:
Age: Younger (≤ 65 y) vs Older (>65 y)
Region
Prior VEGF-targeted therapy
Median OS was not reached in any subgroup except for older patients in placebo group.
Older patients in the placebo group had worse OS than younger patients
The impact of age was mitigated by lenvatinib treatment
No difference in OS between younger and older patients in lenvatinib group
Brose MS et al. Proc ASCO 2015;Abstract 6048.

23. SELECT: Treatment-Related Adverse Events of Special Interest
Effect (%)
Lenvatinib (N = 261)
Placebo (N = 131)
All grades
Grade ≥3
Hypertension
67.8
41.8
9.2
2.3
Diarrhea
59.4
8.0
8.4
Fatigue or asthenia
59.0
27.5
Decreased appetite
50.2
5.4
11.5
Decreased weight
46.4
9.6
Nausea
41.0
13.7
0.8
Stomatitis
35.6
4.2
3.8
Palmar–plantar erythrodysesthesia syndrome
31.8
3.4
Proteinuria
31.0
10.0
1.5
Schlumberger M et al. N Engl J Med 2015;372(7):

24. Phase II Trials of Everolimus Combined with Sorafenib in Refractory Thyroid Cancer
Endpoint
NCT
(n = 33)
NCT
(n = 38)
Complete response (CR) 0% NR
Partial response (PR) 3%
55%
Stable disease (SD)
37%
Clinical benefit
(CR + PR + SD ≥6 mo)
58%
Disease progression 8%
Median PFS
13.7 mo
NR = not reported
1 Brose MS et al. Proc ASCO 2015;Abstract 6072; 2 Sherman EJ et al. Proc ASCO 2015;Abstract 6069.

25. Clinical Responses to Vemurafenib in Patients with Metastatic Papillary Thyroid Cancer Harboring BRAF V600E Mutation
3 subjects treated
1 PR (31% reduction in pulmonary target lesion)
2 SD
TTP = 11.4 to 13.2 months
Kim KB et al. Thyroid 2013;23(10):

26. Vemurafenib Vemurafenib Phase I study
1/3 thyroid cancer with response; other 2 with stable disease
Phase II study in thyroid cancer completed
Recurrent, unresectable or metastatic papillary thyroid cancer
BRAF V600 mutation-positive by cobas
Radioactive iodine refractory
Evidence of progression within 14 months
VEGFR2i naïve
(n = 26)
Vemurafenib 960 mg BID until disease progression or unacceptable toxicity
VEGFR2i pretreated
(n = 25)
Brose MS et al. ECCO/ESMO 2013;Abstract 28.

27. Vemurafenib Response Rate
VEGFR2i naïve
VEGFR2i pretreated
Complete response
Partial response
35%
26%
Stable disease 6 mo
23%
10%
Clinical benefit rate
58%
36%
Median PFS
15.6 months
6.8 months
Brose MS et al. ESMO/ECC 2013;Abstract 28.

28. Single-Institution, Single-Arm Pilot Study Investigating the Potential for the BRAF Inhibitor Dabrafenib to Induce Radioiodine Uptake in BRAF-Mutant, Radioiodine-Refractory PTC
Primary endpoint: Increased radioiodine uptake by 4mCi 131-I whole body scan.
All 7 patients on study had negative 131-I scans within 14 months of enrollment.
6/10 evaluable patients demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib.
2 patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months.
Thyroglobulin decreased in 4 of 6 patients who received treatment.
Rothenberg SM et al. Clin Cancer Res 2015;21(5):

29. Selumetinib Response Rate
All number (%)
Evaluable number (%)
BRAF V600E number (%)
Total number 39 32 12
Complete response
0 (0%)
Partial response
1 (3%)
1 (8%)
Stable disease
21 (54%)
21 (66%)
9 (75%)
Progression
11 (28%)
10 (31%)
2 (17%)
No data on response
6 (15%)
Hayes DN et al. Clin Cancer Res 2012;18(7):

30. Impact of Selumetinib on 124I Incorporation
Patients with new/increased 124I incorporation after selumetinib
12/20
Patients who went on to receive therapeutic RAI
8/20
Tumor genotype
Patients with increased lesional iodine incorporation after selumetinib (fraction of total)
Patients who received RAI (fraction of total)
BRAF
4/9
1/9
NRAS
5/5
RET/PTC
2/3
1/3
Wild type
Total
12/20
8/20
Ho AL et al. N Engl J Med 2013;368(7):

31. Response to Iodine-131 Therapy with Selumetinib Treatment
Patient number
Genotype
Response
Serum thyroglobulin values (ng/mL)
Before selumetinib (wk 1)
After selumetinib (wk 5)
1 mo after radioiodine
2 mo after radioiodine
6 mo after radioiodine 1
RET/PTC SD
650
780
240
200
740 2 WT
360
880
270
210
194 3
NRAS PR
2,700
3,200
3,700
480 4
510
1,300 NA 31 22 5
220
530
11.3
0.4
<0.2 6
840
570 46
100 7
6,500
1,070
170 66 57 8
BRAF 82 23 14
SD = stable disease; WT = wild type; PR = partial response; NA = not available
Ho AL et al. N Engl J Med 2013;368(7):

32. A Phase I/II Study of Cediranib (CED) and Lenalidomide (LEN) in Patients with Advanced Differentiated Thyroid Cancers
Dose escalation of CED and LEN
PHASE I
Determine maximum tolerated dose (MTD) of combined therapy
Cohort A: CED 30 mg
Cohort B: CED + LEN at MTD
PHASE II
Progression-free survival
Brown RL et al. The Endocrine Society’s 94th Annual Meeting and Expo 2012;Abstract SUN-281.

33. Alternative 3 splice sites
RET
N-terminal signal sequence
10q11.2
3 functional domains
Genotype-phenotype correlations
Signals through multiple pathways to regulate survival, cell growth, differentiation
Cadherin-like domain
Cysteine-rich domain
MEN 2A/FMTC
Transmembrane domain
FMTC
Tyrosine kinase domain
MEN 2B
Alternative 3 splice sites
COOH 33

34. Phase III ZETA Study Design
Patients with unresectable locally advanced or metastatic hereditary or sporadic MTC (N = 331)
2:1 randomization
Vandetanib 300 mg/day n = 231
Placebo n = 100
Follow for progression
Follow for progression
Discontinue blinded treatment at progression*
Optional open-label vandetanib 300 mg/day
Follow for survival
*Progression as assessed by the site investigator
NCT

35. Phase III ZETA Study: PFS by Central Independent Review
Vandetanib 300 mg
Placebo
Time (months)
231
196
169
140 40 1
100 71 57 45 13
No. at risk
0.6
0.8
Progression-Free Survival (proportion)
0.9
0.1
0.2
0.3
0.4
0.5
0.7
1.0 6 12 18 24 30 36
Wells, SA Jr et al: J Clin Oncol 30 (2), 2012: Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved.

36. ZETA Study: Other Notable Features
Significantly higher objective response rate
45% versus 13%; odds ratio = 5.48, 95% CI: , p < 0.001
12 of 13 responses in the placebo arm were seen during treatment with open-label vandetanib
Objective responses were durable
Biochemical response rate
Calcitonin (69% versus 3%; odds ratio = 72.9, 95% CI: , p < 0.001)
CEA (52% versus 2%; odds ratio = 52.0, 95% CI: , p < 0.001)
Statistically significant delay in time to worsening of pain with vandetanib versus placebo (hazard ratio = 0.61; p = 0.006)
Median overall survival: Not yet reached
Wells SA Jr et al. J Clin Oncol 2012;30(2):

37. Cabozantinib
A potent oral targeted therapy that inhibits MET, VEGFR2 and RET1
Clinical activity observed in MTC patients in a Phase I study2
29% objective response rate per RECIST
68% disease control rate
Stable disease for >6 months or confirmed partial response
1 Yakes FM et al. Mol Cancer Ther 2011;10(12): ; 2 Kurzrock R et al. J Clin Oncol 2011;29(19):

38. Secondary: OS, ORR per RECIST
EXAM: Phase III Trial of Cabozantinib in Medullary Thyroid Carcinoma with RECIST Progression at Baseline
Trial design
Endpoints
Study sites
Phase III, randomized, placebo controlled
Primary: PFS
Secondary: OS, ORR per RECIST
Global
Cabozantinib
140 mg qd
N = 219
Progression
Survival follow-up 2
Medullary thyroid carcinoma
Unresectable locally advanced or metastatic disease
Documented RECIST progression within 14 mo
No limit to prior therapies R
Placebo qd
N = 111 1
No crossover allowed.
Schlumberger M et al. Proc ASCO 2015;Abstract 6012.

39. EXAM Study: Survival, Response and AEs
Endpoint
Cabozantinib
Placebo
Hazard
ratio
p-value
Median PFS
11.2 mo
4.0 mo
0.28
<0.001
ORR (all partial responses)*
28% 0% —
* ORR for RET mutation-positive and negative subgroups receiving cabozantinib was 32% and 25%, respectively
Ninety-four percent (170 of 180) of patients with measurable disease at baseline and at least one postbaseline assessment who received cabozantinib had a detectable decrease in target lesion size compared to 27% (24 of 89) of patients in the placebo group.
Common Grade ≥3 cabozantinib-related AEs
Diarrhea:
15.9%
Palmar-plantar erythrodysesthesia:
12.6%
Decreased weight:
4.7%
Decreased appetite:
Nausea:
1.4%
Fatigue:
9.3%
Treatment discontinuation in 16% of cabozantinib and 8% placebo
Elisei R et al. J Clin Oncol 2013;31(29):

40. EXAM: Response and Survival According to RET M918T Status
Endpoint
RET M918T Positive
RET M918T Negative
Cabozantinib (n = 81)
Placebo (n = 45)
Cabozantinib (n = 75)
Placebo (n = 32)
ORR
34% 0%
20%
Median OS (mo)
44.3
18.9
20.2 mo
21.5mo
OS HR (95% CI)
0.60 ( )
1.12 ( )
p-value
0.0260
0.6308
Median PFS (mo)
13.9
4.0
5.7
5.4
PFS HR (95% CI)
0.15 ( )
0.67 ( )
<0.0001
0.1875
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; HR = hazard ratio
Schlumberger M et al. Proc ASCO 2015;Abstract 6012.

41. Genomic Landscape of Anaplastic Thyroid Cancer (ATC)
Exome-seq on 13 cases of ATC including 2 cases of concomitant papillary thyroid cancer (PTC) and ATC in the same patient, showed:
Mutations related with ATC include TP53 (30%); RAS (29%), PIK3CA (23%), STAT (23%), BRAF (15%) and mutations in genes involved in SWI/SNF (15%), CDK (15%) and hedgehog (15%) pathways
Significantly different genomic background with few common root mutations between PTC and ATC
Subclonal oncogenic BRAF and NRAS mutations enriched in PTC but decreased in ATC
Driver mutations TP53, PI3KCA, STAT and PDGFR detectable only in ATC
Capdevila J et al. Proc ASCO 2015;Abstract 6033.

42. RTP ON DEMAND: Head and Neck Cancer Ezra W Cohen
University of California, San Diego 42

43. Anatomic Sites of Head and Neck Cancer
Heterogeneous group of cancers; varying primary sites
Squamous histology in 95% of cases
Anatomic sites
Oral cavity
Nasopharynx/oropharynx/hypopharynx
Larynx
Other anatomic sites
Paranasal sinuses
Lip
Salivary glands
Nasal Cavity
Nasopharynx
Oropharynx
Base of tongue
Soft palate
Tonsillar pillar and fossa
Oral Cavity
Lip
Buccal mucosa
Alveolar ridge
Retromolar trigone
Floor of mouth
Hard palate
Oral tongue (anterior two thirds)
Tongue
Pharynx
Jaw
Hypopharynx
Larynx
Supraglottis
Glottis
Subglottis
Esophagus
Adapted from SEER training modules, head & neck cancer. National Institutes of Health, National Cancer Institute.

44. Two Distinct SCCHN Entities
HPV+
HPV-
Anatomic slide
Tonsil/base of tongue
All sites
Histology
Basaloid
Keratinized
Age
Younger
Older
Gender
3:1 men
Risk factors
Sexual behavior
Alcohol/tobacco
Incidence
Rising
Declining
Survival
Improved
Worse
Molecular
PI3K pathway alterations
p53, p16, CCDN1, FAT1
Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000).1
1 Chaturvedi AK et al. J Clin Oncol 2011;29(32):

45. Gene Expression Subtypes of SCCHN
Proportion
Key characteristics
Basal
31%
Expression patterns in basal layer of human airway epithelium; low levels of SOX2 relative to TP63
Mesenchymal
27%
Expression markers of epithelial to mesenchymal transformation including VIM, DES, TWIST1, PDGFRA/B
Atypical
24%
Includes all HPV+; little evidence for chromosome 7 amplification
Classical
18%
Heaviest smoking histories; elevation expression levels of oxidative stress response genes, including NFE2L2
The Cancer Genome Atlas Network. Nature 2015;517:576-82

46. Treatment Algorithm for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
R/M HNSCC
Locally recurrent or
distant metastases
Fit with aggressive
symptomatic disease
Good performance
status with active
disease
Frail or indolent
asymptomatic disease
Cisplatin/carboplatin
+ 5-FU + cetuximab
Platinum doublet*
Cisplatin/paclitaxel
Carboplatin/paclitaxel
Cisplatin/docetaxel
+/- cetuximab
Single-agent therapy:
Paclitaxel/docetaxel
Cetuximab*
Capecitabine
Vinorelbine
Methotrexate
Observation
Best supportive care
* Consider if platinum resistant
Price KA, Cohen EE. Curr Treat Options Oncol 2012;13(1):35-46.

47. Single-Agent Response Rates of EGFR-Targeted mAbs and TKIs in SCCHN
Drug
Phase
Reference RR
Cetuximab II
Vermorken et al, 2007
13%
Erlotinib
Soulieres et al, 2004 4%
Gefitinib
Cohen et al, 2003
11%
Cohen et al, 2005 2%
III
Stewart et al, 2009 8%
Lapatinib
Abidoye et al, 2006 (ASCO) 0%
Zalutumumab
Machiels et al, 2010 (ASCO) 6%
Vermorken JB et al. J Clin Oncol 2007;25(16):2171-7; Soulieres D et al. J Clin Oncol 2004;22(1):77-85; Cohen EE et al. J Clin Oncol 2003;21(10):1980-7; Cohen EE et al. Clin Cancer Res 2005;11(23): ; Kirby AM et al. Br J Cancer 2006;94(5):631-6; Stewart JS et al. J Clin Oncol 2009;27(11): ; Abidoye OO et al. Proc ASCO 2006;Abstract 5568; Machiels JH et al. Proc ASCO 2010;Abstract LBA5506; Seiwert TY et al. ESMO 2010;Abstract 1010PD. -

48. R EXTREME Study Design Group A Cetuximab 400 mg/m2 initial dose
then 250 mg/m2 weekly +
EITHER carboplatin (AUC 5, d1)
OR cisplatin (100 mg/m2 IV, d1)
+ 5-FU (1,000 mg/m2 IV, d1-4):
3-week cycles
Group B
EITHER carboplatin (AUC 5, d1)
OR cisplatin (100 mg/m2 IV, d1)
+ 5-FU (1,000 mg/m2 IV, d1-4):
3-week cycles
6 chemotherapy cycles maximum
Cetuximab
No treatment
Progressive disease or unacceptable toxicity
Vermorken JB et al. N Engl J Med 2008;359(11):

49. EXTREME Study: Overall Survival
Cetuximab + platinum/fluorouracil
(n = 222)
Platinum/fluorouracil alone
(n = 220)
Hazard ratio
(95% CI)
p-value
Median overall survival
10.1 mo
7.4 mo
0.80
( )
0.04
Vermorken JB et al. N Engl J Med 2008;359(11):

51. Phase II Trial of Dacomitinib: Response, Survival and Grade 3/4 AEs
Response (n = 63)
n (%)
Complete response (CR)
0 (0)
Partial response (PR)
8 (12.7)
Stable disease (SD)
≥24 weeks <24 weeks
36 (57.1)
9 (14.3)
27 (42.9)
Progressive disease
17 (27)
Indeterminate
2 (3.2)
Objective response rate (CR + PR)
Clinical benefit rate (CR + PR + SD ≥24 weeks)
17 (27.0)
Survival (n = 69)
Median progression-free survival
12.1 weeks
Median overall survival
34.6 weeks
Most common Grade ≥3 AEs
Diarrhea: %
Acneiform dermatitis: 8.7%
Fatigue: %
Abdul Razak AR et al. Ann Oncol 2013;24(3):761-9.

52. Chemotherapy + cetuximab + VTX-2337 Chemotherapy + cetuximab + placebo
ACTIVE8: Phase II Trial of Chemotherapy and Cetuximab in Combination with VTX-2337 in Recurrent or Metastatic SCCHN
Trial ID: NCT
Estimated enrollment: 175 (open)
Chemotherapy + cetuximab + VTX-2337
Up to 6 cycles
Eligibility criteria:
Locoregionally recurrent or metastatic SCCHN
PS 0 or 1
Cetuximab R PD
Chemotherapy + cetuximab + placebo
Up to 6 cycles
1:1
Cetuximab
Primary endpoint: Progression-free survival
Accessed April 2015.

53. SPECTRUM: Cisplatin + 5-FU ± Panitumumab in Recurrent/Metastatic SCCHN
Open-label, randomized Phase III trial
Stratified by previous treatment, primary tumor site, ECOG PS
Max six 3-wk cycles
Panitumumab 9 mg/kg day 1 Cisplatin 100 mg/m2 day 1 5-FU 1,000 mg/m2 days 1-4 (n = 327)
Optional panitumumab maintenance q3wk
Patients with distant metastatic and/or locally recurrent SCCHN, ECOG PS ≤1
(N = 657)
Cisplatin 100 mg/m2 day 1 5-FU 1,000 mg/m2 days 1-4 (n = 330)
Primary endpoint: OS
Secondary endpoints: PFS, ORR, DOR, TTR, safety
Vermorken JB et al. Lancet Oncol 2013;14(8):

54. SPECTRUM Study: Overall Survival
Cisplatin/5-FU + panitumumab
(n = 327)
Cisplatin/5-FU (n = 330)
Hazard ratio
(95% CI)
p-value
Median overall survival
11.1 mo
9.0 mo
0.873
( )
0.1403
Vermorken JB et al. Lancet Oncol 2013;14(8):

55. Mechanisms of Resistance to EGFRi
Chen LF et al. Clin Cancer Res 2010;16: 55 55

56. Phase II Study of Afatinib versus Cetuximab
Afatinib 50 mg po daily
Cetuximab 400/250 mg/m2 IV weekly
Metastatic recurrent HNSCC
N = 124 (62 per arm) R
Continue until PD or undue AEs
Continue until PD or undue AEs
Cetuximab 400/250 mg/m2 IV weekly
Afatinib 50 mg po daily
Stratum: No. prior chemotherapies for R/M disease (0 or ≥1)
Stage 1
Stage 2
CT/MRI q8wk
HNSCC = head and neck squamous cell carcinoma; IV = intravenous; PD = progressive disease;
CT = computed tomography scan; MRI = magnetic resonance imaging; R/M = recurrent/metastatic
Seiwert TY et al. Ann Oncol 2014;25(9):

57. Independent central review
Phase II Study of Afatinib versus Cetuximab: Maximum Tumor Shrinkage in Target Lesions
Investigator review
Independent central review
Afatinib
Cetuximab
Total randomized, n 62
ORR (CR, PR), n (%)
95% CI
10 (16.1)
4 (6.5)
5 (8.1)
6 (9.7)
p-value
0.09
0.78
Seiwert TY et al. Ann Oncol 2014;25(9):

58. Phase II Study of Afatinib versus Cetuximab: Progression-Free and Overall Survival
Stage 1
Afatinib
(n = 62)
Cetuximab
Hazard ratio
(95% CI)
p-value
Median progression-free survival
13.0 wk
15.0 wk
0.93
( )
0.71
Stage 2
(n = 36)
(n = 32)
Hazard ratio (95% CI)
9.3 wk
5.7 wk
0.64
( )
0.08
Stage 1 and Stage 2
Median overall survival
35.9 wk
47.1 wk
1.06
( )
0.78
Seiwert TY et al. Ann Oncol 2014;25(9):

59. Phase II Study of Afatinib versus Cetuximab: Tumor Shrinkage in Stage 2
Afatinib after prior cetuximab in Stage 1, n
Cetuximab after prior afatinib in Stage 1, n
Maximum % tumor shrinkage
≥20% 6 11
≥0% and <20% 12 7
>-30% and <0%
≤30% 1
Seiwert TY et al. Ann Oncol 2014;25(9):

60. Phase II Study of Afatinib versus Cetuximab: Treatment-Related Adverse Events in ≥10% of Patients (Stage 1)
Afatinib (n = 61)
Cetuximab (n = 60)
All grades
Grade 3-4
Total, n (%)
59 (96.7)
32 (52.5)
51 (85.0)
11 (18.4)
Rash/acne
48 (78.7)
11 (18.0)
46 (76.7)
5 (8.3)
Diarrhea
9 (14.8)
12 (20.0)
Stomatitis
21 (34.4)
7 (11.5)
14 (23.3)
Fatigue
20 (32.8)
3 (4.9)
13 (21.7)
1 (1.7)
Nausea
17 (27.9)
1 (1.6)
Vomiting
10 (16.4)
8 (13.3)
Dry skin
15 (25.0)
Dehydration
8 (13.1)
5 (8.2)
Decreased appetite
Nail effects
4 (6.6)
6 (10.0)
Ocular effects
Constipation
2 (3.3)
7 (11.7)
Seiwert TY et al. Ann Oncol 2014;25(9):

61. LUX-Head & Neck 1: Second-Line Afatinib versus Methotrexate in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Progressing After Platinum-Based Therapy
Trial design
Endpoints
Study sites
Phase III, randomized, open-label
Primary: PFS
Key secondary: OS
Global
Afatinib 40 mg qd
N = 316 2
Relapsed/metastatic squamous cell carcinoma
Failure of platinum-based chemotherapy for relapsed/metastatic disease
Documented PD
PS 0-1
Maximum of 1 chemotherapy regimen for relapsed/metastatic disease
No prior EGFR TKIs R
Treatment until PD
Methotrexate 40 mg/m2 qwk
N = 158 1
PFS = progression-free survival; OS = overall survival; PD = progressive disease
Machiels J et al. ESMO 2014;Abstract LBA29_PR.

62. LUX-Head & Neck 1: Efficacy
Endpoint
Afatinib
(n = 322)
Methotrexate (n = 161)
Hazard ratio
p-value
Progression-free survival
2.6 mo
1.7 mo
0.80
0.03
Overall survival
6.8 mo
6.0 mo
0.96 NS
Disease control rate
49.1%
38.5% —
0.04
Overall response rate
10.2%
5.6%
0.10
Afatinib delayed deterioration of global health status, pain and swallowing (all p ≤0.03) and provided improvement in pain (p = 0.03)
Most frequent Grade 3/4 drug-related AEs
Afatinib: Rash/acne (9.7%), diarrhea (9.4%)
Methotrexate: Leukopenia (15.6%), stomatitis (8.1%)
Fewer treatment-related dose reductions, discontinuations and fatal events with afatinib
Machiels J et al. ESMO 2014;Abstract LBA29_PR.

63. LUX-Head & Neck 1: Select Drug-Related Adverse Events
Afatinib (n = 320)
Methotrexate (n = 160)
All grades
Grade 3
Grade 4
 More frequent with afatinib
Rash/acne 74 10 8
Diarrhea 72 9 1 12 2
Paronychia 14
Decreased appetite 13 3
Vomiting
<1
Dry skin 11
More frequent with methotrexate
Stomatitis 39 6 43
Fatigue 25 32
Nausea 20 23
Neutropenia 19
Anemia 7 5
Machiels J et al. ESMO 2014;Abstract LBA29_PR.

64. LUX-Head & Neck 2: Adjuvant Afatinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Trial design
Endpoints
Study sites
Phase III, randomized, placebo controlled
Primary: DFS
Secondary: 2-year DFS rate, OS, safety
Global
Afatinib 40 mg qd
N = 446
Locally advanced squamous cell carcinoma of the head and neck
Unresected
Stage III–IVb
Previous chemoradiation therapy
Excludes nonsmokers with oropharyngeal cancer
PS 0-1
NED after chemoradiation therapy 2 R
Treatment for 18 months/ until recurrence
Placebo qd
N = 223 1
NED = no evidence of disease

65. Basis for Immunotherapy — Immune Escape
Expression of PD-L1 on tumor cells and macrophages can suppress immune surveillance.
In mouse models antibodies blocking PD-1/PD-L1 interaction lead to tumor rejection.
Clinical prognosis correlates with presence of TILs and PD-L1 expression in multiple cancers.
Adapted from Seiwert TY et al. Proc ASCO 2014;Abstract 6011; Melero I et al. Clin Cancer Res 2013;19(5):

66. KEYNOTE-012: Multicenter, Nonrandomized, Phase Ib Squamous Cell Carcinoma of the Head and Neck Expansion Cohort
Recurrent or metastatic head and neck cancer
PD-L1-positive
Investigator- assessed HPV status
HPV-negative cohort
Pembrolizumab 10 mg/kg q2wk
Treat until PD*
HPV-positive
cohort
Pembrolizumab 10 mg/kg q2wk
* Treatment beyond initial PD allowed; radiation therapy to progressive lesion allowed
PD = progressive disease
Seiwert TY et al. Proc ASCO 2014;Abstract 6011.

67. KEYNOTE-012: Best Overall Response
Total head/neck
N = 56
HPV (+)
N = 20
HPV (-)
N = 36*
Response evaluation
n (%)
95% CI
Complete response (CR)
1 (1.8)
0.0, 9.6
1 (5.0)
0.1, 24.9
0 (0.0)
0.0, 9.7
Partial response (PR)
10 (17.9)
8.9, 30.4
3 (15.0)
3.2, 37.9
7 (19.4)
8.2, 36.0
Best overall response
(CR + PR)†
11 (19.6)
10.2, 32.4
4 (20.0)
5.7, 43.7
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
No assessment
4 (7.1)
2.0, 17.3
3 (8.3)
1.8, 22.5
Based on RECIST 1.1 per site assessment; includes confirmed and unconfirmed responses
* Includes 2 patients for whom HPV data were unavailable.
† A single patient with PD followed by PR on treatment was classified as PR.
PD-L1 expression correlates with response
Using a Youden-Index derived, preliminary PD-L1 cut point:
Above cut point: 45.5% (5/11) RR
Below cut point: 11.4% (5/44) RR
Seiwert TY et al. Proc ASCO 2014;Abstract 6011.

68. KEYNOTE-012: PD-L1 Screening Results
104 patients screened:
PD-L1-positive: 78% (81)
Study eligible n = 61*
HPV (-) n = 36
HPV (+) n = 23
HPV (na) n = 2
PD-L1-negative: 22% (23)
PD-L1 staining in tumors of screened patients (N = 104)
Staining (%)
1-10
11-20
21-30
31-40
41-50
51-60
61-70
71-80
81-90
91-100 n
26* 24 8 9 3 2 4 21
* Three patients with tumor (-) but stroma (+) by IHC
Seiwert TY et al. Proc ASCO 2014;Abstract 6011.

69. KEYNOTE-012: Efficacy by HPV Status
Clinical endpoint
Overall
(n = 117)
HPV (+)
(n = 34)
HPV (-)
(n = 81)
ORR, n (%)
29 (24.8)
7 (20.6)
22 (27.2)
Complete response
1 (0.9)
1 (2.9)
0 (0)
Partial response
28 (23.9)
6 (17.6)
Seiwert TY et al. Proc ASCO 2015;Abstract LBA6008.

70. KEYNOTE-012: Select Drug-Related Adverse Events
All grades
Grades 3-5 n %
Any drug-related event 35
58.3 10
16.7
Fatigue
0.0
Pruritus 6
10.0
Rash 5
8.3 2
3.3
Nausea 4
6.7
Decreased appetite 3
5.0
Myalgia
Seiwert TY et al. Proc ASCO 2014;Abstract 6011.

71. Phase I Study of MEDI4736 in Recurrent/Metastatic SCCHN: Results Summary
Efficacy outcomes
29 SCCHN patients evaluable
7 patients had radiographic shrinkage of target tumor lesions ranging from 7% to 76%
5 of 7 have been followed for at least 12 weeks
4 patients have partial responses
0 patients have evidence of objective progression
Safety outcomes
50 patients evaluable
39% had treatment-related AEs (TRAEs)
Most frequent were nausea, diarrhea, rash and dizziness
No pneumonitis observed
No TRAE led to treatment discontinuation
Fury M et al. Proc ESMO 2014;Abstract 988PD.

72. Role for Induction Chemotherapy (IC) in Locally Advanced Head and Neck Cancer Prior to Concomitant Chemoradiation Therapy (CCRT)
Meta-analysis of randomized controlled trials showed with IC:
No significant effect on OS or PFS
Advantage in complete response and disease control
Trend to improved overall survival
Selected patients may benefit from the addition of IC to CCRT
Future studies are warranted to evaluate role of IC in subpopulations of patients with locally advanced head and neck cancer
Popovtzer A et al. ASCO 2015;Abstract 6068.

73. Elective Neck Dissection (n=243) Physical Exam + Ultrasonography
NCT : Phase III Trial of Elective Neck Dissection versus Watch and Wait Policy (Therapeutic Neck Dissection)
Elective Neck Dissection (n=243)
Physical Exam
Histologically proven SCC cT1/T2N0 oral cavity squamous cell cancers
Amenable to per-oral excision
Treatment naive R1 R2
Watch & Wait/
Therapeutic Neck
Dissection
(n=253)
Physical Exam + Ultrasonography
Treatment
Follow-Up
D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.

74. Survival: Elective versus Therapeutic Neck Dissection
Endpoint
Elective neck dissection (n = 243)
Therapeutic neck dissection (n = 253)
Hazard ratio
p-value
Three-year overall survival
80%
67.5%
0.64
0.014
Three-year disease-free survival
69.5%
45.9%
0.45
<0.001
D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.

75. PET-CT guided “active surveillance”
PET-NECK: A Phase III Trial Comparing PET-CT Guided Active Surveillance to Planned Neck Dissection (ND) for Locally Advanced Nodal Metastases in Patients with HNSCC Treated with Primary Radical Chemoradiation Therapy (CRT)
PET-CT guided “active surveillance”
(n = 282 )
Oropharyngeal, laryngeal, oral, hypopharyngeal or occult HNSCC
Nodal metastases Stage N2 (a, b, or c) or N3 on CT/MRI
Indication for curative radical concurrent CRT
Suitable for ND
CRT
PET-CT & assessment* R
1:1
ND before or after CRT
Standard treatment
“planned ND” (n = 282)
CT & assessment*
* 9-13 wk after CRT completion
Mehanna H et al. ASCO 2015;Abstract 6009.

76. PET-NECK Trial Conclusions
PET-CT guided surveillance resulted in equivalent OS to standard treatment of planned ND:
Only 20% of patients received neck dissections
Fewer neck dissection complications
Fewer serious adverse events
Similar quality of life
Surveillance arm was more cost-effective
Mehanna H et al. ASCO 2015;Abstract 6009.