MANAGEMENT OF THYROID MALIGNANCIES

Transcription

1 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

2 Disclosures Research funding Novartis, Bayer, AstraZeneca Advisory Board Pfizer, Lilly, Eisai, Amgen/Onyx 2

3 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 3

4 Origin and histotypes of thyroid cancer Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol

5 Targets and targeted therapies Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol

6 Survival of patients with differentiated thyroid carcinoma ( ) I II III N=2936 Jonklass J, et al, Thyroid 2006 Jonklass J, et al, Thyroid

7 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

8 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 Read 9 and M Schlumberger 7 Wells et al. J Clin Oncol Jan 10;30(2):

9 Study design Patients with unresectable locally advanced or metastatic MTC (N=331) 2:1 randomization Vandetanib 300 mg/day n=231 Placebo n=100 Follow for progression Follow for progression Discontinue blinded treatment at progression Optional open-label vandetanib 300 mg/day Follow for survival Wells et al. J Clin Oncol Jan 10;30(2):

10 Wells et al. J Clin Oncol Jan 10;30(2):

11 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 2:1 Randomization Placebo PROGRESSION No Cross-Over No Unblinding Survival follow-up 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 Oct 10;31(29):

12 PFS and ORR per IRC Probability 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) p < Time, mo Tumor response rate of 28% in carbozantinib arm vs. 0% in placebo arm 1 Median tumor response duration of 14.7 months 1 Determined in patients with measurable disease 13

13 Effect of Carbozantinib on PFS in Hereditary and Sporadic MTC Hereditary Disease (N=20) Sporadic Disease (N=283) 1.0 Cabozantinib Placebo 1.0 Cabozantinib Placebo Fraction event free Fraction event free Time (weeks) Median PFS Time (weeks) Median PFS Carbozantinib 36 weeks Carbozantinib 48 weeks Placebo 24 weeks Placebo 17 weeks 14

14 Brose, M et al. Lancet July 26; 384(9940):

15 Primary endpoint - PFS Brose, M et al. Lancet July 26; 384(9940):

16 Secondary endpoints: OS and RR Brose, M et al. Lancet July 26; 384(9940):

17 Lenvatinib versus placebo in iodine refractory thyroid cancer Lenvatinib - receptor tyrosine kinase (RTK) inhibitor Targets VEGFR, FGFR, PDGFR-alpha Inhibits pathogenic angiogenesis Schlumberger et al. N Engl J Med 2015;372:

18 Lenvatinib versus placebo in iodine refractory thyroid cancer ORR: 64.8 vs. 1.5 CR: 4 vs. 0 PR: 63.2 vs. 1.5 SD: 23.0 vs PD: 6.9 vs Schlumberger et al. N Engl J Med 2015;372:

19 Overall Survival, ITT population 22

20 Treatment-emergent Adverse Events (TEAEs) 23

21 Approved targeted agents in thyroid cancer Drug N RR (%) PFS (months) HR (CI) Clinical considerations Vandetanib vs ( ) MTC; REMS due to risk for QT prolongation Cabozantinib vs ( ); p<0.001 MTC; diarrhea Sorafenib vs ( ) DTC; Hand & Foot Syndrome Lenvatinib vs ( ) DTC; cardiovascular toxicity 24

22 Other targets and therapeutic strategies in thyroid cancer Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol TCGA Network; Cell 159 (3) 2014, Pages

23 In vivo activity of everolimus and pasireotide LAR in thyroid cancer Owonikoko et al. manuscript submitted 26

24 Study design Patient Assignment and Treatment Schema Arm A: Eligible Patients Stratification: Histology Randomize Start with Everolimus - Add Pasireotide LAR at progression Arm B: Start with Pasireotide LAR - Add Everolimus at progression Arm C: Concurrent Everolimus and Pasireotide LAR - Continue until progression 27

25 Treatment PFS1 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 PFS2 Time of first progression Add pasireotide LAR to everolimus Add everolimus to pasireotide LAR Off study Time of second progression 28

26 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. Khuri 1,4 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 86 th Annual Meeting of the ATA, September 24 th, 2016, Denver, CO USA 29

27 Patient and tumor characteristics Variable Level Arm A (19) Arm B (11) Arm C (12) Total N (%) Race White (83.8) AA (16.2) Others (NA) Ethnicity Hispanic/Latino (7.7) Non-Hispanic (92.3) Unknown (NA) Age Mean Median Gender Female 17 Male 25 Histology DTC (76.2) MTC (23.8) 30

28 Response by RECIST criteria Arm (N) CR(%) PR (%) SD(%) PD(%) NE (%) A B C No objective responses observed across all arms of the study 31

29 Final Analysis (N=42) PFS1 PFS2 Arm N Median PFS (95% CI) 1-year PFS rate A (3.7, 26.3) 49.9% B (1.7, 15.6) 36.4% C (3.7, 13.8) 25.0% Arm N Median PFS (95% CI) 1-year PFS rate A (8.3, NA) % B (2.1, 30.7) 70.0% C (3.7, 13.8) 25.0% 32

30 Overall survival Arm N Median OS (95% CI) 1-yr OS 2-year OS A (17.8, NA) 100.0% 72.2% B (8.4, NA) 81.8% 81.8% C (13.1, NA) 91.7% 58.3% 33

31 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% 34

32 Dabrafenib versus Dabrafenib + Trametinib in BRAF(+) Papillary Thyroid Cancer Randomized phase II Clinical trial: NCT 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 Manisha Shah et al. J Clin Oncol 35, 2017 (suppl; abstr 6022) 35

33 Dabrafenib and trametinib in patients BRAF V600E mutated anaplastic thyroid cancer Phase 2, open-label trial (NCT ) 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 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% Vivek Subbiah et al. J Clin Oncol 35, 2017 (suppl; abstr 6023) 36

34 RAI resensitization with targeted therapies Ho AL et al. N Engl J Med 2013; 368:

35 RAI potentiation with targeted agents 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 PI: Taofeek Owonikoko CO-PI: Nikita Patel, MD 38

36 Other ongoing thyroid cancer trials Study NCT# Title Strategy NCT NCT NCT NCT NCT Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer Iodine I-131 With or Without Selumetinib in Treating Patients With Recurrent or Metastatic Thyroid Cancer Pembrolizumab and Lenvatinib in Treating Metastatic or Recurrent Differentiated Thyroid Cancer That Cannot Be Removed by Surgery Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer Ceritinib in Mutation and Oncogene Directed Therapy in Thyroid Cancer RAI resensitization RAI resensitization MKI + Immunecheckpoint Immunecheckpoint TKI in ALK(+) subset 39

37 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 40