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

Ezra W CohenUniversity of California, San Diego

RTP ON DEMAND: Thyroid Cancer

Thyroid CancerNewly Detected 2015 (n = 62,450)

Cancer Facts & Figures 2015.

Papil-lary82%

Fol-licu-lar

10%

5%

Anaplastic1%

Medullary2%

Hürthle

Five- and 10-Year Cumulative Incidences of Death Among Patients with Thyroid Cancer

Yang L et al. J Clin Oncol 2013;31(4):468-74.

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 1.9 3.5 65-74 6.8 10.3 ≥75 12.2 16.0Histologic subtype

<0.001

Papillary 1.3 2.2 Follicular 2.6 4.8 Medullary 9.3 9.3 Anaplastic 77.8 78.9 Other 27.4 29.3

* Gray's test

Five- and 10-Year Cumulative Incidences of Death Among Patients with Thyroid Cancer by Age

Yang L et al. J Clin Oncol 2013;31(4):468-74.

CharacteristicCumulative 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 1.9 3.5

65-74 6.8 10.3

≥75 12.2 16.0

Other 27.4 29.3 <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”?

Colevas AD et al. Proc ASCO 2014;Discussant.

Agent FGFR VEGFR PDGFR BRAF CKIT FLT3 CMET TIE2 EGFR RET

Sorafenib X X X X X

Sunitinib X X X X X

Cabozantinib X X X X X X

Vandetanib X X X

Lenvatinib X X X X X

Lenalidomide X

Axitinib X X

Motesanib X X X X

Pazopanib X X X

Vemurafenib X

Agent ORR (RECIST) mPFS

Axitinib1,2 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

VEGFRi in Thyroid Cancer — Phase II Trials

1 Cohen EE et al. J Clin Oncol 2008;26(29):4708-13; 2 Locati LD et al. Cancer 2014;120(17):2694-703; 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.

Cohen EE et al. J Clin Oncol 2008;26(29):4708-13.

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

Efficacy of Pazopanib in a Phase II Study in Progressive, Radioiodine-Refractory, Metastatic Differentiated Thyroid Cancer

Bible KC et al. Lancet Oncol 2010;11(10):962-72.

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)

Vandetanib in Locally Advanced or Metastatic Differentiated Thyroid Cancer: Progression-Free Survival in a Randomised, Double-Blind, Phase II Trial

Leboulleux S et al. Lancet Oncol 2012;13(9):897-905.

Vandetanib

(n = 72)Placebo(n = 73)

Hazard ratio(95% CI) p-value

Median progression-free survival

11.1 mo 5.9 mo 0.63(0.54-0.74) 0.008


Phase III Trials of Lenvatinib and Sorafenib in Radioiodine-Refractory Differentiated Thyroid Cancer

SELECT1 DECISION2

EndpointLenvatinib(n = 261)

Placebo(n = 131)

Sorafenib(n = 207)

Placebo(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):319-28.

Phase III DECISION Study Design

Brose MS et al. BMC Cancer 2011;11:349; www.clinicaltrials.gov, NCT00984282.

R

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

Placebo Orally twice daily

Randomization 1:1

Primary endpointProgression-free

survival

• 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 rateSafetyTime to progressionDisease control rateDuration of responseSorafenib exposure (AUC 0-12 hours)

DECISION Study: Response, Survival and AEs

EndpointSorafenib(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

* 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: 68.6%• Alopecia: 67.1%• Rash or desquamation: 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

Schlumberger M et al. N Engl J Med 2015;372(7):621-30.

Stratification• Geographic

region (Europe, North America, other)

• Prior VEGF/VEGFR-targeted therapy (0, 1)

• Age (≤65 years, >65 years) 2:1

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

R

Lenvatinib (n = 261)24 mg daily PO

Primary endpoint• PFS

Secondary endpoints• ORR• OS• Safety

Lenvatinib

(optional, open label)

Treatment until disease

progression confirmed

by IRR (RECIST v1.1)

Placebo (n = 131)24 mg daily PO

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 1 2 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)

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 progression-free survival Lenvatinib Placebo


TKI naïve (n = 299) 18.7 mo 3.6 mo 0.20

(0.14-0.27)

<0.0001

One prior TKI regimen (n = 93)

15.1 mo 3.6 mo0.22

(0.12-0.41)<0.0001



Events/N Median (months)

Lenvatinib Placebo HR (95% CI) Lenvatinib Placebo

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) 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

Bone metastasis

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

Lung metastasis

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

SELECT: Progression-Free Survival Subgroup Analysis

NE = not evaluable/estimable (not reached)

SELECT: Response Rates


Lenvatinib (N = 261)

Placebo(N = 131)

Odds ratio (95% CI)

Response rate — no. (%)* 169 (64.8) 2 (1.5) 28.87

(12.46–66.86)†

Complete response 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)

* 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

SELECT: Best Tumor Response

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.

Best Overall Response (n = 245)CR (n = 4) PR (n = 165)SD (n = 60)PD (n = 16)

Best Overall Response (n = 126)PR (n = 2)SD (n = 71)PD (n = 51)NE (n = 2)

Treatment group: Placebo

Treatment group: Lenvatinib

Per

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Fro

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Per

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CR = complete response; NE = not evaluable/estimable (ie, not reached); PD = progressive disease; PR = partial response; SD = stable disease


SELECT: Overall Survival, ITT Population

Lenvatinib(n = 261)

Placebo(n = 131)


Median overall survival

NR NR0.73

(0.50-1.07)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.

SELECT: Effect of Age and Lenvatinib Treatment on Overall Survival

Brose MS et al. Proc ASCO 2015;Abstract 6048.

• 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

SELECT: Treatment-Related Adverse Events of Special Interest


Effect (%)

Lenvatinib (N = 261) Placebo (N = 131)

All grades Grade ≥3 All grades Grade ≥3

Hypertension 67.8 41.8 9.2 2.3

Diarrhea 59.4 8.0 8.4 0

Fatigue or asthenia 59.0 9.2 27.5 2.3

Decreased appetite 50.2 5.4 11.5 0

Decreased weight 46.4 9.6 9.2 0

Nausea 41.0 2.3 13.7 0.8

Stomatitis 35.6 4.2 3.8 0

Palmar–plantar erythrodysesthesia syndrome

31.8 3.4 0.8 0

Proteinuria 31.0 10.0 1.5 0

Phase II Trials of Everolimus Combined with Sorafenib in Refractory Thyroid Cancer

EndpointNCT012639511

(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%

Median PFS 13.7 mo NR

1 Brose MS et al. Proc ASCO 2015;Abstract 6072; 2 Sherman EJ et al. Proc ASCO 2015;Abstract 6069.

NR = not reported

Kim KB et al. Thyroid 2013;23(10):1277-83.

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

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 progressionwithin 14 months

Vemurafenib

Brose MS et al. ECCO/ESMO 2013;Abstract 28.

VEGFR2i naïve(n = 26) Vemurafenib

960 mg BID until disease progression

or unacceptable toxicityVEGFR2i pretreated

(n = 25)

Vemurafenib Response Rate

Brose MS et al. ESMO/ECC 2013;Abstract 28.

VEGFR2i naïveVEGFR2i

pretreated

Complete response 0 0

Partial response 35% 26%

Stable disease 6 mo 23% 10%

Clinical benefit rate 58% 36%

Median PFS 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 (%)

Total 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%)

Hayes DN et al. Clin Cancer Res 2012;18(7):2056-65.

Impact of Selumetinib on 124I Incorporation

Ho AL et al. N Engl J Med 2013;368(7):623-32.

N = 20

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 5/5

RET/PTC 2/3 1/3

Wild type 1/3 1/3

Total 12/20 8/20

Ho AL et al. N Engl J Med 2013;368(7):623-32.

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



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

A Phase I/II Study of Cediranib (CED) and Lenalidomide (LEN) in Patients with Advanced Differentiated Thyroid Cancers

Brown RL et al. The Endocrine Society’s 94th Annual Meeting and Expo 2012;Abstract SUN-281.

PHASE I

PHASE II

Dose escalation of CED and LEN

Cohort A: CED 30 mg

Cohort B: CED + LEN at MTD

Progression-free survival

Determine maximum tolerated dose (MTD) of combined therapy

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

Cysteine-rich domain

Transmembrane domain

Tyrosine kinase domain

MEN 2A/FMTC

FMTC

MEN 2B

Alternative 3 splice sites

COOH

Phase III ZETA Study Design

Vandetanib 300 mg/dayn = 231

Follow for progression Follow for progression

Optional open-label vandetanib 300 mg/day

Follow for survival

Patients with unresectable locally advanced or metastatic hereditary or sporadic MTC (N = 331)

Placebon = 100

2:1 randomization

Discontinue blinded treatment at progression*

*Progression as assessed by the site investigator

www.clinicaltrials.gov, NCT00410761.

Phase III ZETA Study: PFS by Central Independent Review

0

Vandetanib 300 mg

Placebo

Time (months)

231 196 169 140 40 1 0

100 71 57 45 13 0 0

No. at risk

Vandetanib 300 mg

Placebo

0.6

0.8

Pro

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ree

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pro

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n)

0.9

0

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: 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: 2.99-

10.79, 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: 16.0-

320.3, 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.

Trial design Endpoints Study sites

Phase III, randomized, placebo controlled

Primary: PFSSecondary: OS, ORR per RECIST Global

EXAM: Phase III Trial of Cabozantinib in Medullary Thyroid Carcinoma with RECIST Progression at Baseline

2

1

R

• 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

Placebo qdN = 111

Progression

No crossover allowed.

Schlumberger M et al. Proc ASCO 2015;Abstract 6012.

Survival follow-

up

EXAM Study: Survival, Response and AEs

Endpoint Cabozantinib PlaceboHazard

ratio p-value

Median PFS 11.2 mo 4.0 mo 0.28 <0.001

ORR (all partial responses)* 28% 0% — <0.001

* 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.

Elisei R et al. J Clin Oncol 2013;31(29):3639-46.

Common Grade ≥3 cabozantinib-related AEsDiarrhea: 15.9%Palmar-plantar erythrodysesthesia: 12.6%Decreased weight: 4.7%Decreased appetite: 4.7%Nausea: 1.4%Fatigue: 9.3%Treatment discontinuation in 16% of cabozantinib and 8% placebo

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% 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)

p-value 0.0260 0.6308

Median PFS (mo) 13.9 4.0 5.7 5.4

PFS HR (95% CI) 0.15 (0.08-0.28) 0.67 (0.37-1.23)

p-value <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.

Genomic Landscape of Anaplastic Thyroid Cancer (ATC)

Capdevila J et al. Proc ASCO 2015;Abstract 6033.

• 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

Ezra W CohenUniversity of California, San Diego

RTP ON DEMAND: Head and Neck Cancer

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

Adapted from SEER training modules, head & neck cancer. National Institutes of Health, National Cancer Institute.

Oral CavityLipBuccal mucosaAlveolar ridgeRetromolar trigoneFloor of mouthHard palateOral tongue (anterior two thirds)

LarynxSupraglottisGlottisSubglottis

Nasal Cavity

Tongue

Esophagus

Jaw

Nasopharynx

OropharynxBase of tongueSoft palateTonsillar pillar and fossa

Hypopharynx

Pharynx

Two Distinct SCCHN Entities

HPV+ HPV-

Anatomic slide Tonsil/base of tongue All sites

Histology Basaloid Keratinized

Age Younger Older

Gender 3:1 men 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):4294-301.

Subtype 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

Gene Expression Subtypes of SCCHN

The Cancer Genome Atlas Network. Nature 2015;517:576-82

ObservationBest supportive care

Treatment Algorithm for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Fit with aggressivesymptomatic disease

Good performance status with active

disease

Frail or indolentasymptomatic disease

• Cisplatin/carboplatin+ 5-FU + cetuximab

• Platinum doublet*• Cisplatin/paclitaxel• Carboplatin/paclitaxel• Cisplatin/docetaxel+/- cetuximab

Single-agent therapy:

• Paclitaxel/docetaxel• Cetuximab*• Capecitabine• Vinorelbine• Methotrexate

R/M HNSCC Locally recurrent or distant metastases

* Consider if platinum resistant

Price KA, Cohen EE. Curr Treat Options Oncol 2012;13(1):35-46.

Single-Agent Response Rates of EGFR-Targeted mAbs and TKIs in SCCHN

-

Drug Phase Reference RRCetuximab II Vermorken et al, 2007 13%

Erlotinib II Soulieres et al, 2004 4%

Gefitinib

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%

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 ACetuximab 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 BEITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1,000 mg/m2 IV, d1-4):

3-week cycles

Cetuximab No treatment

Progressive disease or unacceptable toxicity

6 chemotherapy cycles maximum

Vermorken JB et al. N Engl J Med 2008;359(11):1116-27.

EXTREME Study: Overall Survival

Vermorken JB et al. N Engl J Med 2008;359(11):1116-27.

Cetuximab + platinum/fluo

rouracil(n = 222)

Platinum/fluorouracil

alone (n = 220)


Median overall survival 10.1 mo 7.4 mo 0.80(0.64-0.99) 0.04

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) 8 (12.7)

Clinical benefit rate (CR + PR + SD ≥24 weeks) 17 (27.0)

Abdul Razak AR et al. Ann Oncol 2013;24(3):761-9.

Most common Grade ≥3 AEsDiarrhea: 15.9%Acneiform dermatitis: 8.7%Fatigue: 8.7%

Survival (n = 69) Median progression-free survival 12.1 weeks

Median overall survival 34.6 weeks

Eligibility criteria:• Locoregionally

recurrent or metastatic SCCHN

• PS 0 or 1

Primary endpoint: Progression-free survival

PD

Trial ID: NCT01836029Estimated enrollment: 175 (open)

www.clinicaltrials.gov; Accessed April 2015.

ACTIVE8: Phase II Trial of Chemotherapy and Cetuximab in Combination with VTX-2337 in Recurrent or Metastatic SCCHN

1:1

R

Chemotherapy + cetuximab + VTX-2337

Up to 6 cycles

Chemotherapy + cetuximab + placebo

Up to 6 cycles

Cetuximab

Cetuximab

Vermorken JB et al. Lancet Oncol 2013;14(8):697-710.

SPECTRUM: Cisplatin + 5-FU ± Panitumumab in Recurrent/Metastatic SCCHN

• Open-label, randomized Phase III trial

Patients with distant metastatic and/or locally

recurrent SCCHN, ECOG PS ≤1

(N = 657)

Stratified by previous treatment, primary tumor

site, ECOG PS

Optional panitumumab maintenance q3wk

Panitumumab 9 mg/kg day 1Cisplatin 100 mg/m2 day 15-FU 1,000 mg/m2 days 1-4

(n = 327)

Cisplatin 100 mg/m2 day 15-FU 1,000 mg/m2 days 1-4

(n = 330)

Max six 3-wk cycles

• Primary endpoint: OS• Secondary endpoints: PFS, ORR, DOR, TTR, safety

SPECTRUM Study: Overall Survival

Vermorken JB et al. Lancet Oncol 2013;14(8):697-710.

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(0.729-1.046) 0.1403

Chen LF et al. Clin Cancer Res 2010;16:2489-2495

Mechanisms of Resistance to EGFRi

HNSCC = head and neck squamous cell carcinoma; IV = intravenous; PD = progressive disease; CT = computed tomography scan; MRI = magnetic resonance imaging; R/M = recurrent/metastatic

Stage 1 Stage 2

CT/MRI q8wk

Phase II Study of Afatinib versus Cetuximab

Metastatic recurrent HNSCC

N = 124 (62 per arm)

R

Afatinib50 mg po daily

Cetuximab400/250 mg/m2 IV weekly

Continue until PD or undue AEs

Continue until PD or undue AEs

Cetuximab400/250 mg/m2 IV weekly

Afatinib50 mg po daily

Stratum: No. prior chemotherapies for R/M

disease (0 or ≥1)

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 Independent central review

Afatinib Cetuximab Afatinib Cetuximab

Total randomized, n 62 62 62 62

ORR (CR, PR), n (%) 95% CI

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 0.09 0.78

Phase II Study of Afatinib versus Cetuximab: Progression-Free and Overall Survival


Stage 1

Afatinib(n = 62)

Cetuximab (n = 62)


Median progression-free survival 13.0 wk 15.0 wk 0.93

(0.62-1.38) 0.71

Stage 2

Afatinib(n = 36)

Cetuximab (n = 32)

Hazard ratio (95% CI) p-value

Median progression-free survival 9.3 wk 5.7 wk 0.64

(0.38-1.05) 0.08

Stage 1 and Stage 2

Afatinib (n = 62)

Cetuximab (n = 62)

Hazard ratio (95% CI) p-value

Median overall survival 35.9 wk 47.1 wk 1.06 (0.70-1.62) 0.78

Phase II Study of Afatinib versus Cetuximab: Tumor Shrinkage in Stage 2


Afatinib after prior

cetuximab in Stage 1, nCetuximab after prior afatinib in Stage 1, n

Maximum % tumor shrinkage

≥20% 6 11

≥0% and <20% 12 7

>-30% and <0% 11 7

≤30% 1 1

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 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



Phase III, randomized, open-label

Primary: PFS Key secondary: OS Global

2

1

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

R

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

Afatinib 40 mg qdN = 316

Methotrexate 40 mg/m2 qwk

N = 158

Treatment until PD

Machiels J et al. ESMO 2014;Abstract LBA29_PR.

PFS = progression-free survival; OS = overall survival; PD = progressive disease

LUX-Head & Neck 1: Efficacy

EndpointAfatinib(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

LUX-Head & Neck 1: Select Drug-Related Adverse Events


Afatinib (n = 320) Methotrexate (n = 160)

All grades Grade 3 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


Phase III, randomized, placebo controlled

Primary: DFSSecondary: 2-year DFS rate, OS, safety Global

LUX-Head & Neck 2: Adjuvant Afatinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

NED = no evidence of disease

2

1

R

• 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

Afatinib 40 mg qdN = 446

Placebo qdN = 223

Treatment for 18 months/

until recurrence

Basis for Immunotherapy — Immune Escape

Adapted from Seiwert TY et al. Proc ASCO 2014;Abstract 6011; Melero I et al. Clin Cancer Res 2013;19(5):997-1008.

• 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.

KEYNOTE-012: Multicenter, Nonrandomized, Phase Ib Squamous Cell Carcinoma of the Head and Neck Expansion Cohort

Seiwert TY et al. Proc ASCO 2014;Abstract 6011.

Recurrent or metastatic head and neck cancer• PD-L1-positive• Investigator-

assessed HPV status

HPV-negative cohort

HPV-positivecohort

Treat until PD*

* Treatment beyond initial PD allowed; radiation therapy to progressive lesion allowed

PD = progressive disease

Pembrolizumab10 mg/kg q2wk

Pembrolizumab10 mg/kg q2wk

KEYNOTE-012: Best Overall Response


Total head/neck

N = 56HPV (+)N = 20

HPV (-)N = 36*

Response evaluation n (%) 95% CI n (%) 95% CI 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 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

No assessment 4 (7.1) 2.0, 17.3 1 (5.0) 0.1, 24.9 3 (8.3) 1.8, 22.5

• 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

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.

KEYNOTE-012: PD-L1 Screening Results

104 patients screened:

PD-L1 staining in tumors of screened patients (N = 104)

Staining (%) 0 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 2 4 3 2 21

* Three patients with tumor (-) but stroma (+) by IHC

PD-L1-positive: 78% (81)• Study eligible n = 61*

- HPV (-) n = 36- HPV (+) n = 23- HPV (na) n = 2

PD-L1-negative: 22% (23)


Clinical endpointOverall

(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) 22 (27.2)

KEYNOTE-012: Efficacy by HPV Status

Seiwert TY et al. Proc ASCO 2015;Abstract LBA6008.

KEYNOTE-012: Select Drug-Related Adverse Events


All grades Grades 3-5

n % n %

Any drug-related event 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

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)

Elective Neck Dissection

(n=243)

Watch & Wait/Therapeutic Neck

Dissection (n=253)

D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.

Treatment

Physical Exam

Physical Exam + Ultrasonography

Follow-Up

R1 R2

• Histologically proven SCC cT1/T2N0 oral cavity squamous cell cancers

• Amenable to per-oral excision

• Treatment naive

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.

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 ND1:1

R

PET-CT & assessment*

C

R

T

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 )

Standard treatment “planned ND”

(n = 282)

Mehanna H et al. ASCO 2015;Abstract 6009.

CT & assessment** 9-13 wk after CRT completion

ND before or after CRT

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.

Documents

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