Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma

$Page 1: Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma$
Treatment of radioactive iodine-refractory differentiated thyroid

carcinoma

Mauricio Lema Medina MD – Clínica de oncología Astorga, Clínica SOMA, Medellín

ACHO, Bogotá, 29.07.2016

Page 2

@onconerd

Mauricio Lema Medina

Conflicts of interest

Consulting and honoraria as a speaker: Pfizer, MSD, Novartis, ROCHE, Aztra-Zeneca, Boehringer-Ingelheim.

Harrisons’s, 19th Ed.

>5.0cm2.1-5.0cm

Thyroid cancer in the United States

0-1.0cm1.1-2.0cm

Davies, JAMA 2006 295:2164

Medullary Anaplastic

Papillary Follicular

Differentiated Thyroid Cancer (DTC)



Thyroid Cancer: Treatment Strategy

• High Risk: (Age >45, male, metastasis, extrathyroidal extension, >4cm)– Total Thyroidectomy– RAI (131I) Ablation– TSH Suppression Therapy with Thyroid

Hormone– Follow Serial Thyroglobulin Levels (Tg)– XRT for recurrent local disease/positive margins– Surveillance: NeckUS, Tg, Neck MRI, Chest CT,

RAI Whole body scan, FDG-PET

NCCN: Thyroid cancer – Papillary and Follicular

Page 9NCCN, 1.2016

RAI-Refractory Disease• 25-50% of Metastatic Thyroid Cancers loose ability to

take up Iodine

• This is attributed to down regulation of the Na+/I- Symporter (NIS) and other genes of NaI metabolism

In other words, the cancer cells “forget” how to take up iodine and so

they are immune to the treatment.


Fig. 1. Survival after the discovery of metastases according to the presence or absence of 131I uptake in the metastases.

Published in: C. Durante; N. et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899.DOI: 10.1210/jc.2005-2838Copyright © 2006

Fig. 2. Survival after the discovery of distant metastases according to the age at discovery and to the extent of disease. 131I uptake was not taken into account, but was closely linked to the two other prognostic factors, and was invariably present in young patients with small metastases (group 1) and rarely present in older patients with large metastases (group 2). Group 1, Patients younger than 40 yr of age with metastases that were not visible on radiographs or that were micronodular (<1 cm in diameter). Group 2, Patients older than 40 yr with macronodular lung metastases or multiple bone metastases. Group 3, Patients older than 40 yr with normal x-rays or micronodular metastases and patients younger than 40 yr with macronodular lung metastases.

Published in: C. Durante; et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899.DOI: 10.1210/jc.2005-2838Copyright © 2006

Less than 40 yo with small

metastases

Older than 40 yo with macronodular lung metastases or bone metastases

RAI-Sensitive

RAI-Refractory

Fig. 3. Survival after the discovery of distant metastases. Group 1, Patients with 131I uptake who attained negative imaging studies. Group 2, Patients with 131I uptake who did not attain negative imaging studies. Group 3, Patients with no 131I uptake.

Published in: C. Durante; et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899.DOI: 10.1210/jc.2005-2838Copyright © 2006

Attained negative imaging studies

Did not attain negative imaging studies


Schlumberger M et al. N Engl J Med 2015;372:621-630.

Iodine-Refractory mDTC: diagnostic criteria

Evidence of radiologic progression within 13 months and at least one of the following criteria:

At least one measurable lesion without iodine uptake on any iodine-131 scan,

At least one measurable lesion that had progressed according to the Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1, criteria within 12 months after iodine-131 therapy despite iodine-131 avidity at the time of treatment,

Or cumulative activity of iodine-131 that was >600 mCi


RAI-refractory disease• Standard Chemotherapy has minimal efficacy.

1974 Doxorubicin became the only FDA approved drug for the treatment of advanced thyroid cancer.

•No longer used because recent data shows response is 5%

•High toxicity in patient with otherwise good QOL

Cooper DS, et al. Thyroid. 2009;9:1176-214.Hodak SP, Carty SE. Oncology. 2009;23:775-6.

Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22:1279-95,xi.

Overcoming iodine resistance in DTC

Page 19

Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer

RET NTRK1 RAS BRAF

70% of PTC have one of these mutually exclusive mutations

MAP Kinase pathway

DECREASE of theNa-I Symporter

Thyroid biosynthesis genesThyroid peroxidaseHo AL et al. N Engl J Med 2013;368:623-632.


Inhibition of BRAF RestoresNa-I Symporter

Ho AL et al. N Engl J Med 2013;368:623-632.



Protocol Design and Changes in Iodine Uptake.



Patients screened 24Patients that could be evaluated 20BRAF mutations 9NRAS mutations 5Increased Iodine-24 uptake 12Increased Iodine-24 uptake enough for RAI therapy 8Increased Iodine-24 uptake in BRAF mutated patients 4/9Increased Ioding-24 uptake in NRAS mutated patients 5/5

Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease.


Response to Iodine-131 Therapy with Selumetinib Treatment.


Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses.


Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine.

Targeted therapy in mDTC

Page 28

Page 29

Thyroid Cancer is associated with aberrant cell signaling

Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35%Total >70% >65%

MA

P K

inas

ePI

3K/A

KT

Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007

Thyroid Cancer is associated with aberrant cell signaling

Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35%Total >70% >65%

MA

P K

inas

ePI

3K/A

KT

Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007

Cell signalling in differentiated thyroid cancer

Graphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:778-83.

RET/PTC

• HIF1a• Inhibition of apoptosis• Migration

EGFR

PI3K

VEGFR-2

Endothelial Cell

• Migration• Angiogenesis

Ras

B-Raf

MEK

ERK

PI3K

AKT

mTOR

S6K

Ras

Raf

MEK

ERK

AKT

mTOR

S6K

Tumor Cell

• Growth• Survival• Proliferation



MotesanibSorafenibSunitinibVandetanibXL-184

Axitinib MotesanibSorafenibSunitinibVandetanib

Vandetanib

Sorafenib Sorafenib

Targeting cell signaling in thyroid cancer

RET/PTC


EGFR

PI3K

VEGFR-2

Endothelial Cell


Ras

B-Raf

MEK

ERK

PI3K

AKT

mTOR

S6K

Ras

Raf

MEK

ERK

AKT

mTOR

S6K

Tumor Cell



EverolimusSirolimus

EverolimusSirolimus

Targets of Kinase InhibitorsCompound Name VEGFR BRAF

PDGFR KIT RET Other

Sorafenib + + + + + FLT-3

Sunitinib + + + FLT-3Axitinib (AG-013736) + + + Motesanib (AMG-706) + + + +Pazopanib(GW786034) + + +

Vandetanib + + EGFRCabozantinib (XL184) + + C-METLenvatinib(E7080) + + + + FGFR


UPCC 03305: Sorafenib in Advanced Thyroid Cancer February 2006-February 2011

Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9

n=55

Eligibility criteria

• Metastatic, iodine refractory thyroid cancer

• Life expectancy >3 months

• Evidence of PD within 6 months of study entry

• ECOG 0–2

• Good organ and bone marrow function

Sorafenib400mg b.i.d.

Primary endpoints• RECIST• PFS• Response rate

b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal

UPCC 03305: Best Response in 46 Evaluable Patients

PapillaryFollicular/Hürthle CellMedullaryPoorly Differentiated/Anaplastic

302010

0–10–20–30–40–50–60–70–80–90–10 C

hang

e in

sum

of t

arge

t les

ion

by R

ECIS

Tco

mpa

red

to b

asel

ine

(%)

PD SD PR

Best response of advanced thyroid cancer patients to sorafenib

Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)

Eligibility criteria• Locally advanced

or metastatic DTC• Progression

within 14 months • RAI refractory • No prior targeted

therapy, chemotherapy or thalidomide

Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial

• An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC

www.clinicaltrials.gov. NCT00984282

Offstudy

Disease progression

Crossover or continue

sorafenib 400mg orally b.i.d.

Ran

dom

isat

ion

(1:1

)(n

=380

)Progression

Sorafenib400mg orally

b.i.d.

Placebo

Investigator’s decisionn=190

n=190

Primary Endpoint:PFS (RECIST)Independent reviewMet primary endpointJanuary 2013

Secondary Endpoints:OS, TTP, RR, DCR, PRO, PKSafetyExploratory Biomarkers

Brose M, DECISION trial, ASCO, 2013Brose M, DECISION trial, Lancet, 2014




LENVATINIB

Schlumberger M, et al. NEJM, 2015



Kaplan–Meier Estimate of Progression-free Survival in the Intention-to-Treat Population.



Copyright © 2016 Elsevier Ltd Terms and Conditions

BRAFm - RAI-Refractory PTC 51

No prior multikinase therapy (Cohort 1) 26

Prior multikinase therapy (Cohort 2) 25

Vemurafenib 960 mg PO twice a day

Endpoint: investigator-assessed ORR

Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised,

multicentre, open-label, phase 2 trial

Brose MS, Lancet Oncol, 2016

http://www.elsevier.com/termsandconditions

The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8) Copyright © 2016 Elsevier Ltd Terms and Conditions

Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial


The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8) Copyright © 2016 Elsevier Ltd Terms and Conditions

No prior multikinase therapy Prior multikinase therapy


Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised,

multicentre, open-label, phase 2 trial

Copyright © 2016 Elsevier Ltd Terms and Conditions

BRAFm - RAI-Refractory PTC 51

No prior multikinase therapy (Cohort 1) 25

Prior multikinase therapy (Cohort 2) 26

PR in Cohort 1 10/26

DCR in Cohort 1 9/26

Median DOR Cohort 1 16 months

PR in Cohort 2 6/22

6-mo DCR in Cohort 2 6/22

Median DOR in Cohort 2 27 weeks

“Vemurafenib showed antitumour activity in patients with progressive, BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients”.

Brose MS, Lancet Oncol, 2016


Progression after TKIs

Page 52

De Souza JA, ASCO, 2016, Abstract 6013

Proc ASCO, 2013, Abstract 6024

Overcoming Sorafenib Resistance

De Souza JA, ASCO, 2016, Abstract 6013

Ann Wild Gramza, ASCO, 2016


MotesanibSorafenibSunitinibVandetanibXL-184

Axitinib MotesanibSorafenibSunitinibVandetanib

Vandetanib

Sorafenib Sorafenib

Targeting cell signaling in thyroid cancer

RET/PTC


EGFR

PI3K

VEGFR-2

Endothelial Cell


Ras

B-Raf

MEK

ERK

PI3K

AKT

mTOR

S6K

Ras

Raf

MEK

ERK

AKT

mTOR

S6K

Tumor Cell



EverolimusSirolimus

EverolimusSirolimus

UPCC 19309: Everolimus + Sorafenib for DTC patients who progress on Sorafenib alone

n=35

Eligibility criteria

• Metastatic, iodine refractory thyroid cancer

• Life expectancy >3 months

• PD on sorafenib• ECOG 0–2

• Good organ and bone marrow function

Sorafenib + Everolimus

Intra-patientDose escalation

Primary endpoints• RECIST• PFS• Response rate

b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal

22 patients accrued so far

Min Lim S, Oncotarget, 2016

Somatic mutations that confer exceptional response to everolimus (NGS)



Somatic mutations that confer exceptional response to everolimus (NGS)

NCCN: Thyroid cancer – Papillary and Follicular

Page 62NCCN, 1.2016

Conclusions

RAI-Refractory mDTC

Sorafenib

Lenvatinib

Selumetinib + RAI in NRAS mutated

Vemurafenib in BRAF mutatedPreferred, unavailable

Not ready for prime-time

Needs more data

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Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma