LENVATINIBIN ADVANCED THYROID CANCERIN ADVANCED THYROID CANCER

Jaume Capdevila, MDp ,GI and Endocrine Tumor UnitVall d’Hebron University HospitalB l S iBarcelona - Spain

Experts, acollidors i solidaris

OUTLINE

• Background of DTC

• Rationale for the use of TKIs in DTC

• Lenvatinib as a new TKI with new properties

• SELECT study

EPIDEMIOLOGY OF THYROID CANCER

THYROID CANCER

FOLLICULAR ORIGIN 90-95% C-CELL ORIGIN

WELL DIFFERENTIATED

POORLY DIFFERENTIATED ANAPLASTIC

(2%)MEDULLARY

(3 5%)(5-10%) (2%) (3-5%)

INSULAR LARGE CELL

PAPILLARY (65-80%)FOLLICULAR (15-25%)HÜRTLE CELL (3%)

MANAGEMENT AND OUTCOME OF THYROID C.

Main treatment: total or near-total thyroidectomy.Radioactive Iodine treatment: Tumors > 1 5 cm benefit inRadioactive Iodine treatment: Tumors > 1.5 cm benefit in recurrence rate, disease-progression and overall survival.Thyroid hormone suppression therapy: high-risk patients (stage III and IV).

10 y OS:10-y OS:Papillary 93%Follicular 85%Medullary 50-75%

Recurrence rate: 30%Locoregional 80% (cervical lymph nodes, thyroid remnant)Distant 20% (lung, bone, SNC)Distant 20% (lung, bone, SNC)

3-y OS refractory setting: 50% Mazzaferri EL, J Clin Endocrinol Metab 2001

Hundahl S, et al. Cancer 1998

Chemotherapy of Thyroid Cancer with Adriamycin — Experience with 30 Patients

Jeffrey A Gottlieb M D and C Stratton Hill Jr M DJeffrey A. Gottlieb, M.D., and C. Stratton Hill, Jr., M.D.N Engl J Med 1974; 290:193-197

3 months 7-8 months

Gottlieb JA, et al. NEJM, 1974; Shimaoka K, et al. Cancer, 1985

ORPHAN TUMOR: LOW CLINICAL EVIDENCE

CHT SCHEDULE RESPONSE RATE* AUTHOR/YEAR

ORPHAN TUMOR: LOW CLINICAL EVIDENCE

DOXORUBICIN 1/4 (25%) Gottieb/1974

DOXORUBICIN+ 2/6 (33%) Shimoaka/1985

CISPLATIN

STREPTOZOCIN/5FUor 3/20 (15%) Schlumberger/1995

DTIC/5FU/ ( ) g /

LANREOTIDE+ 0/7** Vitale/2000+

INTERFERON α2b0/7 Vitale/2000

* Tumor Evaluation: physical exam chest radiography neck or liver ultrasound tumor markers decrease* Tumor Evaluation: physical exam, chest radiography, neck or liver ultrasound, tumor markers decrease

** Tumor Evaluation: CT scan. Symptomatic improvement and tumor marker decrease in 6/7 pts

MULTISTEP MODEL OF THYROID CARCINOGENESIS

Puxeddu E, Curr Opin Oncol 2011

RET PATHWAY IN DTC

Murakumo Y, Pituitary 2006

RET PATHWAY IN DTC

PTC

PTC

RET

RET

Modified from Hallberg and Palmer. N Engl J Med 2010

PREVALENCE OF MUTATIONS IN THYROID CANCER

Tumor type Prevalence (%)Papillary carcinomaPapillary carcinomaBRAF 45RET/PTC 20 66% Anaplastic carcinoma

p53 70RAS 10Follicular carcinomaRAS 45 80%

p53 70β-catenin 65RAS 55

PAX8-PPAR 35PI3K <10PTEN 10

80% BRAF 20PI3K 20PTEN 10PTEN <10

Poorly differentiated carcinoma

PTEN 10Medullary carcinomaFamilial forms RET >95

RAS 35β-catenin 20P53 20

Sporadic RET 40-50

Nikiforova MN, Expert Rev Mol Diagn 2008

P53 20BRAF 15

ANGIOGENESIS

Higher VEGF levels and microvessel density in thyroid cancers compared with normal thyroid tissuecompared with normal thyroid tissue.VEGF levels correlated with stage, large tumor size, nodal involvement, extrathyroidal invasion and metastases.VEGF levels correlated with risk of recurrence and inferior recurrence-free survival.LOH of VHL tumor suppressor gene has been described in thyroidLOH of VHL tumor suppressor gene has been described in thyroid cancer. VHL loss leads HIF1α, HIF2α accumulation angiogenic events (↑ VEGF, PDGF, TGFα...).

Bauer AJ, Ann Clin Lab Sci 2003Viglietto G, Oncogene 1995Klein M, J Endocrinol 1999Yu XM, Clin Cancer Res 2005

TARGETED THERAPIES IN THYROID CANCER

LENVATINIBSORAFENIBVANDETANIBCABOZANTINIBCABOZANTINIBSUNITINIB

LENVATINIB

LENVATINIBLENVATINIB

LENVATINIB

Capdevila J, et al. Target Oncol, 2009

Phase II trials in thyroid cancerStudy Drug N Population Response Rate Stable Progression freeStudy Drug N Population Response Rate Stable

diseaseProgression-free Survival

Gupta Sorafenib 30 DTC 23% 53% 20 monthsKloss Sorafenib 41 PTC 15% 56% 15 monthsKloss Sorafenib 41 PTC 15% 56% 15 monthsCapdevila Sorafenib 34 DTC

MTC20% (DTC)50% (MTC)

48% 12 months

Sherman Motesanib 93 DTC 24%* 67% 10 monthsC h A iti ib 60 All t 30% 38% 18 thCohen Axitinib 60 All types 30% 38% 18 monthsRavaud Sunitinib 17 DTC & MTC 8.3% (DTC)

12.5% (MTC)66.7% (DTC)87.5% (MTC)

NR

Carr Sunitinib 33 DTC & MTC 13% (DTC) 68% (DTC) NRCarr Sunitinib 33 DTC & MTC 13% (DTC)0% (MTC)

68% (DTC)83% (MTC)

NR

De Souza Sunitinib 25 MTC 33% 54% 12 monthsLeboulleux Vandetanib 145 DTC 8.3% vs 5.5% 48% vs 37% 11 vs 5.8 monthsWells Vandetanib 331 MTC 20% 30% NRBible Pazopanib 37 DTC 49% 46% 11.7 monthsSherman Lenvatinib 58 DTC 59% 36% 13.3 monthsPennell Gefitinib 27 All types 0 48% 3.7 monthsAin Thalidomide 36 DTC & MTC 18% 32% NRAin Lenalidomide 18 DTC 39% 50% NRDTC: differentiated thyroid cancer; PTC: papillary thyroid cancer; MTC: medullar thyroid cancer; NR: notDTC: differentiated thyroid cancer; PTC: papillary thyroid cancer; MTC: medullar thyroid cancer; NR: not reported; *10% of unconfirmed responses.

Capdevila J, et al. Endocr Relat Cancerl, 2012

Targeted therapies in thyroid cancerSmall molecules inhibitors of multiple proteins with kinase activity in clinical trials for thyroid carcinomas.

Drug Targets with IC50 values (nmol/l)RET VEGFR1 VEGFR2 VEGFR3 PDGFRα PDGFRβ BRAF KIT FLT OtherRET VEGFR1 VEGFR2 VEGFR3 PDGFRα PDGFRβ BRAF KIT FLT3 Other

Sorafenib(BAY-439006)

47 26 90 20 - 57 25 68 33

Motesanib(AMG 706)

59 2 3 6 - 84 8 33

Axitinib(AG 013736)

1.2 1.2 0.16 0.29 5.2 1.6 - 1.7 -(AG-013736)

Sunitinib(SU011248)

100 - 4 - - 39 - 1-10 8-14

V d t ib 130 40 110 EGFRVandetanib(ZD6474)

130 - 40 110 - - - - - EGFR500

Pazopanib(GW786034)

- 10 30 47 - 84 - 74 -( )

Lenvatinib(E7080)

35 22 4 5.2 - 39 - - - FGFR146

Cabozantinib 4 - 0.035 - - - - - - C-MET

Capdevila J, et al. Target Oncol, 2009

(XL-184) 1.8

POTENTIAL MECHANISMS OF ANTIANGIOGENIC RESISTANCE

Bottsford-Miller JN, et al. J Clin Oncol 2012

NEW TARGETS FOR ANGIOGENESIS INHIBITION

PIGF VEGF

Soluble VEGFR1

FGFs HGFAng 1

A 2

NRP-1

VEGFR1 Ang 2

VEGFR2VEGFR1 FGFRs C-Met Integrins Tie-2

PPPP PP PPFak1

αα ββ

PI3KPLC-

MAPK

Scr

NOAkt

Bcl-2

PKC

RAFMEK

NO

BadCaspase

Courtesy of Dr. E. Grande Proliferation Survival Permeability Migration

LENVATINIB

Lenvatinib Inhibits Lenvatinib Inhibits Phosphorylation of VEGFR PDGFR RET and FGFR1Phosphorylation of VEGFR PDGFR RET and FGFR1

Cellular

Phosphorylation of VEGFR, PDGFR, RET and FGFR1Phosphorylation of VEGFR, PDGFR, RET and FGFR1

Receptor tyrosine kinase (RTK)

Cellular IC50* (nmol)Ligand-binding

VEGFR1 22VEGFR2 4

domain

Cell surface

VEGFR3 5.2PDGFRβ 39

Kinasedomains

*Receptor phosphorylationFGFR1 46RET 35

Matsui J, et al. Clin Cancer Res 2008

LENVATINIB: PRECLINICAL DATA

Matsui J, et al. Clin Cancer Res 2008

LENVATINIB DEVELOPMENT IN SOLID TUMORS

Clinicaltrials.gov

LENVATINIB IN DIFFERENTIATED THYROID CARCINOMA

Sherman SI, et al. ASCO 2011

LENVATINIB IN DIFFERENTIATED THYROID CARCINOMA

Prior VEGFR therapy: PR: 47%SD: 47%

N i VEGFR thNo prior VEGFR therapy: PR: 63%SD: 32%

Sherman SI, et al. ASCO 2011

LENVATINIB IN DIFFERENTIATED THYROID CARCINOMA

Ball D, et al. ASCO 2012

LENVATINIB IN MEDULLARY THYROID CARCINOMA

Prior VEGFR therapy:Prior VEGFR therapy: PR: 35%SD: 38%

No prior VEGFR therapy: PR: 36%SD: 48%

Schlumberger M, et al. ASCO 2012

LENVATINIB IN MEDULLARY THYROID CARCINOMA

Schlumberger M, et al. ASCO 2012

LENVATINIB IN THYROID CARCINOMA

Schlumberger M, et al. ASCO 2012Sherman SI, et al. ASCO 2011

SELECT TRIALPhase III Study of Lenvatinib in RaI-Refractory DTC

P ti t ith d d R I R f t

C

RAN

Lenvatinib 24 mg qdPatients with advanced RaI-Refractory DTC in Progression within prior 12 months (N = 360)• DTC including PTC, FTC, Hurtle Cell,

Insular Poorly Differentiated Treatmentuntil disease progression

Crossover allowed attime of PD

2:1DOMIZ

Insular, Poorly Differentiated• Centrally confirmed radiologic

progression ≤12 months• Prior antiVEGFR therapy allowed

D fi iti f R I R f t i ZE Placebo 24 mg qd

M lti h i CT MRI f d 12 k

• Definition of RaI Refractoriness:• ≥1 lesions with no uptake in

radioiodine scan• Progression of lesions with RaI

t k ithi 12 th ft Multiphasic CT or MRI performed every 12 weeksuptake within 12 months after I131 therapy

• >600 mCui of cumulative I131

Secondary Endpoints:St tifi ti bSt tifi ti b

Primary Endpoint:• PFS

• OS • ORR • Biomarkers • Safety

Stratification by

•Geographic region

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

Stratification by

•Geographic region

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

Enrollment July 2011-September 2012PD = progressive disease; ORR = overall response rate; PK = pharmacokinetics

Safety • PK

•Age (≤65 years vs >65 years)•Age (≤65 years vs >65 years)

SELECT TRIALPhase III Study of Lenvatinib in RaI-Refractory DTC

209 Centers209 Centers Worldwide

>600 Screenings

SELECT TRIALPhase III Study of Lenvatinib in RaI-Refractory DTC

LENVATINIB SCENARIO IN DIFFERENTIATED THYROID CARCINOMA

Targeted Agent Phase N Histology PR, % SD, % PFS, mo Grade 3 or 4 AEs

SORAFENIBSORAFENIB

Gupta- II 30 DTC 23 53 20 HFS, Rash, FatiguepAbramson

, , g

Hoftijzer II 31 DTC 25 34 13.5 HFS, Hypertension, weight loss

Kloos II 41 DTC 15 56 15 HFS arthralgia fatigueKloos II 41 DTC 15 56 15 HFS, arthralgia, fatigue

Brose II 55 DTC (90%) 36 46 14.5 Hypertension, HFS, rash

Ahmed II 29 DTC (55%) 15 85 NA HFS, rash, hypertension

Capdevila II 34 DTC (49%) MTC (44%)ATC (7%)

205033

53430

13.310.54.4

HFS, diarrhea, fatigue

13 months

Kloos RT, et al. J Clin Oncol, 2009; Capdevila J, et al. Endocr Relat Cancer, 2012

LENVATINIB SCENARIO IN DIFFERENTIATED THYROID CARCINOMA

LTR

IAL

SIO

N

DE

CI

TAKE HOME MESSAGES

Classic cytotoxic drugs have demonstrated modestresponses and no significant effect in overall survivalresponses and no significant effect in overall survival

Thyroid cancer represents a fascinating model and aThyroid cancer represents a fascinating model and aparticularly promising paradigm for targeted therapy

Key oncogenic events (RET/PTC, RAS, BRAF, PAX8-PPARγ) occurs early in thyroid cancer developmentPPARγ) occurs early in thyroid cancer development

Two large phase III studies have been completed in DTCTwo large phase III studies have been completed in DTCand two in MTC in a record time !

TAKE HOME MESSAGES

SELECT study is the first international, placebo-controlled, centrally confirmed progression status phase, y p g pIII trial completed in DTC

RET mutations are essential in pathogenesis, butangiogenesis is also essential for thyroid cancerd l M h i f i i idevelopment. Mechanisms for revert antiangiogenesisresistance are needed

Role of sequential therapy??

Documentation of disease progression should bemandatory previous initiation of TKIs therapy due to themandatory previous initiation of TKIs therapy due to thenatural history of DTC

Gracias Por Vuestra AtenciónGracias Por Vuestra Atención

jacapdevila@vhebron.net jacapde a@ eb o etjcapdevila@onco.cat