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, AstraZeneca • Advisory Board • Pfizer, Lilly, Eisai, Amgen/Onyx Winship Cancer Institute | Emory University 2
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 Winship Cancer Institute | Emory University 3
Origin and histotypes of thyroid cancer 4 Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol. 2016.19 Winship Cancer Institute | Emory University 4
Targets and targeted therapies 5 Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol. 2016.19 Winship Cancer Institute | Emory University 5
Survival of patients w ith differentiated thyroid carcinoma (1987-2001) I II III N=2936 Jonklass J, et al, Thyroid 2006 Jonklass J, et al, Thyroid 2006 Winship Cancer Institute | Emory University 6
Chemotherapy and Thyroid Cancer Regimen # of RR PFS Remarks Patients Adriamycin# 18 15% NR Medullary only Cisplatin# 14 21% NR Medullary only Adriamycin ± 92 17% vs.. NR Increased toxicity 26% with combination Cisplatin* 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 Winship Cancer Institute | Emory University 7
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. 2012 Jan 10;30(2):134-41 Winship Cancer Institute | Emory University 8
Study design Patients with unresectable locally advanced or metastatic MTC (N=331) 2:1 randomization Vandetanib 300 mg/day Placebo n=231 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. 2012 Jan 10;30(2):134-41 Winship Cancer Institute | Emory University 9
Wells et al. J Clin Oncol. 2012 Jan 10;30(2):134-41 Winship Cancer Institute | Emory University 10
Cabozantinib Versus Placebo in Medullary Thyroid Cancer Treatment until progression or unacceptable toxicity Locally advanced Carbozantinib 140 mg PROGRESSION or metastatic MTC with No Cross-Over Survival documented 2:1 Randomization No Unblinding follow-up RECIST progression (N=330) Placebo • Key eligibility criterion – L ocally 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 Winship Cancer Institute | Emory University 12
PFS and ORR per IRC 1.0 Carbozantinib Placebo 0.9 0.8 Median PFS 11.2 mo 4.0 mo 0.7 Probability 1 year PFS 47.3% 7.2% 0.6 HR (95% CI) 0.28 (0.19, 0.40) 0.5 0.4 0.3 p <0.0001 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 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 Winship Cancer Institute | Emory University 13
Effect of Carbozantinib on PFS in Hereditary and Sporadic MTC H e re d ita ry D is e a s e (N = 2 0 ) S p o ra d ic D is e a s e (N = 2 8 3 ) C a b o z a n tin ib C a b o z a n tin ib 1 .0 1 .0 P la c e b o P la c e b o F ra c tio n e v e n t fre e F ra c tio n e v e n t fre e 0 .8 0 .8 0 .6 0 .6 0 .4 0 .4 0 .2 0 .2 0 .0 0 .0 0 2 0 4 0 6 0 8 0 0 2 0 4 0 6 0 8 0 T im e (w e e k s ) T im e (w e e k s ) Median PFS Median PFS Carbozantinib 36 weeks Carbozantinib 48 weeks Placebo 24 weeks Placebo 17 weeks Winship Cancer Institute | Emory University 14
Brose, M et al. Lancet. 2014 July 26; 384(9940): 319–328 Winship Cancer Institute | Emory University 17
Primary endpoint - PFS Brose, M et al. Lancet. 2014 July 26; 384(9940): 319–328 18 Winship Cancer Institute | Emory University 18
Secondary endpoints: OS and RR Brose, M et al. Lancet. 2014 July 26; 384(9940): 319–328 19 Winship Cancer Institute | Emory University 19
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;372:621-30. 20 Winship Cancer Institute | Emory University 20
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. 54.2 PD: 6.9 vs. 39.7 Schlumberger et al. N Engl J Med 2015;372:621-30. 21 Winship Cancer Institute | Emory University 21
Overall Survival, ITT population Winship Cancer Institute | Emory University 22
Treatment-emergent Adverse Events (TEAEs) Winship Cancer Institute | Emory University 23
Approved targeted agents in thyroid cancer Drug N RR PFS HR (CI) Clinical considerations (%) (months) 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); MTC; diarrhea p<0.001 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 Winship Cancer Institute | Emory University 24
Other targets and therapeutic strategies in thyroid cancer TCGA Network; Cell 159 (3) 2014, Pages 676–690 Bible, K. C. & Ryder, M. (2016) Nat. Rev. Clin. Oncol. 2016.19 25 Winship Cancer Institute | Emory University 25
In vivo activity of everolimus and pasireotide LAR in thyroid cancer Winship Cancer Institute | Emory University 26 Owonikoko et al. manuscript submitted
Study design Patient Assignment and Treatment Schema Arm A: Start with Everolimus Stratification: Histology Eligible Patients - Add Pasireotide LAR at progression Arm B: Randomize Start with Pasireotide LAR - Add Everolimus at progression Arm C: Concurrent Everolimus and Pasireotide LAR - Continue until progression Winship Cancer Institute | Emory University 27
Treatment PFS2 PFS1 • Arm A: • Everolimus 10mg once daily Add pasireotide LAR to Time of second progression everolimus Time of first progression • Arm B: • Pasireotide LAR, 60 mg im Q 4 weeks Add everolimus to pasireotide LAR • Arm C: • Everolimus 10mg once daily • Pasireotide LAR, 60 mg im Q 4 Off study weeks Winship Cancer Institute | Emory University 28
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 Winship Cancer Institute | Emory University 29
Patient and tumor characteristics Total N Variable Level Arm A (19) Arm B (11) Arm C (12) (%) 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 64.05 Median 65.00 Gender Female 17 Male 25 Histology DTC 14 9 9 32 (76.2) MTC 5 2 3 10 (23.8) Winship Cancer Institute | Emory University 30
Response by RECIST criteria Arm CR(%) PR (%) SD(%) PD(%) NE (%) (N) 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 Winship Cancer Institute | Emory University 31
Final Analysis (N=42) PFS1 PFS2 Arm N Median PFS (95% CI) 1-year PFS rate Arm N Median PFS (95% CI) 1-year PFS rate A 19 26.3 (8.3, NA) 78.4.0% A 19 8.3 (3.7, 26.3) 49.9% B 11 17.5 (2.1, 30.7) 70.0% B 11 1.8 (1.7, 15.6) 36.4% C 12 8.1 (3.7, 13.8) 25.0% C 12 8.1 (3.7, 13.8) 25.0% Winship Cancer Institute | Emory University 32
Overall survival Median OS Arm N (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% Winship Cancer Institute | Emory University 33
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