SYSTEMIC THERAPY IN MANAGING RADIOACTIVE IODINE (RAI)-REFRACTORY DIFFERENTIATED THYROID CANCER (DTC)

Challenges and Solutions

Thyroid Cancer

  Thyroid cancer (TC) is the most common endocrine malignancy1  TC is the fifth most

common cancer in women

  The most frequent subtype is the differentiated TC (DTC) derived from epithelial cells2

Major Histological Types of TC1

(%)

Differentiated (DTC)

Papillary (PTC)

85

Follicular (FTC)

11

Medullary 3

Anaplastic 1

2

1.  Jasim S et al. Biologics. 2014;8:281–291. 2.  Alonso-Gordoa T et al. Ther Adv Med Oncol. 2015;7(1):22–38.

Pathophysiology of DTC 3

  RAS/RAF/mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)/Akt RAS/are the main oncogenic pathways involved in DTC

Alonso-Gordoa T et al. Ther Adv Med Oncol. 2015;7(1):22–38.

Mutational Profile in DTC 4

Type of DTC Gene Mutation Percentage

Papillary TC

BRAF 40-60

RAS (N-RAS) 10-20

RET/PTC 10-20

PIK3CA amplification 16

TRK <5

Follicular TC

RAS (N-RAS) 40-50

PAX/PPARγ 30-35

PIK3CA mutation/amplification <10/30

PTEN <10 BRAF=B-type rapidly accelerated fibrosarcoma; PAX=Paired box gene; PI3KC= phosphatidylinositide 3-kinase C; PPAR=peroxisome proliferator-activated receptor; PTC=Papillary thyroid tumor; RAS=Rat sarcoma; RTC=Rearranged during transfection; TRK= Receptor tyrosine kinase.

Alonso-Gordoa T et al. Ther Adv Med Oncol. 2015;7(1):22–38.

Standard Therapy for Localized DTC 5

  Standard therapy for most patients with localized differentiated thyroid cancer (DTC) includes  Surgery  Radioactive iodine  Thyroid hormone replacement

Jasim S et al. Biologics. 2014;8:281–291.

Chemotherapy in DTC: Systemic 6

  Systemic Chemotherapy  Patients with progressive disease are candidates for

cytotoxic chemotherapy  Major drugs in this group include

 doxorubicin   paclitaxel   cisplatin

  Systemic chemotherapy is highly toxic and has very low response rates

Jasim S et al. Biologics. 2014;8:281–291.

Targeted Therapy in DTC 7

  An important subset of patients with DTC will develop progressive local or metastatic disease that no longer responds to radioiodine (RAI)

  Recent advances have led to the development of new treatments with targeted agents based on the characterization of molecular pathways involved in DTC   Tyrosine- Kinase Inhibitors (TKIs)   BRAF Inhibitors  mTOR inhibitors   TKI combination therapies

Jasim S et al. Biologics. 2014;8:281–291.

Phase II Clinical Trials With TKIs for Advanced DTC

8

RET RET/PTC

EGFR MET BRAF MEK FLT3 VEFGFR (1-3)

PDGFR c-kit

Axitinib X X X

Gefitinib X

Motesanib X X X X

Pazopanib X

Selumetenib X

Sorafenib X X X X X

Sunitinib X X X X X

Vandetanib X X X

Targets of TKIs in Reported Phase II Clinical Trials for Advanced DTC1,2

1.  Haugen BR et al. Endocr Rev. 2013;34(3):439-455. 2.  Haraldsdottir S et al. Curr Opin Oncol 2014;26(1):36-44.

Phase II Trial Outcomes With TKIs for Advanced DTC

9

Drug Reference N %PR/%SD PFS, months

Axitinib Cohen, 2008 60 31/42 18.1

Gefitinib Pennell, 2008 17 0/24 3.7

Motesanib Sherman, 2008 93 14/67 9.3

Pazopanib Bible, 2010 37 49/NR 11.7

Selumetenib Ho, 2013 20 63/37 NR

Sorafenib Gupta-Abramson, 2008; Kloos, 2009; Hoftijzer, 2009; Ahmed, 2011

30; 4; 31;19

23/53;15/56;15/46; 16/74

2;15;14.5; 16.5

Sunitinib Carr, 2010 33 28/46 12.8

Vandetanib Leboulleux, 2012 145 (72 active RX)

8/57 (on active RX)

11

PR=Partial response; PFS=Progression free survival; SD=Stable disease; NR=Not reported

TKI-Related Side Effects 10

  The most common side effect of antiangiogenic drugs is hypertension

  Proteinuria can be caused by disturbed microvascular permeability as a result of TKI treatment

  Hepatic transaminase and bilirubin elevation are seen with certain TKI treatments

  Hematological side effects of TKIs are bone marrow suppression, thrombosis, and tumor-related hemorrhage

  The most common dermatological side effects of TKIs, especially with sorafenib, are hand–foot skin reaction and rash.

Jasim S et al. Biologics. 2014;8:281–291.

Addressing Challenges in the Management of Advanced Thyroid Cancer

•  Variations exist in the definition of RAI-refractory disease •  Need for consensus definition of RAI-refractory DTC

Criteria for Characterizing Radioactive Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC)

•  Depends on criteria used for defining progressive disease •  Requires a consensus criteria based on clinical presentation of

the patient as well as imaging studies

Optimal Timing of Initiation of Targeted Therapy

•  Need for multidisciplinary and collaborative care for shared decision making across medical specialties

Coordination of Care During Transition from Local to Systemic Targeted Therapy

Sacks  W  and  Braunstein  GD.  Endocr  Pract.  2014;20(3):263-­‐275.    

Evolving Strategies in the Targeted Therapy of Advanced Thyroid Cancer

•  Target therapies using drug combinations •  Everolimus and sorafenib •  Temsirolimus and sorafenib

Increasing efficacy and preventing resistance to

targeted therapy1

•  Identification of predictive biomarkers •  Lower expression levels of nuclear pAKT

may predict better response to sorafenib

Identifying molecular predictors of response to targeted therapy2

•  Optimal dosing

•  Sarcopenia correlated with the toxicity observed in thyroid cancer patients treated with sorafenib

Managing toxicities of targeted drugs3

1.  Sacks W and Braunstein GD. Endocr Pract. 2014;20(3):263-275. 2.  Yarchoan M et al. J Clin Oncol. 2014; 32:5s. (suppl; abstr 6088). 3.  Huillard O et al. The Oncologist. 2014;19:e3.