Kinase Inhibitors for Advanced Medullary Thyroid Cancer

Kinase Inhibitors for Advanced Medullary

Thyroid Cancer:

Sequencing and what is next?

Francis P Worden, MD

Professor

Department of Medicine

Division of Hematology/Oncology

Comprehensive Cancer Center

The University of Michigan

Ann Arbor, MI

Disclosures

• Companies: None

• Relationships: None

• There are currently only FDA approved agents for

progressive MTC and DTC other than doxorubicin, and

include cabozantinb and vandetanib for MTC; all other

discussed agents are in the context of clinical trials.

2

CHROMOGRANIN +

CALCITONIN +

THYROGLOBULIN -

100 0

5

0

Su

rviv

al

%

PTC

FTC

MTC

ATC

years

50

0 2 5 1 0 1 5 2 0

100

0

Medullary Thyroid Carcinoma ≠ Papillary and Follicular Thyroid Carcinoma

Overview

• Background on Medullary Thyroid Cancer. What you

need to know about MTC

• Coordination of Care for MTC patients – Who, What and

When – The role of surgeon, endocrinologist, oncologist

and active surveillance

• The pivotal Phase III studies ZETA and SELECT

• Taking it to your offices—using vandetanib and

cabozantinib in the clinic: What you need to know – Which systemic treatment to use

– Managing adverse events

– Monitoring progress on treatment

4

Overview










– Monitoring progress on treatment

5

MSB

05/30/09

Thyroid Cancer: Clinical Pathology

American Cancer Society. www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins. 2005.

Parafollicular cells

Follicular cells Differentiated

Anaplastic

Medullary

Papillary

Follicular

Hurtle Cell

Sporadic

Familial

Medullary Thyroid Cancer

• From calcitonin-producing parafollicular

C cells

• Accounts for 2%-5% of thyroid cancers

– ~1,400 cases per year in US

– Disproportionate number of thyroid cancer

deaths

– 350,000 Americans living with thyroid cancer

• 75% of cases are sporadic

• 30%-40% of sporadic MTC bear somatic RET mutations

• Heritable in 25% of cases (~90% harbor RET mutations)

• Mutations in the RET gene cause familial MTC–multiple

endocrine neoplasia 2 (MEN2A and MEN2B)

Survival Curve in MTC Patients With and Without RET Somatic Mutations

n = 100, Mean Follow-Up 10 Years

30,0025,0020,0015,0010,005,000,00

Follow-up

1,0

0,8

0,6

0,4

0,2

0,0

Cu

m S

urv

iva

l

Sì-censored

No-censored

Sì

No

Mutante

Survival FunctionsLog rank

P = .006

RET+

RET-

Elisei R, et al. J Clin Endocrinol Metab. 2008;93(3):682-687.

Lymph Node Metastases at Diagnosis Is the Most Important Negative Prognostic Factor

(Mayo Clinic Series)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

Lymph node mets.

Extrathyroidal

invasion

Distant mets.

Intrathyroidal

Survival, Years

Gharib H, et al. Mayo Clin Proc. 1992;67(10):934-940.

• 10-year overall survival: 40%

• Median overall survival: 3.2 years

Plasma Markers in MTC

• Calcitonin

– Synthesized and excreted by C cells of the

thyroid and by some medullary thyroid tumors

– Diarrhea and flushing at high levels

– Calcitonin levels can be affected by RET

inhibition

• Carcinoembryonic antigen (CEA)

– Synthesized and excreted by some medullary

thyroid tumors

– Synthesized by other types of tumors as well

Prognostic Impact of Serum CT and CEA Doubling-Times in Patients with Medullary Thyroid Carcinoma

Barbet J, et al. J Clin Endocrinol Metab.

2005;90(11):6077-6084.

Prognostic Factors in the

Follow Up

Overview







• Taking it to the streets – using vandetanib and



– Monitoring Progress on treatment

12

MTC: Initial Treatment • Surgery

– Total thyroidectomy (only curative treatment)

– Metastasis (lymph node or systemic) is present at diagnosis in

40-50% of sporadic cases of MTC

– Extent of surgery depends on stage of disease

• Curable vs noncurable

• Central neck dissection

• Ipsilateral neck dissection

• Contralateral neck dissection

– Goal

• Early disease: removal of all neoplastic disease

• Advanced disease: airway protection

– Referrals

• Endocrinology if no signs of distant disease

• Oncology if distant metastases are present

ATA-ETA Guidelines

Kloos RT, et al. Thyroid. 2009;19(6):565- 612.

Barbet. JCEM. 2005.

Risk Stratification Using Serum Calcitonin DT • Calcitonin DT highly predictive of mortality

• Independent predictor in multivariate analysis, controlled for

TNM stage

• Rapid DT could identify stage II and III patients at higher risk

for death

• Risk Stratification dictates surveillance interval, not therapy!

Patients with Bulky Neck or Mediastinal Lymph Nodes

First explore the possibility of a surgical excision

of neck or mediastinal lymph nodes with

thyroidectomy

Yes

and complete

Yes, big debulking

but not complete,

+ adjuvant EBRT

Not

possible

TKI

CT scan Ct/CEA

measurements

3-4 months later

If new disease and/or

lung progression

External Beam Irradiation (EBRT)

– Adjunctive and palliative treatment for extensive neck or

mediastinal disease

– Palliative treatment for bony metastasis/pain

– Radioactive Iodine is ineffective in the treatment of MTC!!!

Overview







• Taking it to the streets – using vandetanib and




18

Rationale for RET as a Therapeutic Target

• (>60% of progressive cases presenting for

clinical trials)

• Somatic mutations of RET are associated

with a poor prognosis

• Limited expression outside the thyroid,

potentially high therapeutic index

Rationale for RET as a Therapeutic Target (Activated by mutations in ~50% of cases)

BRAF

MEK

ERK

RAS

RET

AKT

VEGF

VEGFR PLC-g

PKC

Tumor Cell

End

othelial C

ell

PI3K

cMET

EGFR

“Hepatocyte growth factor”

Multikinase inhibitor activities relevant to MTC

Clinical Studies Molecular

Targets

Phase/

N

Partial

Response %

Stable Dz %

Imatinib C-kit, RET, bcr-abl,

PDGFR II – 24 0 38 %(9)

Sorafenib RAF, VEGFR, PDGFR,

RET II - 16 10% (2) 86% (18)

Motesanib VEGFR, c-kit, RET,

PDGFR II - 91 2% (2) 81% (74)

Vandetanib 300 mg VEGFR, EGFR, RET II - 30 20% (6) 53% (16)

Vandetanib 100 mg VEGFR, EGFR, RET II - 19 16% (3) 53% (10)

Sunitinib RET, VEGFR, PDGFR II - 24 33% 46% (5)

Cabozantinib (XL-184) RET, MET, VEGFR2 I - 35 29 (10) 41% (15)

Vandetanib 300 mg VEGFR, EGFR, RET III –

231/100

45% vs. 13% 87% vs. 71%

Cabozantinib 140 mg RET, MET, VEGFR2,

c-kit, FLT3 III-

219/111

28% vs. 0% 97% vs. 27%

ZETA – Phase III Study of

Vandetanib in patin

Vandetanib 300 mg/day

n=231

Follow for progression Follow for progression

Optional open-label vandetanib 300 mg/day

Follow for survival

MTC – locally advanced or metastatic (hereditary or sporadic) (N=331)

Placebo

n=100

2:1 randomization

Discontinue blinded treatment at progression

Wells et al. J Clin Oncol Jan 2012

ZETA Study: Vandetanib

Significantly Prolonged PFSa vs Placebo

Hazard Ratio 0.46

P = .001

Wells SA, et al. J Clin Oncol. 2012;30(2):134-141.

aPFS is defined as time from the date of randomization until the date of objective disease progression based on Response

ZETA STUDY Overall Survival

Wells SA, et al. J Clin Oncol. 2012;30(2):134-141.

Tumor Response Secondary Objective

Vandetanib

Placebo

P

Objective

Response Rate

45% 13% < 0.001

Disease Control

Rate

87% 71% 0.001

Biochemical

Response Rate

(Calcitonin)

69% 3% < 0.001

Biochemical

Response Rate

(CEA)

52% 2% < 0.001

• 12 of 13 responses on the placebo arm occurred while patients were receiving vandetanib in the open-label phase

Wells et al. J Clin Oncol Jan 2012

Vandetanib and Mediastinal Lymph Node Metastases

11/15/2004 8/2/2005

Vandetanib Phase III ZETA: Grade 3+ Toxicity

Wells, SA. et al JCO, 2011

Cabozantinib in MTC: Phase 3 Study

Rationale and Design (EXAM)

Treatment until progression

or unacceptable toxicity

Locally

advanced or

metastatic MTC

with

documented

RECIST

progression

Cabozantinib 140 mg

Placebo

2:1 Randomization

PR

OG

RE

SS

ION

No Cross-Over

No Unblinding

Survival

follow-up

Cabozantinib Phase III in MTC

Progression Free Survival by IRC

Cabozantinib

Placebo

Median PFS (months)

11.2 4.0

1 year PFS 47.3% 7.2%

HR (95% CI) 0.28 (0.19, 0.40)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Months

Pro

bab

ilit

y

219 121 78 55 31 12 2 1

111 35 11 6 3 2 0 0

Cabozantinib

Placebo

p<0.0001p < 0.0001

• Significant difference in tumor response rate – 28% in cabozantinib vs. 0% placebo; p<0.0001

• Median duration of response: 14.6 months Elisei R et al, JCO 2013

Patients with RET M918T Demonstrate Prolonged PFS

Relative to Patients with Other RET Mutations

Note: RET M918T negative group includes RET mutation negative patients

Median PFS

Cabozantinib 61 weeks

Placebo 17 weeks

HR (95%CI) = 0.15 (0.08, 0.28)

Median PFS

Cabozantinib 36 weeks

Placebo 24 weeks

HR (95%CI) = 0.70 (0.26, 1.87)

T im e

Fra

cti

on

ev

en

t fr

ee

0 2 0 4 0 6 0 8 0

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0C a b o z a n tin ib

P la c e b o

p < 0 .0 0 0 1

R E T M 9 1 8 T (N = 1 2 6 )

T im e

Fra

cti

on

ev

en

t fr

ee

0 2 0 4 0 6 0 8 0

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0C a b o z a n tin ib

P la c e b o

p = 0 .4 7 2 9

O th e r R E T M u ta tio n (N = 4 3 )

Maximum Regression in Target Lesions from

Baseline by IRC

Prior tyrosine kinase inhibitor therapy Elisei R et al. J Clin Oncol 31:3639-3646, 2013

4 months of Cabozantinib

May 2010 September 2010

a Worst Grade AE during the treatment period is reported b Sponsor defined grouping of preferred terms

Most Frequent Adverse Events

(>25% Incidence)

Cabozantinib (N=214) Placebo (N=109)

Median Duration of Exposure

6.7 months 3.4 months

Adverse Eventa All Grades n (%)

Grade ≥ 3 n (%)

All Grades n (%)

Grade ≥ 3 n (%)

Diarrhea 135 (63) 34 (16) 36 (33) 2 (2)

Hand foot skin reaction 107 (50) 27 (13) 2 (2) -

Decreased weight 102 (48) 10 (5) 11 (10) -

Decreased appetite 98 (46) 10 (5) 17 (16) 1 (1)

Nausea 92 (43) 3 (1) 23 (21) -

Fatigue 87 (41) 20 (9) 31 (28) 3 (3)

Dysgeusia 73 (34) 1 (0.5) 6 (6) -

Hair color changes 72 (34) 1 (0.5) 1 (1) -

Hypertensionb 70 (33) 18 (8) 5 (5) 1 (1)

Stomatitis 62 (29) 4 (2) 3 (3) -

Constipation 57 (27) - 6 (6) -

Elisei R et al. J Clin Oncol 31:3639-3646, 2013

AEs* Commonly Associated with VEGF Pathway Inhibition

Cabozantinib

N=214

Placebo

N=109

Adverse Event All

n (%)

Grade ≥ 3

n (%)

All

n (%)

Grade ≥ 3

n (%)

Hypertension 70 (33) 18 (8) 5 (5) 1 (0.9)

Hemorrhage 54 (25) 7 (3) 17 (16) 1 (0.9)

Venous thrombosis 12 (6) 8 (4) 3 (3) 2 (2)

GI perforation 7 (3) 7(3) 0 0

Non-GI fistula 8 (4) 4 (2) 0 0

Overall deaths for any reason were balanced between treatment arms

Deaths within 30 days of treatment cessation for reasons other than PD

• 5.6% in the cabozantinib arm vs 2.8% in the placebo arm

- 1.9% in the cabozantinib arm from causes typically associated with VEGF inhibition

(4 patients including 3 cases of fistula formation and 1 hemorhage) * ≥ Grade 3 with >1% incidence in either arm

FDA Approves cabozantinib in MTC 11/29/2011

• Approved for progressive or symptomatic

disease only (activity in bone mets)

• Black box warnings about gastrointestinal

perforations and fistula formations. DO

NOT use in patients with possible tracheal

or esophageal invasion

• Starting dose 140 mg/d; however, I often

start at 80-100 mg/d.

Overview











36

stable value Imaging: stable disease

Wait and see

Imaging: progression of the disease

Time to treat

Increasing values

Waiting for evidence of disease progression

When to treat with a systemic therapy ?

Serum Ct/CEA

TKIs and Pain

NO CLEAR DATA FROM PHASE III STUDIES

but…

FROM CLINICAL/PRACTICAL EXPERIENCE

PAIN WHEN LESIONS SIZE

ECTOPIC CUSHING’s SYNDROME

High levels of cortisol and ACTH

Mifepristone

or

Bilateral adrenalectomy

What about TKI ?

Key Points: MTC for Oncologists

• Success of treatment will be strongly dependent

on attention to kinase-related symptom

management

– IVFs for dehydration

– Urea and steroid creams for rashes

– Loperamide, Lomotil, and tincture of opium for diarrhea

– KNOWING WHEN TO GIVE PATIENTS A BREAK!

• Monitor for response with CT and MRI of the

liver, DO NOT initiate or change treatment for

tumor marker increase alone!

Key Points: MTC for Oncologists

• At the end of the day, most patients will be treated

by both cabozantinib and vandetanib, choice of

which is first will be decided mostly by disease

characteristics, including location and rate of

progression, as well as other comorbidities

• There is a NEW UNMET NEED to identify a third-

line agent for patients who have progressed after

both agents.

Other Kinase Inhibitors with activity in MTC

• Sorafenib (Lam et al, J Clin Oncol. 2010 May 10;

28(14):2323-30.; Ahmed et al Eur J Endocrinol. 2011 Aug;

165(2):315-22.

• Lenvatinib (Schlumberger et al. J Clin Oncol 30, 2012

(suppl; abstr 5591)

• Pazopanib (Bible et al, J Clin Endocrinol Metab. 2012 Sep;

97(9):3179-84.)

• Sunitinib (De Souza et al., J Clin Oncol. 2010;15(Suppl)

Abstr 5504)

Summary: Targeted Therapies for MTC

• Vandetanib and Cabozantinib have received FDA approval for MTC

• Cabozantinib should not be used in cases where there is possible visceral invasion

• Due to QTC prolongation, REMS is required for

vandetanib; oncologists are required to follow

EKGs and electorlytes closely

• Response in these patients result in prolonged disease control and may improve QOL

O t o l a r y n g o l o g y - H e a d & N e c k S u r g e r y

U N I V E R S I T Y O F M I C H I G A N H E A L T H S Y S T E M

The University of Michigan

Comprehensive Cancer Center

Ann Arbor, Michigan

Documents

Kinase Inhibitors for Advanced Medullary Thyroid Cancer