sign in sign up
<<
Home , Lenvatinib, Motesanib, Selumetinib

Oncology: Radioiodine-refractory DTC New Developments in Targeted Therapies Targeted Treatments

Giuseppe COSTANTE, MD, Head, Endocrinology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Thyroid Incidence

http://seer.cancer.gov/cgi-bin/csr/1975_2008 Thyroid (1975-2008)

All cancer sites (1988-2008)

Rate per 100,000 per Rate

Years of Diagnosis

G. Costante Incidence

Screening

Ahn, 2014

G. Costante Differentiated Thyroid Cancer Epidemiology

Stage specific trend (1975-2008)

Enewold , 2009

G. Costante Thyroid Cancer Incidence

Ahn, 2014 Screening

G. Costante Differentiated Thyroid Cancer Treatement

131 Total I Thyroidectomy Ablation

Suppressive Therapy Differentiated Thyroid Cancer Epidemiology

Stage at SEER summary stage 2000-2007 Diagnosis

Intrathyroidal 5% High Risk Patients Regional metastases Distant metastases Unknown

G. Costante Differentiated Thyroid Cancer Long Term Outcome High Risk Patients

Jonklaas, 2006

G. Costante Differentiated Thyroid Cancer Long Term Outcome High Risk Patients

Disease free 25 Persistence

20

15

N. Cases N. 10

Durante, 2013 5

0 Diagnosis End follow up

G. Costante Differentiated Thyroid Cancer Distant Metastases Long Term survival

Jonklaas, 2006

G. Costante Differentiated Thyroid Cancer Distant Metastases 131I-Treatment 1.0 131 1 Survival & I 0.9 avidity 127 pts 0.8 Group 1: 0.7 •131I-avid lesions 0.6 • remission 0.5 Group 2:

Survival 168 pts 0.4 • no/low 131I uptake 0.3 3 • persistent disease 0.2 Group 3: 0.1 2 149 pts • 131I-avid lesions 0.0 0 5 10 15 20 25 30 35 40 • persistent disease Years after metastasis discovery G. Costante Durante, 2006 Differentiated Thyroid Cancer

RAI refractory disease 131  Index lesion that did not take up I on a RAI scan

 RAI-avid index lesion that do not respond to RAI treatment within 6-12 months

 issue of lesion dosimetry

 Cumulative treatment > 600 mCi

G. Costante Differentiated Thyroid Cancer Response to

Complete Response 40 Progression No Response

30

20 N. Cases N.

10

0 Doxo Doxo+CisPl Shimaoka, 1985 Thyroid Cancer Tumorigenesis Intracellular Signalling Pathways

PTC FTC VEGF-A165 Endothelial cell RET/PTC EGFR VEGFR-2 C-MET

Ras Ras

PI3K B-Raf Raf PI3K

AKT MEK MEK AKT

ERK mTOR ERK mTOR

S6K S6K

• Growth • HIF1a • Growth • Migration • Survival • Inhibition of • Survival • Angiogenesis • Proliferation • Migration • Proliferation Keefe et al. Clin Cancer Res 2010;16:778. Thyroid Cancer Tumorigenesis Molecular Events

Giordano, 2014

G. Costante Thyroid Cancer Tumorigenesis Targeting Cell Signalling Pathways

Tumor Cell Endothelial Cell

RET/PTC EGFR VEGFR-2 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Ras Ras Vandetanib XL184 XL184 B-Raf PI3K Pazopanib Raf PI3K Lenvatinib AKT MEK Sorafenib MEK AKT Sorafenib mTOR mTOR ERK ERK Selumetinib Sirolimus S6K Everolimus S6K Pasireotide Sirolimus Pasireotide • Growth • HIF1a • Growth • Migration • Survival • Inhibition of apoptosis • Survival • Angiogenesis • Proliferation • Migration • Proliferation

Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Differentiated Thyroid Cancer Targeted Therapies

Approved Drugs for clinical use

 Sorafenib  Lenvatinib

 FDA 2013  FDA 2015

 EMA 2014  EMA 2015 Differentiated Thyroid Cancer Targeted Therapies

Outline

 Safety

 Eligible patients Differentiated Thyroid Cancer Sorafenib

Decision Study

Brose, 2014 Differentiated Thyroid Cancer Lenvatinib

Schlumberger, 2015 Differentiated Thyroid Cancer Targeted Therapies Outline

 Efficacy

 Safety

 Eligible patients Differentiated Thyroid Cancer Sorafenib

Adverse events

Worden, 2015 Differentiated Thyroid Cancer Lenvatinib Adverse events

Schlumberger, 2015 Differentiated Thyroid Cancer Targeted Therapies

Adverse events

 Accurate patient selection

 Close monitoring Differentiated Thyroid Cancer Targeted Therapies Outline

 Efficacy

 Safety

 Eligible patients Differentiated Thyroid Cancer

RAI refractory disease 131  Index lesion that did not take up I on a RAI scan

 RAI-avid index lesion that do not respond to RAI treatment within 6-12 months

 issue of lesion dosimetry

 Cumulative treatment > 600 mCi

 Others?

G. Costante Differentiated Thyroid Cancer

18FDG-PET scan vs survival

Wang, 2000 Differentiated Thyroid Cancer

18-FDG-PET scan vs RAI response

Survival at 60 months

RAI + FDG - 95%

RAI + FDG + 45%

RAI - FDG + 45%

RAI: radioactive iodine FDG: [18F]fluoro-2-deoxy-D-glucose

Robbins, 2006 Differentiated Thyroid Cancer

RAI refractory disease 131  Index lesion that did not take up I on a RAI scan

 RAI-avid index lesion that do not respond to RAI treatment within 6-12 months

 issue of lesion dosimetry

 Cumulative treatment > 600 mCi

18  AvidOthers? FDG lesions

G. Costante Differentiated Thyroid Cancer 131I-Refractory Management Strategy • Close monitoring of disease extension • Consider focal treatment modalities for tumor foci at high risk for complications » Cementoplasty » Stereotactic RT » Thermal ablation

• General strategy planned as early as possible Male, 46 yrs – Insular Thyroid Carcinoma pT3N1M1 April 2013 December 2013 August 2014 Thyroidectomy 131I dose 222 mCi 131I dose 219 mCi 131I dose 217.3 mCi

Stimulated Tg=1049 Stimulated Tg=436 Stimulated Tg=1058

Denosumab G. Costante Male, 46 yrs – Insular Thyroid Carcinoma pT3N1M1 March 2015 June 2015

131I 218.4 mCi 131I cumulative dose 877.7 mCi

1200 1000 131I 800 600 131I 131I 400 131I Stimulated Tg=1423 200 0 0 200 400 600 800 Basal Thyroglobulin

G. Costante Differentiated Thyroid Cancer EligibleAmerican ThyroidPatients Association for guidelines New , DrugsThyroid 2015 Recommendation 96

 Kinase inhibitor therapy should be considered in RAI-refractory DTC patients with metastatic, rapidly progressive, symptomatic and/or imminently threatening disease not otherwise amenable to local control using other approaches………….the impact of these agents on overall survival and quality of life remains to be defined.

 (Weak recommendation, Moderate-quality evidence) G. Costante Differentiated Thyroid Cancer Targeted Therapies

Initiation of systemic treatment

Tumor burden

Progression Small Large (RECIST) (no Target RECIST) >1-2 cm

> 12-14 months No ? High SUV

< 12-14 months No YES

Schlumberger, 2014 Male, 46 yrs – Insular Thyroid Carcinoma

pT3N1M1 March 2015 June 2015

131I 218.4 mCi 131I cumulative dose 877.7 mCi June 2015

1200 1000 131I 800 600 131I 131I 400 131I Stimulated Tg=1423 200 0 0 200 400 600 800 Basal Thyroglobulin

G. Costante Male, 46 yrs – Insular Thyroid Carcinoma 25000 December 2015 20000 July 2015 15000 10000 5000 0 0 500 1000 Basal Thyroglobulin

G. Costante Male, 46 yrs – Insular Thyroid Carcinoma Start Sorafenib

50000

40000

30000

20000

10000 BasalThyroglobulin 0 0 2 4 6 8 Months

G. Costante Differentiated Thyroid Cancer Treatment with MKIs

When to withdraw ?

• At structural progression after the nadir (RECIST +20%) ?

• More pronounced progression ?

No general consensus

G. Costante G. Costante Differentiated Thyroid Cancer Withdrawal of MKIs What to do next ?

• Second line treatment » Lenvatinib

Male, 46 yrs – Insular Thyroid Carcinoma

Start Lenvatinib

Sorafenib

50000

40000

30000

20000

10000

0 0 5 10 15 20 Basal Thyroglobulin

G. Costante Differentiated Thyroid Cancer Withdrawal of MKIs What to do next ? • Clinical protocols » New drugs • • Immunotherapy » Sequential treatment » Association of drugs • UPCC 19309 »Redifferentiation

Differentiated Thyroid Cancer Retinoic Acid Redifferentiation

Prof. Pierre Bourgeois

Schmultzer 2000 G. Costante Differentiated Thyroid Cancer Selumetinib Redifferentiation

DTC Selumetinib 124-I / 124-I / 131- refractory 4 weeks N=20 rhTSH rhTSH I

Ho, 2013 Differentiated Thyroid Cancer Redifferentiation

Ho, 2013