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RTP ON DEMAND:
Thyroid Cancer
Ezra W Cohen
University of California, San Diego
Thyroid Cancer
Newly Detected 2015 (n = 62,450)
Follicular
10%
Anaplastic
Hürthle
1%
5%
Medullary
2%
Papillary
82%
Cancer Facts & Figures 2015.
Five- and 10-Year Cumulative Incidences of
Death Among Patients with Thyroid Cancer
Characteristic
All patients
Age at diagnosis, years
<45
45-64
65-74
≥75
Histologic subtype
Papillary
Follicular
Medullary
Anaplastic
Other
Cumulative incidence of death resulting
from thyroid cancer
5 years (%)
10 years (%)
p-value*
1.9
3.0
—
0.3
1.9
6.8
12.2
0.5
3.5
10.3
16.0
1.3
2.6
9.3
77.8
27.4
2.2
4.8
9.3
78.9
29.3
* Gray's test
Yang L et al. J Clin Oncol 2013;31(4):468-74.
<0.001
<0.001
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*
1.9
3.0
—
<45
0.3
0.5
45-64
1.9
3.5
65-74
6.8
10.3
≥75
12.2
16.0
Other
27.4
29.3
All patients
Age at diagnosis, years
Yang L et al. J Clin Oncol 2013;31(4):468-74.
<0.001
<0.001
Radioactive Iodine-Refractory Differentiated Thyroid
Cancer: Molecular Pathways and Drug Targets
Adapted from Dadu R, Cabanillas ME. Minerva Endocrinol 2012;37(4):335-56.
Selected Agents in Thyroid Cancer and Some of
Their Kinase Targets — Are These “Actionable”?
Agent
VEGFR
PDGFR
BRAF
CKIT
Sorafenib
X
X
X
X
Sunitinib
X
X
Cabozantinib
X
Vandetanib
X
Lenvatinib
FGFR
X
X
FLT3
CMET
TIE2
EGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Axitinib
X
X
Motesanib
X
X
X
Pazopanib
X
X
X
Colevas AD et al. Proc ASCO 2014;Discussant.
X
X
X
Lenalidomide
Vemurafenib
RET
VEGFRi in Thyroid Cancer — Phase II Trials
Agent
ORR (RECIST)
mPFS
30%-35%
16.1-18.1 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
Axitinib1,2
1 Cohen
EE et al. J Clin Oncol 2008;26(29):4708-13; 2 Locati LD et al. Cancer 2014;120(17):2694703; 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):1675-84; 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.
Investigator-Assessed Response to Treatment
in a Phase II Study of Axitinib
Response (n = 60)
No.
%
Complete response
0
0
Partial response
18
30
Stable disease
23
38
Progressive disease
4
7
Indeterminate*
8
13
Missing
7
12
Objective response rate
18
30
95% CI
18.9 to 43.2
CI = confidence interval
* Includes 8 patients who did not meet any response criteria and 7 patients without
postbaseline scans
Cohen EE et al. J Clin Oncol 2008;26(29):4708-13.
Efficacy of Pazopanib in a Phase II Study in
Progressive, Radioiodine-Refractory, Metastatic
Differentiated Thyroid Cancer
Response (n = 37 evaluable patients)
Complete response
Partial response
No. (%)
0 (0)
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):962-72.
Vandetanib in Locally Advanced or Metastatic
Differentiated Thyroid Cancer: Progression-Free
Survival in a Randomised, Double-Blind, Phase II
Trial
Median
progression-free
survival
Vandetanib
(n = 72)
Placebo
(n = 73)
Hazard ratio
(95% CI)
11.1 mo
5.9 mo
0.63
(0.54-0.74)
CI = confidence interval
Leboulleux S et al. Lancet Oncol 2012;13(9):897-905.
p-value
0.008
Phase III Trials of Lenvatinib and Sorafenib in
Radioiodine-Refractory Differentiated Thyroid
Cancer
SELECT1
Endpoint
Response rate
Median PFS
1 Schlumberger
DECISION2
Lenvatinib
(n = 261)
Placebo
(n = 131)
Sorafenib
(n = 207)
Placebo
(n = 210)
64.8%
1.5%
12.2%
0.5%
18.3 mo
3.6 mo
10.8 mo
5.8 mo
M et al. N Engl J Med 2015;372(7):621-30; 2 Brose MS et al. Lancet
2014;384(9940):319-28.
Phase III DECISION Study Design
417 patients
• Locally advanced or
metastatic RAIrefractory DTC
• Progression
(RECIST) within the
previous 14 months
• No prior
chemotherapy,
targeted therapy or
thalidomide
•
•
•
Sorafenib
400 mg orally
twice daily
R
Randomization 1:1
Primary endpoint
Progression-free
survival
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; www.clinicaltrials.gov, NCT00984282.
DECISION Study: Response, Survival and AEs
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
<0.0001
Median OS*
NR
NR
0.80
0.14
Median OS corrected for
crossover†
—
—
0.69
—
ORR
12.2%
0.5%
—
<0.0001
Disease control rate
54.1%
33.8%
—
<0.0001
Endpoint
* 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:
• Diarrhea:
• Alopecia:
• Rash or desquamation:
76.3%
68.6%
67.1%
50.2%
Brose MS et al. Lancet 2014;384(9940):319-28; † Brose MS et al. Proc ASCO 2014;Abstract 6060.
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 VEGFRtargeted therapy
Stratification
• Geographic
region (Europe,
North America,
other)
• Prior
VEGF/VEGFRtargeted therapy
(0, 1)
• Age (≤65 years,
>65 years)
Lenvatinib (n = 261)
24 mg daily PO
R
Schlumberger M et al. N Engl J Med 2015;372(7):621-30.
2:1
Treatment until
disease
progression
confirmed
by IRR
(RECIST v1.1)
Placebo (n = 131)
24 mg daily PO
Primary
endpoint
• PFS
Secondary
endpoints
• ORR
• OS
• Safety
Lenvatinib
(optional,
open label)
SELECT: Patient Characteristics
Variable
Lenvatinib (N = 261)
Placebo (N = 131)
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 1
2 or 3
248 (95.0)
13 (5.0)
129 (98.5)
2 (1.5)
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)
Median age — y
One prior treatment regimen with a tyrosine
kinase inhibitor — no. (%)
Schlumberger M et al. N Engl J Med 2015;372(7):621-30.
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, 621-30. Copyright © 2015
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
SELECT: Progression-Free Survival by
Previous VEGF-Targeted Therapy
Median progressionfree survival
Hazard ratio
(95% CI)
p-value
<0.0001
Lenvatinib
Placebo
TKI naïve (n = 299)
18.7 mo
3.6 mo
0.20
(0.14-0.27)
One prior TKI regimen
(n = 93)
15.1 mo
3.6 mo
0.22
(0.12-0.41)
CI = confidence interval
Schlumberger M et al. N Engl J Med 2015;372(7):621-30.
<0.0001
SELECT: Progression-Free Survival
Subgroup Analysis
Events/N
Median (months)
Lenvatinib
Placebo
HR (95% CI)
Lenvatinib
Placebo
≤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
Papillary
58/132
58/68
0.30 (0.20, 0.44)
16.4
3.5
Poorly differentiated
14/28
18/19
0.21 (0.08, 0.56)
14.8
2.1
Follicular
20/53
20/22
0.07 (0.03, 0.21)
18.8
2.4
Hürthle cell
15/48
17/22
0.22 (0.10, 0.51)
NE
5.3
No
60/157
74/83
0.18 (0.12, 0.27)
20.2
3.7
Yes
47/104
39/48
0.26 (0.16, 0.42)
14.8
2.1
No
17/35
7/7
0.24 (0.08, 0.77)
14.8
2.4
Yes
90/226
106/124
0.21 (0.15, 0.29)
18.7
3.6
Target tumor size at
baseline (mm)
Histology
Bone metastasis
Lung metastasis
NE = not evaluable/estimable (not reached)
Schlumberger M et al. N Engl J Med 2015;372(7):621-30.
SELECT: Response Rates
Lenvatinib
(N = 261)
Placebo
(N = 131)
Odds ratio
(95% CI)
169 (64.8)
2 (1.5)
28.87
(12.46–66.86)†
4 (1.5)
0
Partial response
165 (63.2)
2 (1.5)
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)
Response rate — no. (%)*
Complete response
* 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 < 0.001 for the comparison between the two groups
Schlumberger M et al. N Engl J Med 2015;372(7):621-30.
Percent Change From Baseline at Nadir
Percent Change From Baseline at Nadir
SELECT: Best Tumor Response
Treatment group: Lenvatinib
Best Overall Response (n = 245)
CR (n = 4)
PR (n = 165)
SD (n = 60)
PD (n = 16)
Treatment group: Placebo
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, 621-30. Copyright © 2015
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
SELECT: Overall Survival, ITT Population
Median overall
survival
Lenvatinib
(n = 261)
Placebo
(n = 131)
Hazard ratio
(95% CI)
NR
NR
0.73
(0.50-1.07)
p-value
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):621-30.
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.
SELECT: Treatment-Related Adverse Events of
Special Interest
Lenvatinib (N = 261)
Placebo (N = 131)
All grades
Grade ≥3
Hypertension
67.8
41.8
9.2
2.3
Diarrhea
Fatigue or asthenia
Decreased appetite
Decreased weight
Nausea
Stomatitis
Palmar–plantar
erythrodysesthesia
syndrome
59.4
59.0
50.2
46.4
41.0
35.6
8.0
9.2
5.4
9.6
2.3
4.2
8.4
27.5
11.5
9.2
13.7
3.8
0
2.3
0
0
0.8
0
31.8
3.4
0.8
0
Proteinuria
31.0
10.0
1.5
0
Effect (%)
Schlumberger M et al. N Engl J Med 2015;372(7):621-30.
All grades Grade ≥3
Phase II Trials of Everolimus Combined with
Sorafenib in Refractory Thyroid Cancer
NCT012639511
(n = 33)
NCT011413092
(n = 38)
Complete response (CR)
0%
NR
Partial response (PR)
3%
55%
Stable disease (SD)
55%
37%
Clinical benefit
(CR + PR + SD ≥6 mo)
58%
NR
Disease progression
NR
8%
13.7 mo
NR
Endpoint
Median PFS
NR = not reported
1 Brose
MS et al. Proc ASCO 2015;Abstract 6072; 2 Sherman EJ et al. Proc ASCO 2015;Abstract 6069.
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):1277-83.
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 mutationpositive by cobas
Radioactive iodine
refractory
Evidence of
progression
within 14 months
VEGFR2i naïve
(n = 26)
VEGFR2i pretreated
(n = 25)
Brose MS et al. ECCO/ESMO 2013;Abstract 28.
Vemurafenib
960 mg BID until
disease progression
or unacceptable
toxicity
Vemurafenib Response Rate
Complete response
Partial response
Stable disease
6 mo
Clinical benefit rate
Median PFS
Brose MS et al. ESMO/ECC 2013;Abstract 28.
VEGFR2i naïve
VEGFR2i
pretreated
0
0
35%
26%
23%
10%
58%
36%
15.6 months
6.8 months
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):1028-35.
Selumetinib Response Rate
All
number (%)
Evaluable
number (%)
BRAF V600E
number (%)
39
32
12
Complete response
0 (0%)
0 (0%)
0 (0%)
Partial response
1 (3%)
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%)
Total number
Hayes DN et al. Clin Cancer Res 2012;18(7):2056-65.
Impact of Selumetinib on 124I Incorporation
N = 20
Patients with new/increased
124I
incorporation after selumetinib
12/20
Patients who went on to receive therapeutic RAI
8/20
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
5/5
RET/PTC
2/3
1/3
Wild type
1/3
1/3
12/20
8/20
Tumor genotype
Total
Ho AL et al. N Engl J Med 2013;368(7):623-32.
Response to Iodine-131 Therapy with
Selumetinib Treatment
Patient
number
Genotyp
e
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
SD
360
880
270
210
194
3
NRAS
PR
2,700
3,200
3,700
740
480
4
NRAS
PR
510
1,300
NA
31
22
5
NRAS
PR
220
530
11.3
0.4
<0.2
6
NRAS
SD
840
570
46
31
100
7
NRAS
PR
6,500
1,070
170
66
57
8
BRAF
PR
82
650
NA
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):623-32.
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
PHASE II
Cohort A:
CED 30 mg
Cohort B:
CED + LEN at MTD
Progression-free survival
Brown RL et al. The Endocrine Society’s 94th Annual Meeting and Expo 2012;Abstract SUN-281.
RET
• 10q11.2
• 3 functional domains
• Genotype-phenotype
correlations
• Signals through multiple
pathways to regulate
survival, cell growth,
differentiation
N-terminal signal
sequence
Cadherin-like
domain
MEN 2A/FMTC
Cysteine-rich domain
Transmembrane
domain
FMTC
Tyrosine kinase
domain
MEN 2B
Alternative 3
splice sites
COOH
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
www.clinicaltrials.gov, NCT00410761.
Progression-Free Survival (proportion)
Phase III ZETA Study: PFS by Central Independent
Review
1.0
0.9
Vandetanib 300 mg
0.8
Placebo
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
6
12
24
30
36
Time (months)
No. at risk
Vandetanib 300 mg 231
Placebo 100
18
196
169
140
40
1
0
71
57
45
13
0
0
Wells, SA Jr et al: J Clin Oncol 30 (2), 2012: 134-41. Reprinted with permission. © 2012 American
Society of Clinical Oncology. All rights reserved.
ZETA Study: Other Notable Features
• Significantly higher objective response rate
– 45% versus 13%; odds ratio = 5.48, 95% CI: 2.9910.79, 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:
26.2-303.2, p < 0.001)
– CEA (52% versus 2%; odds ratio = 52.0, 95% CI: 16.0320.3, 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):134-41.
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):2298-308; 2 Kurzrock R et al. J Clin Oncol
2011;29(19):2660-6.
EXAM: Phase III Trial of Cabozantinib in
Medullary Thyroid Carcinoma with RECIST
Progression at Baseline
Trial design
Phase III, randomized,
placebo controlled
Endpoints
Study sites
Primary: PFS
Secondary: OS, ORR per RECIST
Global
2
•
•
•
•
Medullary thyroid carcinoma
Unresectable locally advanced
or metastatic disease
Documented RECIST
progression within 14 mo
No limit to prior therapies
Cabozantinib
140 mg qd
N = 219
R
1
No crossover allowed.
Schlumberger M et al. Proc ASCO 2015;Abstract 6012.
Placebo qd
N = 111
P
r
o
g
r
e
s
s
i
o
n
Survival
followup
EXAM Study: Survival, Response and AEs
Endpoint
Median PFS
ORR (all partial responses)*
Cabozantinib
Placebo
Hazard
ratio
11.2 mo
4.0 mo
0.28
<0.001
28%
0%
—
<0.001
p-value
* 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:
Palmar-plantar erythrodysesthesia:
Decreased weight:
Decreased appetite:
Nausea:
Fatigue:
Treatment discontinuation in 16% of cabozantinib and 8% placebo
Elisei R et al. J Clin Oncol 2013;31(29):3639-46.
15.9%
12.6%
4.7%
4.7%
1.4%
9.3%
EXAM: Response and Survival According to
RET M918T Status
RET M918T Positive
RET M918T Negative
Cabozantinib
(n = 81)
Placebo
(n = 45)
Cabozantinib
(n = 75)
Placebo
(n = 32)
ORR
34%
0%
20%
0%
Median OS (mo)
44.3
18.9
20.2 mo
21.5mo
OS HR (95% CI)
0.60 (0.38-0.95)
1.12 (0.70-1.82)
0.0260
0.6308
Endpoint
p-value
Median PFS (mo)
13.9
PFS HR (95% CI)
0.15 (0.08-0.28)
0.67 (0.37-1.23)
<0.0001
0.1875
p-value
4.0
5.7
5.4
ORR = objective response rate; OS = overall survival; PFS = progression-free survival;
HR = hazard ratio
Schlumberger M et al. Proc ASCO 2015;Abstract 6012.
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.
RTP ON DEMAND:
Head and Neck Cancer
Ezra W Cohen
University of California, San Diego
Anatomic Sites of Head and Neck Cancer
• Heterogeneous group of cancers; varying primary sites
• Squamous histology in 95% of cases
• Anatomic sites
Nasal Cavity
– Oral cavity
– Nasopharynx/oropharynx/hypopharynx
– Larynx
Nasopharynx
• Other anatomic sites
– Paranasal sinuses
– Lip
– Salivary glands
Oral Cavity
Lip
Buccal mucosa
Alveolar ridge
Retromolar
trigone
Floor of mouth
Hard palate
Oral tongue
(anterior two
thirds)
Tongue
Jaw
Oropharynx
Base of tongue
Soft palate
Pharynx
Tonsillar pillar
and fossa
Hypopharynx
Larynx
Supraglottis
Glottis
Subglottis
Esophagus
Adapted from SEER training modules, head & neck cancer. National Institutes of Health, National
Cancer Institute.
Two Distinct SCCHN Entities
HPV+
HPV-
Tonsil/base of tongue
All sites
Histology
Basaloid
Keratinized
Age
Younger
Older
Gender
3:1 men
3:1 men
Sexual behavior
Alcohol/tobacco
Rising
Declining
Improved
Worse
PI3K pathway alterations
p53, p16, CCDN1, FAT1
Anatomic slide
Risk factors
Incidence
Survival
Molecular
•
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):4294-301.
Gene Expression Subtypes of SCCHN
Subtype
Proportion
Key characteristics
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
18%
Heaviest smoking histories; elevation
expression levels of oxidative stress
response genes, including NFE2L2
Basal
Classical
The Cancer Genome Atlas Network. Nature 2015;517:576-82
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
• Cisplatin/carboplatin
+ 5-FU + cetuximab
• Platinum doublet*
• Cisplatin/paclitaxel
• Carboplatin/paclitaxel
• Cisplatin/docetaxel
+/- cetuximab
Good performance
status with active
disease
Frail or indolent
asymptomatic disease
Single-agent therapy:
• Paclitaxel/docetaxel
• Cetuximab*
• Capecitabine
• Vinorelbine
• Methotrexate
* Consider if platinum resistant
Price KA, Cohen EE. Curr Treat Options Oncol 2012;13(1):35-46.
Observation
Best supportive care
Single-Agent Response Rates of EGFRTargeted mAbs and TKIs in SCCHN
Drug
Cetuximab
Phase
II
Reference
Vermorken et al, 2007
RR
13%
II
Soulieres et al, 2004
4%
II
Cohen et al, 2003
11%
II
Cohen et al, 2005
2%
III
Stewart et al, 2009
8%
Lapatinib
II
Abidoye et al, 2006 (ASCO)
0%
Zalutumumab
III
Machiels et al, 2010 (ASCO)
6%
Erlotinib
Gefitinib
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):8418-24; Kirby AM et al.
Br J Cancer 2006;94(5):631-6; Stewart JS et al. J Clin Oncol 2009;27(11):1864-71; 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.
EXTREME Study Design
R
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):1116-27.
EXTREME Study: Overall Survival
Cetuximab +
platinum/fluo Platinum/fluor
rouracil
ouracil alone Hazard ratio
(n = 222)
(n = 220)
(95% CI)
Median overall survival
10.1 mo
7.4 mo
Vermorken JB et al. N Engl J Med 2008;359(11):1116-27.
0.80
(0.64-0.99)
p-value
0.04
Phase II Trial of Dacomitinib: Response,
Survival and Grade 3/4 AEs
Response (n = 63)
Complete response (CR)
Partial response (PR)
Stable disease (SD)
≥24 weeks
<24 weeks
Progressive disease
n (%)
0 (0)
8 (12.7)
36 (57.1)
9 (14.3)
27 (42.9)
17 (27)
Indeterminate
2 (3.2)
Objective response rate (CR + PR)
8 (12.7)
Clinical benefit rate (CR + PR + SD ≥24 weeks)
17 (27.0)
Survival (n = 69)
Median progression-free survival
Median overall survival
Most common Grade ≥3 AEs
Diarrhea:
15.9%
Acneiform dermatitis: 8.7%
Fatigue:
8.7%
Abdul Razak AR et al. Ann Oncol 2013;24(3):761-9.
12.1 weeks
34.6 weeks
ACTIVE8: Phase II Trial of Chemotherapy and
Cetuximab in Combination with VTX-2337 in
Recurrent or Metastatic SCCHN
Trial ID: NCT01836029
Estimated enrollment: 175 (open)
Eligibility criteria:
• Locoregionally
recurrent or
metastatic
SCCHN
• PS 0 or 1
Chemotherapy +
cetuximab + VTX-2337
Up to 6 cycles
Cetuximab
PD
R
1:1
Chemotherapy +
cetuximab + placebo
Up to 6 cycles
Primary endpoint: Progression-free survival
www.clinicaltrials.gov; Accessed April 2015.
Cetuximab
SPECTRUM: Cisplatin + 5-FU ± Panitumumab
in Recurrent/Metastatic SCCHN
• Open-label, randomized Phase III trial
Stratified by previous
treatment, primary tumor
site, ECOG PS
Patients with distant
metastatic and/or locally
recurrent SCCHN,
ECOG PS ≤1
(N = 657)
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
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):697-710.
SPECTRUM Study: Overall Survival
Cisplatin/5-FU
+ panitumumab Cisplatin/5-FU
(n = 327)
(n = 330)
Median overall survival
11.1 mo
9.0 mo
Vermorken JB et al. Lancet Oncol 2013;14(8):697-710.
Hazard ratio
(95% CI)
0.873
(0.729-1.046)
p-value
0.1403
Mechanisms of Resistance to EGFRi
Chen LF et al. Clin Cancer Res 2010;16:2489-2495
Phase II Study of Afatinib versus Cetuximab
Afatinib
50 mg po daily
Metastatic recurrent
HNSCC
N = 124
(62 per arm)
Cetuximab
400/250 mg/m2 IV weekly
Continue until
PD or undue AEs
R
Cetuximab
400/250 mg/m2 IV weekly
Continue until
PD or undue AEs
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):1813-20.
Phase II Study of Afatinib versus Cetuximab:
Maximum Tumor Shrinkage in Target Lesions
Investigator review
Total randomized, n
ORR (CR, PR), n (%)
95% CI
Independent central review
Afatinib
Cetuximab
Afatinib
Cetuximab
62
62
62
62
10 (16.1)
8.0-27.7
4 (6.5)
1.8-15.7
5 (8.1)
2.7-17.8
6 (9.7)
3.6-19.9
p-value
Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.
0.09
0.78
Phase II Study of Afatinib versus Cetuximab:
Progression-Free and Overall Survival
Stage 1
Median progressionfree survival
Afatinib
(n = 62)
Cetuximab
(n = 62)
Hazard ratio
(95% CI)
13.0 wk
15.0 wk
0.93
(0.62-1.38)
Afatinib
(n = 36)
Cetuximab
(n = 32)
Hazard ratio
(95% CI)
9.3 wk
5.7 wk
0.64
(0.38-1.05)
Afatinib
(n = 62)
Cetuximab
(n = 62)
Hazard ratio
(95% CI)
35.9 wk
47.1 wk
1.06
(0.70-1.62)
p-value
0.71
Stage 2
Median progressionfree survival
p-value
0.08
Stage 1 and Stage 2
Median overall survival
Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.
p-value
0.78
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
≥20%
6
11
≥0% and <20%
12
7
>-30% and <0%
11
7
≤30%
1
1
Maximum % tumor shrinkage
Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.
Phase II Study of Afatinib versus Cetuximab: TreatmentRelated Adverse Events in ≥10% of Patients (Stage 1)
Afatinib (n = 61)
Cetuximab (n = 60)
All grades
Grade 3-4
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
48 (78.7)
9 (14.8)
12 (20.0)
0
Stomatitis
21 (34.4)
7 (11.5)
14 (23.3)
0
Fatigue
20 (32.8)
3 (4.9)
13 (21.7)
1 (1.7)
Nausea
17 (27.9)
1 (1.6)
12 (20.0)
1 (1.7)
Vomiting
10 (16.4)
1 (1.6)
8 (13.3)
0
Dry skin
9 (14.8)
0
15 (25.0)
0
Dehydration
8 (13.1)
5 (8.2)
1 (1.7)
0
Decreased appetite
5 (8.2)
3 (4.9)
8 (13.3)
0
Nail effects
4 (6.6)
0
6 (10.0)
1 (1.7)
Ocular effects
4 (6.6)
0
6 (10.0)
1 (1.7)
Constipation
2 (3.3)
0
7 (11.7)
0
Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.
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
Phase III, randomized,
open-label
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
Endpoints
Study sites
Primary: PFS
Key secondary: OS
Global
2
Afatinib 40 mg qd
N = 316
Treatment
until PD
R
1
Methotrexate
40 mg/m2 qwk
N = 158
PFS = progression-free survival; OS = overall survival; PD = progressive disease
Machiels J et al. ESMO 2014;Abstract LBA29_PR.
LUX-Head & Neck 1: Efficacy
Endpoint
Afatinib
(n = 322)
Methotrexate Hazard
(n = 161)
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.
LUX-Head & Neck 1: Select Drug-Related
Adverse Events
Afatinib (n = 320)
All grades
Grade 3
Methotrexate (n = 160)
Grade 4 All grades Grade 3
Grade 4
More frequent with afatinib
Rash/acne
74
10
0
8
0
0
Diarrhea
72
9
1
12
2
0
Paronychia
14
1
0
0
0
0
Decreased appetite
13
3
0
13
1
0
Vomiting
13
1
<1
9
0
0
Dry skin
11
0
0
0
0
0
More frequent with methotrexate
Stomatitis
39
6
<1
43
8
0
Fatigue
25
6
0
32
3
0
Nausea
20
2
0
23
1
0
Neutropenia
<1
<1
0
19
6
1
Anemia
7
1
0
19
5
1
Machiels J et al. ESMO 2014;Abstract LBA29_PR.
LUX-Head & Neck 2: Adjuvant Afatinib in
Locally Advanced Squamous Cell Carcinoma
of the Head and Neck
Trial design
Phase III, randomized,
placebo controlled
•
•
•
•
•
•
•
Endpoints
Study sites
Primary: DFS
Secondary: 2-year DFS rate, OS, safety
Global
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
NED = no evidence of disease
2
Afatinib 40 mg qd
N = 446
Treatment for
18 months/
until recurrence
R
1
Placebo qd
N = 223
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):997-1008.
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
• Investigatorassessed 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.
KEYNOTE-012: Best Overall Response
Total head/neck
N = 56
Response evaluation
HPV (+)
N = 20
HPV (-)
N = 36*
n (%)
95% CI
n (%)
95% CI
n (%)
95% CI
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
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 (CR)
No assessment
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.
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 (%)
0
n
26*
1-10 11-20 21-30 31-40 41-50 51-60 61-70
24
8
9
3
* Three patients with tumor (-) but stroma (+) by IHC
Seiwert TY et al. Proc ASCO 2014;Abstract 6011.
2
2
4
71-80 81-90 91-100
3
2
21
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)
1 (0.9)
1 (2.9)
0 (0)
28 (23.9)
6 (17.6)
22 (27.2)
Complete response
Partial response
Seiwert TY et al. Proc ASCO 2015;Abstract LBA6008.
KEYNOTE-012: Select Drug-Related Adverse
Events
All grades
Grades 3-5
n
%
n
%
35
58.3
10
16.7
Fatigue
10
16.7
0
0.0
Pruritus
6
10.0
0
0.0
Rash
5
8.3
2
3.3
Nausea
4
6.7
0
0.0
Decreased appetite
3
5.0
0
0.0
Myalgia
3
5.0
0
0.0
Any drug-related event
Seiwert TY et al. Proc ASCO 2014;Abstract 6011.
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.
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.
NCT00193765: Phase III Trial of Elective Neck
Dissection versus Watch and Wait Policy
(Therapeutic Neck Dissection)
•
•
•
Histologically
proven SCC
cT1/T2N0 oral
cavity squamous
cell cancers
Amenable to
per-oral excision
Treatment naive
Elective Neck
Dissection
(n=243)
R1
Physical Exam
R2
Watch & Wait/
Therapeutic Neck
Dissection
(n=253)
Treatment
D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.
Physical Exam +
Ultrasonography
Follow-Up
Survival: Elective versus Therapeutic Neck
Dissection
Endpoint
Three-year
overall
survival
Three-year
disease-free
survival
Elective neck
dissection
(n = 243)
Therapeutic
neck dissection
(n = 253)
Hazard
ratio
p-value
80%
67.5%
0.64
0.014
69.5%
45.9%
0.45
<0.001
D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.
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)
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
PET-CT guided
“active surveillance”
(n = 282 )
C
R
T
R
1:1
PET-CT &
assessment*
Standard treatment
“planned ND”
(n = 282)
* 9-13 wk after CRT completion
Mehanna H et al. ASCO 2015;Abstract 6009.
ND before or
after CRT
CT &
assessment*
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.