management of thyroid malignancies · nr: medullary only. ... 29. a 3-arm multicenter randomized...

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MANAGEMENT OF THYROID MALIGNANCIES

Taofeek K. Owonikoko, MD, PhDAssociate Professor

Department of Hematology/Medical OncologyWinship Cancer Institute of Emory University

Atlanta, GA

2Winship Cancer Institute | Emory University

Disclosures

• Research funding• Novartis, Bayer, AstraZeneca

• Advisory Board• Pfizer, Lilly, Eisai, Amgen/Onyx


Outline

• Overview of thyroid cancer burden• Pivotal trials leading to approved targeted therapeutics in thyroid

cancers• Clinical considerations in selecting targeted therapies for MTC and DTC• Other targets and ongoing translational research at Winship


Origin and histotypes of thyroid cancer

4Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol. 2016.19


Targets and targeted therapies

5Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol. 2016.19


Survival of patients with differentiated thyroid carcinoma (1987-2001)

Jonklass J, et al, Thyroid 2006

IIIIII

N=2936

Jonklass J, et al, Thyroid 2006


Chemotherapy and Thyroid CancerRegimen # of

PatientsRR PFS Remarks

Adriamycin# 18 15% NR Medullary only

Cisplatin# 14 21% NR Medullary only

Adriamycin ±Cisplatin*

92 17% vs.. 26%

NR Increased toxicity with combination

Adriamycin + Interferon 17 6% 5.9 Increased toxicity

Gemcitabine/Oxaliplatin 14 57% 10.1 Retrospective single site study

# Droz et al. 1984; *Shimaoka et al. 1986; ^ Argiris et al. 2008; Spano et al. 2012


Vandetanib in locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind Phase III trial (ZETA)SA Wells,1 BG Robinson,2 RF Gagel,3 H Dralle,4 JA Fagin,5 M Santoro,6 E Baudin,7 J Vasselli,8 J Read9 and M Schlumberger7

Wells et al. J Clin Oncol. 2012 Jan 10;30(2):134-41


Study design

Vandetanib 300 mg/dayn=231

Follow for progression Follow for progression

Optional open-label vandetanib 300 mg/day

Follow for survival

Patients with unresectable locally advanced or metastatic MTC (N=331)

Placebon=100

2:1 randomization

Discontinue blinded treatment at progression



Cabozantinib Versus Placebo in Medullary Thyroid Cancer

Treatment until progression or unacceptable toxicity

Locally advanced or metastatic

MTC with documented

RECIST progression

(N=330)

Carbozantinib 140 mg

Placebo

2:1 Randomization

PRO

GR

ESSI

ON

Survival follow-up

No Cross-OverNo Unblinding

• Key eligibility criterion– Locally advanced or metastatic MTC with radiographic progressive disease within 14 months

per mRECIST*

• Key study endpoints– Primary: PFS per mRECIST* determined by IRC. – Secondary: response rate per mRECIST and overall survival

Elisei R. et al. J Clin Oncol. 2013 Oct 10;31(29):3639-46


PFS and ORR per IRC

Carbozantinib Placebo

Median PFS 11.2 mo 4.0 mo

1 year PFS 47.3% 7.2%HR (95% CI) 0.28 (0.19, 0.40)

0.00.10.20.30.40.50.60.70.80.91.0

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

Prob

abili

ty

Time, mo

p <0.0001

• Tumor response rate of 28% in carbozantinib arm vs. 0% in placebo arm1

• Median tumor response duration of 14.7 months

1Determined in patients with measurable disease


Effect of Carbozantinib on PFS in Hereditary and Sporadic MTC

Median PFS

Carbozantinib 36 weeks

Placebo 24 weeks

Median PFS

Carbozantinib 48 weeks

Placebo 17 weeks

T im e (w e e k s )

Fra

cti

on

ev

en

t fr

ee

0 2 0 4 0 6 0 8 00 .0

0 .2

0 .4

0 .6

0 .8

1 .0

H e re d ita ry D is e a s e (N = 2 0 )

P la c e b o

C a b o z a n tin ib

T im e (w e e k s )

Fra

cti

on

ev

en

t fr

ee

0 2 0 4 0 6 0 8 00 .0

0 .2

0 .4

0 .6

0 .8

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

P la c e b o

S p o ra d ic D is e a s e (N = 2 8 3 )


Brose, M et al. Lancet. 2014 July 26; 384(9940): 319–328


Primary endpoint - PFS

18



Secondary endpoints: OS and RR

19



Lenvatinib versus placebo in iodine refractory thyroid cancer

Schlumberger et al. N Engl J Med 2015;372:621-30.

20

• Lenvatinib - receptor tyrosine kinase (RTK) inhibitor

• Targets VEGFR, FGFR, PDGFR-alpha• Inhibits pathogenic angiogenesis


Lenvatinib versus placebo in iodine refractory thyroid cancer

21Schlumberger et al. N Engl J Med 2015;372:621-30.

ORR: 64.8 vs. 1.5 CR: 4 vs. 0PR: 63.2 vs. 1.5SD: 23.0 vs. 54.2PD: 6.9 vs. 39.7


Overall Survival, ITT population


Treatment-emergent Adverse Events (TEAEs)


Approved targeted agents in thyroid cancer

Drug N RR (%)

PFS (months)

HR (CI) Clinical considerations

Vandetanib 331 45 30.5 vs. 19.3 0.46 (0.31-0.69) MTC; REMS due to risk for QT prolongation

Cabozantinib 330 27 11.2 vs. 4 0.28 (0.19-0.40); p<0.001

MTC; diarrhea

Sorafenib 397 24 10.8 vs. 5.8 0.59 (0.45-0.76) DTC; Hand & Foot Syndrome

Lenvatinib 392 65 18.3 vs. 3.6 0.21 (0.14-0.31) DTC; cardiovascular toxicity


Other targets and therapeutic strategies in thyroid cancer

25TCGA Network; Cell 159 (3) 2014, Pages 676–690Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol. 2016.19


In vivo activity of everolimus and pasireotide LAR in thyroid cancer

Owonikoko et al. manuscript submitted


Eligible Patients

Stratification: Histology Arm C:

Concurrent Everolimus and Pasireotide LAR - Continue until progression

Arm B:

Start with Pasireotide LAR- Add Everolimus at progression

Arm A:

Start with Everolimus - Add Pasireotide LAR at progression

Patient Assignment and Treatment Schema

Study design

Randomize


Treatment

• Arm A: • Everolimus 10mg once daily

• Arm B: • Pasireotide LAR, 60 mg im Q 4

weeks

• Arm C: • Everolimus 10mg once daily• Pasireotide LAR, 60 mg im Q 4

weeksT

ime of first progression

Add pasireotide LAR to everolimus

Add everolimus to pasireotide LAR

Off study

PFS1T

ime of second

progression

PFS2


A 3-arm multicenter randomized phase II study of single agent, immediate and delayed combination of everolimus and pasireotide LAR in advanced thyroid cancer

Taofeek K. Owonikoko,1 Julie Bauman,2,3 Zhengjia Chen,1 Chao Zhang,1 M. Renea Stinson,1 Vanessa H. Phelan,1 Jacene Myrie,1 Stephen Brandt,1 Gerald M. McGorisk,1 Sumathi Srivatsa,1 Amy Chen,1 Conor Steuer,1 Dong M. Shin,1 Suresh S. Ramalingam,1 Robert L. Ferris,2 Nabil F. Saba,1 Fadlo R. Khuri1,4

1: Winship Cancer Institute of Emory University, Atlanta GA USA; 2: University of Pittsburgh Cancer Institute, Pittsburgh, PA USA; 3: The University of Arizona Comprehensive Cancer Center, Tucson, AZ; 4: American University of Beirut, Beirut Lebanon

Presented at the 86th Annual Meeting of the ATA, September 24th, 2016, Denver, CO USA


Patient and tumor characteristicsVariable Level Arm A (19) Arm B (11) Arm C (12) Total N

(%)Race White 15 5 11 31 (83.8)

AA 2 4 0 6 (16.2)Others 2 2 1 5 (NA)

Ethnicity Hispanic/Latino 0 1 2 3 (7.7)Non-Hispanic 18 9 9 36 (92.3)

Unknown 1 1 1 3 (NA)

Age Mean 67 65 59 64.05Median 65.00

Gender Female 17Male 25

Histology DTC 14 9 9 32 (76.2)MTC 5 2 3 10 (23.8)


Response by RECIST criteriaArm (N)

CR(%) PR (%) SD(%) PD(%) NE (%)

A 0 0 82 0 18

B 0 0 80 18 9

C 0 0 100 0

No objective responses observed across all arms of the study


Final Analysis (N=42)PFS1 PFS2

Arm N Median PFS (95% CI) 1-year PFS rateA 19 26.3 (8.3, NA) 78.4.0%B 11 17.5 (2.1, 30.7) 70.0%C 12 8.1 (3.7, 13.8) 25.0%

Arm N Median PFS (95% CI) 1-year PFS rateA 19 8.3 (3.7, 26.3) 49.9%B 11 1.8 (1.7, 15.6) 36.4%C 12 8.1 (3.7, 13.8) 25.0%


Overall survival

Arm NMedian OS

(95% CI) 1-yr OS 2-year OSA 19 41.6 (17.8, NA) 100.0% 72.2%B 11 39.4 (8.4, NA) 81.8% 81.8%C 12 24.3 (13.1, NA) 91.7% 58.3%


Grade ≥3 Adverse eventsArm A Arm B Arm C

Grade 3 % Grade 3 % Grade 3 %

Anemia 5% Blindness 9% Elevated GGT 8%

Edema 5% Blood infection 9% Hyperglycemia 25%

Fatigue 11% Dyspnea 9% Hypokalemia 8%Gastric Hemorrhage 5% Hypertension 9% Kidney stone 8%

Hypertension 5% Hyperglycemia 27% Mucositis 8%

Hypocalcemia 5% Pain 8%

Leukopenia 5%

Pneumonitis 11% Grade 4Hyperglycemia 8%


Dabrafenib versus Dabrafenib + Trametinibin BRAF(+) Papillary Thyroid Cancer

Dabrafenib(N=26)

Dabrafenib + Trametinib (N=27)

P-value

Objective Response 50% 54% 0.78Median PFS (months) 11.4 (3.8 – NR) 15.1 (11.7 –NR) 0.27

Median DOR (months) 15.6 (4.2 – NR) 13.3 (9.7 – NR) 0.87

Randomized phase II Clinical trial: NCT01723202

Manisha Shah et al. J Clin Oncol 35, 2017 (suppl; abstr 6022)


Dabrafenib and trametinib in patients BRAF V600E–mutated anaplastic thyroid cancer

Dabrafenib + Trametinib (N=27)Objective Response 69% (95% CI, 41%-89%)Median PFS (months) NRMedian DOR (months) Not estimable12-month PFS and OS rates 79% and 80%

• Phase 2, open-label trial (NCT02034110)• ATC patients with BRAF V600E mutations treated with Dabrafenib (150 mg

BID) + Trametinib (2 mg QD) • Primary endpoint was investigator-assessed overall response rate (ORR)• Secondary endpoints: Duration of response (DOR), PFS and OS

Vivek Subbiah et al. J Clin Oncol 35, 2017 (suppl; abstr 6023)


RAI resensitization with targeted therapies

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


Enroll patients with RAI

sensitive disease with early

disease progression

Lenvatinib for 8 weeks

Repeat RAI at same dose as last RAI dose

Biomarker monitoring with TG Q3 monthsImaging Q4-6

months

RAI potentiation with targeted agents

PI: Taofeek OwonikokoCO-PI: Nikita Patel, MD


Other ongoing thyroid cancer trials

Study NCT# Title Strategy

NCT02152995 Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer

RAI resensitization

NCT02393690 Iodine I-131 With or Without Selumetinib in Treating Patients With Recurrent or Metastatic Thyroid Cancer

RAI resensitization

NCT02973997 Pembrolizumab and Lenvatinib in Treating Metastatic or Recurrent Differentiated Thyroid Cancer That Cannot Be Removed by Surgery

MKI + Immunecheckpoint

NCT03072160 Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer

Immunecheckpoint

NCT02289144 Ceritinib in Mutation and Oncogene Directed Therapy in Thyroid Cancer

TKI in ALK(+) subset


Summary

• Sorafenib and Lenvatinib are approved targeted treatment agents for advanced symptomatic DTC patients

• Lenvatinib more likely to achieve objective tumor shrinkage; preferred for patients with bulky symptomatic disease; watch out for cardiovascular complications of Lenvatinib

• Vandetanib and Cabozantinib offer targeted treatment options for advanced symptomatic MTC patients

• QT prolongation a unique toxicity of vandetanib (REMS) while cabozantinib more likely to worsen diarrhea

• Everolimus and pasireotide LAR showed anticancer efficacy in advanced thyroid cancer patients

• Various strategies with targeted and immunecheckpoint inhibitors are currently under study

management of thyroid malignancies · nr: medullary only. ... 29. a 3-arm multicenter randomized...

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