Advanced Thyroid Cancer:

A New Disease for Medical Oncology

Thomas Semrad MD, MAS, FACP

Assistant Professor of Medicine

Division of Hematology/Oncology

Recent Developments in Cancer Therapy

Disclosures

• Speakers Bureau: Novartis

• Consulting: Amgen, Genentech, Genomic

Health, Onyx

• Research Funding: Astex, Eisai,

Genentech, Millenium, Morphotek,

Novartis

Outline

• Thyroid Cancer Landscape

• Differentiated Thyroid Cancer – What is Iodine Refractory?

– Multi-kinase inhibitors targeting VEGFR

• Medullary Thyroid Cancer – Multi-kinase inhibitors targeting RET

Who To Treat and Who Not To Treat

Differentiated Thyroid Cancer

Medullary Thyroid Cancer

Anaplastic Thyroid Cancer

Follicular Thyroid Cancer

Papillary Thyroid Cancer

Hereditary

Sporadic

Lymphoma and Other

5%

12%

80%

2%

1%

~25%

~75%

Thyroid Cancer 101

Hughes et al. Thyroid 2011;(21)3:231-236

New

cases o

f papill

ary

thyro

id c

ancer

in the U

nited s

tate

s b

y a

ge

>45

Years old

<45 years

old

Principles of Treatment High Risk Patients

• Total Thyroidectomy

• Radioiodine – Gross Extrathyroidal Extension

– > 4cm primary

– Distant metastases

• Neck Dissection – Clinical or US-detected disease

– Locoregional recurrence

• TSH Suppression – <0.1 for those at high risk or with known residual

disease ATA Guidelines. Cooper et al. Thyroid 2009. 19(11).

NCCN Guidelines. Thyroid Carcinoma v2.2013.

Radioiodine Refractory Criteria

A. One or more (measurable) lesions that do

not demonstrate 131I uptake on diagnostic

radioiodine scan

B. One or more lesions that has progressed

within 12 months of 131I therapy.

C. Cumulative activity of 131I of > 600 mCi

Radioiodine Refractory Prognosis

Outcome1

– Median Survival 3-6

years

– 10-year survival less

than 15%

Prognostic Factors2,3

– Age

– BRAF Mutation

– PET positivity

Durante et al. J Clin Endocrinol Metab 2006;91(8):2892–2899.

Elisei et. al, J Clin Endocrinol Metab 2008;93(10):3943-9

Robbins and Weil. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1047-59

Cytotoxic Agents for DTC

• Adriamycin is the most studied agent

– Others include bleomycin, platinums,

etoposide, and pemetrexed

• 1974, 37% PR in 30 patients1

– Based on > 50% decrease on x-rays

• 5-17% in subsequent trials2

• Common AEs include myelosuppression,

nausea, vomiting, and cardiotoxicity

1 Gottleib et al. NEJM 1974 2 Matuszczyk et al Horm Metab Res 2008

Cytotoxics have no established role

for the management of DTC

Molecular Pharmacology of DTC

Kapiteijn et al. Annals Oncology 2011

20 - 40% PTC

~50% PTC

10% PTC

50% FTC

Molecular Pharmacology of DTC

Kapiteijn et al. Annals Oncology 2011

gefitinib

vemurafenib

? sorafenib

sorafenib

sunitinib

axitinib

pazopanib

lenvatinib

cabozantinib

selumetinib

tremetinib

everolimus

temsirolimus

vandetanib

sunitinib

cabozantinib

Phase II Trials of Kinase Inhibitors

Agent Phase N ORR (%) DCR (%) PFS

(mos) Ref

Gefitinib II 27 0 81 3.7 Thyroid 2008;18:317-323

Motesanib II 93 14 81 9.2 NEJM 2008;359:31-42

Axitinib II 60 30 68 18.1 JCO 2008;26:4708-4713

Sunitinib II 29 28 78 12.8 Clin Cancer Res 2010;

16:5260-5268

Pazopanib II 39 49 NR 11.7 Lancet 2010; 11:962-972

Sorafenib UPENN

II 30 23 76 18.2 JCO 2008;26:4714-4719

Sorafenib OHSU

II 56 12 77 15 JCO 2009;27:1675-1684

Lenvatinib E7080

II 58 50 95 13.3 ASCO 2011, abstract

5503

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DECISION Design

DTC (including

poorly differentiated)

Measurable

Disease

PS 0-2

RECIST

progression in prior

14 months

Adequate TSH

suppression

I131 refractory

Sorafenib 400 mg BID

Primary Objective: • Progression-free

Survival (PFS)

Secondary

Objectives: • Overall Survival

• Response Rate

• Safety and

tolerability

• DCR

• Duration of disease

control

• Sorafenib Exposure

Placebo

R 1:1

Stratified by: Geographic region, age

International n = 417

Crossover

allowed at

progression

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RAI-refractory DTC 2013

DECISION establishes sorafenib as a standard therapy

Multiple Questions Raised

Who to treat?

With what agent?

Can we identify alternative targets? • Will selective BRAF V600E inhibitors be effective?

Sorafenib resistance?

Is this the right strategy?

With what agent? E7080 (lenvatinib) phase II results

Overall (n=58)

CR 0

PR 26 (45%)

SD 27 (46%)

PD 3 (5%)

DCR 53 (91%)

Sherman et al. ASCO 2011, abstr 5503

Overcoming sorafenib resistance Targeting alternative pathways

J Clin Oncol 31, 2013 (suppl; abstr 6024)

Are there better strategies? Restoration of Radioiodine Sensitivity

Ho et al. N Engl J Med 2013;368:623-32.

Take Home Message

Who To Treat?

• Radioiodine Refractory

– Negative RAI Scan

– Progression Despite

Recent RAI

– >600 mCi prior RAI

• Non-surgical candidates

• Established Progression

– Threatened Symptoms

Who Not To Treat?

• No radiographic disease

(TG only)

• RAI Sensitive

• No progression

• Very slow progression

without threatened

symptoms

Refer to Clinical Trials Whenever Possible!

Medullary Thyroid Cancer

Sites of Metastases

• Liver

• Bone

Tumor Markers

• Calcitonin

• CEA

Not of Follicular Origin

• No role for RAI

• No role for TSH suppression

Houvras. JCO 2012;30:200-202.

A Disease of RET Mutations

ZETA Phase III Study design

Vandetanib 300 mg/day

n=231

Follow for progression Follow for progression

Optional open-label vandetanib 300 mg/day

Follow for survival

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

Placebo

n=100

2:1 randomization

Discontinue blinded treatment at progression

Wells et al. JCO 2012;30:134-141.

PFS (primary endpoint)

0

Hazard ratio = 0.46 (0.31–0.69); P<0.0001

Median: not reached (vandetanib); 19.3 months (placebo)

Vandetanib 300 mg

Placebo

Time (months)

231 198 171 141 42 1 0

100 72 57 45 13 0 0

At risk (n)

Vandetanib

Placebo

0.6

0.8

Pro

gre

ssio

n-f

ree s

urv

ival

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

6 12 18 24 30 36

Wells et al. JCO 2012;30:134-141

Vandetanib (%) Placebo (%)

ORR 45 13

DCR 87 71

Calcitonin

Response

69 3

CEA Response 52 2

Vandetanib 300 mg

(n=231)

Placebo

(n=99)

Diarrhea 25 (11%) 2 (2%)

Hypertension 20 (9%) 1 (1%)

ECG QT prolonged 18 (8%) 1 (1%)

Fatigue 13 (6%) 1 (1%)

Decreased appetite 10 (4%) 0

Rash 8 (3%) 1 (1%)

Asthenia 6 (3%) 1 (1%)

Dyspnea 4 (2%) 3 (3%)

Back pain 1 (0.4%) 3 (3%)

Syncope 0 2 (2%)

Most common grade 3+ adverse events (>2% incidence in either arm)

FDA REMS Program: Frequent EKG monitoring required

Wells et al. JCO 2012;30:134-141

EXAM Phase III Design

MTC

Measurable

Disease

PS 0-2

RECIST

progression in prior

14 months

Cabozantinib 140 mg

daily Primary Objective: • Progression-free

Survival (PFS)

Secondary

Objectives: • Overall Survival

• Response Rate

• Safety and

tolerability Placebo

R 2:1

International n = 330

Elisei et al. JCO 2013;31:3639-3646.

PFS by Independent Review

ORR 28% in cabozantinib arm, 0% in placebo arm, p<0.001

Median Duration of Response 14.6 months

Elisei et al. JCO 2013;31:3639-3646.

Unfair Comparison

Parameter Vandetanib (ZETA) Cabozantinib (EXAM)

ORR 45% 28%

PFS Not reached, 30.5

months estimated

11.2 months

PFS HR 0.46 0.28

Placebo PFS 19.0 months 4.0 months

These trials are not comparable!

Unanswered Question:

Which drug for which patient?

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Wells et al. JCO 2012;30:134-141

Concluding Thoughts

Kinase inhibitors have changed the landscape of RAI-refractory DTC and MTC.

• Patient selection is paramount.

• More questions than answers: – Who

– What

– When

– Why

• No one has been cured…

SEE YOU NEXT YEAR!!!!