MANAGEMENT OF THYROID MALIGNANCIES Taofeek K. Owonikoko, MD, PhD - - PowerPoint PPT Presentation

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MANAGEMENT OF THYROID MALIGNANCIES Taofeek K. Owonikoko, MD, PhD - - PowerPoint PPT Presentation

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MANAGEMENT OF THYROID MALIGNANCIES Taofeek K. Owonikoko, MD, PhD Associate Professor Department of Hematology/Medical Oncology Winship Cancer Institute of Emory University Atlanta, GA 1 Disclosures Research funding Novartis, Bayer,

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MANAGEMENT OF THYROID MALIGNANCIES

Taofeek K. Owonikoko, MD, PhD Associate Professor Department of Hematology/Medical Oncology Winship Cancer Institute of Emory University Atlanta, GA

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2 Winship Cancer Institute | Emory University

Disclosures

  • Research funding
  • Novartis, Bayer, AstraZeneca
  • Advisory Board
  • Pfizer, Lilly, Eisai, Amgen/Onyx
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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
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Origin and histotypes of thyroid cancer

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

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Targets and targeted therapies

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

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Survival of patients w ith differentiated thyroid carcinoma (1987-2001)

Jonklass J, et al, Thyroid 2006

I II III N=2936

Jonklass J, et al, Thyroid 2006

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Chemotherapy and Thyroid Cancer

Regimen # of Patients RR 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

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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

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Study design

Vandetanib 300 mg/day n=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) Placebo n=100 2:1 randomization Discontinue blinded treatment at progression

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

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

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Cabozantinib Versus Placebo in Medullary Thyroid Cancer

Treatment until progression

  • r unacceptable toxicity

Locally advanced

  • r metastatic

MTC with documented RECIST progression (N=330) Carbozantinib 140 mg Placebo 2:1 Randomization PROGRESSION Survival follow-up

No Cross-Over No 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

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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)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Probability 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

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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 ) F ra c tio n e v e n t fre e

2 0 4 0 6 0 8 0 0 .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 ) F ra c tio n e v e n t fre e

2 0 4 0 6 0 8 0 0 .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 )

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

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Primary endpoint - PFS

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

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Secondary endpoints: OS and RR

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

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Lenvatinib versus placebo in iodine refractory thyroid cancer

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

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  • Lenvatinib - receptor tyrosine

kinase (RTK) inhibitor

  • Targets VEGFR, FGFR, PDGFR-alpha
  • Inhibits pathogenic angiogenesis
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Lenvatinib versus placebo in iodine refractory thyroid cancer

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

ORR: 64.8 vs. 1.5

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

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Overall Survival, ITT population

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Treatment-emergent Adverse Events (TEAEs)

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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

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Other targets and therapeutic strategies in thyroid cancer

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

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In vivo activity of everolimus and pasireotide LAR in thyroid cancer

Owonikoko et al. manuscript submitted

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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

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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

weeks

Time of first progression Add pasireotide LAR to everolimus Add everolimus to pasireotide LAR Off study

PFS1

Time of second progression

PFS2

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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

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Patient and tumor characteristics

Variable Level Arm A (19) Arm B (11) Arm C (12) Total N (%)

Race White 15 5 11 31 (83.8) AA 2 4 6 (16.2) Others 2 2 1 5 (NA) Ethnicity Hispanic/Latino 1 2 3 (7.7) Non-Hispanic 18 9 9 36 (92.3) Unknown 1 1 1 3 (NA) Age Mean 67 65 59 64.05 Median 65.00 Gender Female 17 Male 25 Histology DTC 14 9 9 32 (76.2) MTC 5 2 3 10 (23.8)

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Response by RECIST criteria

Arm (N) CR(%) PR (%) SD(%) PD(%) NE (%) A 82 18 B 80 18 9 C 100 No objective responses observed across all arms of the study

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Final Analysis (N=42)

PFS1 PFS2

Arm N Median PFS (95% CI) 1-year PFS rate A 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 rate A 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%

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Overall survival

Arm N Median OS (95% CI) 1-yr OS 2-year OS A 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%

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Grade ≥3 Adverse events

Arm 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 4 Hyperglycemia 8%

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Dabrafenib versus Dabrafenib + Trametinib in BRAF(+) Papillary Thyroid Cancer

Dabrafenib (N=26) Dabrafenib + Trametinib (N=27) P-value Objective Response 50% 54% 0.78 Median 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)

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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) NR Median DOR (months) Not estimable 12-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)

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RAI resensitization w ith targeted therapies

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

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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 months Imaging Q4-6 months

RAI potentiation w ith targeted agents

PI: Taofeek Owonikoko CO-PI: Nikita Patel, MD

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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

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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