2014 Debates and Didactics in Hematology and Oncology New treatments in the management of thyroid cancer

Transcription

1 2014 Debates and Didactics in Hematology and Oncology New treatments in the management of thyroid cancer Taofeek K. Owonikoko, MD/PhD Associate Professor Department of Hematology/Medical Oncology Emory University August 9, 2014

2 Objectives Review the pathology and epidemiology of thyroid cancer Overview of newly established systemic therapy approaches for advanced thyroid cancer Evolving and future approaches in advanced thyroid cancer treatment

3 Histologic Variants Well-Differentiated 90% Papillary 80% Follicular 5-10% Hurthle Cell - <5% Medullary 5% Familial As part of MEN2 Syndrome Sporadic Poorly Differentiated/Anaplastic 5% Others - <1% Lymphoma, sarcoma, etc.

4 Cancer Statistics 2013 Siegel R. et al. CA CANCER J CLIN 2013;63:11 30

5 US Incidence of Thyroid Cancer by Size and Histology Davies, L. et al. JAMA 2006;295:

6 Survival in differentiated thyroid carcinoma 2936 patients ( ) Surviving Time FuTimeFINAL to Death, Yrs I II III IV Jonklass J, et al, Thyroid 2006

7 Cytotoxic chemotherapy 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

8 Gemcitabine/Oxaliplatin in refractory thyroid cancer Spano et al. Med Oncol :

9 Aberrant signaling pathway in thyroid cancer 20-30% FTC Ras PDTC, ATC PTC 15-20% RET/PTC PI3K Ras 15-20% Pax8-PPARγ 20-30% AKT BRAF 40-60% βcatenin PDTC MEK-ERK NIS Tumor growth, dedifferentiation p53 PDTC, ATC Abbosh and Nephew, Thyroid:15, , 2005

10 Multikinase inhibitors Thyroid carcinoma Drug IC 50 (nm) VEGFR1 VEGFR2 VEGFR3 RET RET/PTC3 RAF Other Axitinib PDGFR 1.7 Lenvatinib FGFR 46 Motesanib PDGFR 84 Pazopanib PDGFR 74 Sorafenib PDGFR 58 Sunitinib Vandetanib EGFR 500 Carbozantinib C-MET 1.8 Sherman SI, JCEM, 2009

11 Phase II evaluation of biologic agents in thyroid cancer Drug # of patients RR/SD/CBR PFS (months) Molecular and Biologic Target Axitinib 60 30%/38%/68% 18.1 VEGFR 1, 2, & 3; Angiogenesis Pazopanib 32 19%/69%/88% NR VEGFR 1, 2, 3 Motesanib (WDC) Motesanib (medullary) 93 14%/67%/81% 10 VEGFR 1, 2, 3; PDGFR; c-kit; 91 2%/81%/83% 11 Angiogenesis; Carr et al. J Clin Oncol 27:15s, 2009; Cohen et al. J Clin Oncol 26: 2008; Cohen et al. J Clin Oncol. 26(29): , 2008; Bible KC et al. J Clin Oncol 27:15s, #

12 Phase II evaluation of biologic agents in thyroid cancer Drug Patients RR / SD / CBR PFS (months) Sunitinib Sunitinib Sorafenib Sorafenib Molecular and Biologic Target 43 13%/68%/81% NR Angiogenesis; RET tyrosine 33 34%/48%/82% 6.5 kinase 41 15%/56%/71% 15 B-Raf VEGFR 1, 2, %/53%/76% 19 Kloos et al. J Clin Oncol ; Gupta-Abramson et al. J Clin Oncol 2008

13 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 1 Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 2 Kolling Institute of Medical Research, University of Sydney, Australia 3 University of Texas MD Anderson Cancer Center, Houston, TX 4 Martin Luther University Halle-Wittenberg, Halle, Germany 5 Memorial Sloan-Kettering Cancer Center, New York, 6 Universita' di Napoli Federico II, Naples, Italy 7 Institut Gustave Roussy, Villejuif, France 8 AstraZeneca, Wilmington, DE 9 AstraZeneca, Macclesfield, UK

14 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

15 Patient demographics and Male (%) Female (%) baseline characteristics Vandetanib 300 mg (n=231) 134 (58) 97 (42) Placebo (n=100) 56 (56) 44 (44) Mean age, years Locally advanced disease (%) Metastatic disease (%) No prior systemic therapy for MTC (%) 1 prior therapy for MTC (%) Hereditary disease (%) Sporadic or unknown disease (%) RET mutation positive (%) RET mutation negative (%) RET mutation status unknown (%) 14 (6) 217 (94) 141 (61) 90 (39) 28 (12) 203 (88) 137 (59) 2 (1) 92 (40) 3 (3) 97 (97) 58 (58) 42 (42) 5 (5) 95 (95) 50 (50) 6 (6) 44 (44)

16 Summary of PFS analyses Primary analysis 73 / 231 (32%) Events / patients (n) Vandetanib Placebo 51 / 100 (51%) HR (95% CIs) 0.46 ( ) P-value Predefined secondary/sensitivity analyses Excluding open-label 64 / / ( ) < Investigator RECIST assessments 101 / / ( ) < Other sensitivity analyses (Cox, per protocol, and Whitehead) were consistent with the primary endpoint Hazard ratio <1 favors vandetanib

17 Progression-free survival 1.0 PFS (primary endpoint) 0.9 Vandetanib 300 mg 0.8 Placebo Hazard ratio = 0.46 ( ); P< Median: not reached (vandetanib); 19.3 months (placebo) 0.1 At risk (n) Vandetanib Placebo Time (months) Hazard ratio <1 favors vandetanib

18 Objective tumor assessments Intention to treat analysis* Vandetanib 300 mg (n=231) Placebo (n=100) Objective response rate 45% (104) 13% (13) Odds ratio (95% CI) 5.48 ( ), P< of 13 responses on the placebo arm occurred while patients were receiving vandetanib in the open-label phase Objective responses were durable; median duration of response not reached at 24 months of follow-up Odds ratio >1 favors vandetanib *Including all scans until progression according to central read

19 Biochemical response (randomized phase) Vandetanib 300 mg (n=231) Placebo (n=100) Calcitonin 160 (69%) 3 (3%) Odds ratio (95% CI) 72.9 ( ), P< Carcinoembryonic antigen 119 (52%) 2 (2%) Odds ratio (95% CI) 52.0 ( ), P< Biochemical response: Complete response (confirmed complete normalization of serum levels) Partial response ( 50% decrease from baseline levels maintained for at least 4 weeks) Odds ratio >1 favors vandetanib

20 Proportion of event-free patients Time to worsening of pain * Vandetanib 300 mg Placebo Hazard ratio = 0.61 ( ); P=0.006 Median (months): 7.85 (vandetanib); 3.25 (placebo) At risk (n) Vandetanib Placebo Time (months) *Determined from patient-reported opioid analgesic use and responses to the Brief Pain Inventory questionnaire Hazard ratio <1 favors vandetanib

21 Overall survival of vandetanib versus placebo in MTC Wells et al. J Clin Oncol Jan 10;30(2):134-41

22 Most common grade 3+ adverse events (>2% incidence in either arm) Vandetanib 300 mg (n=231) Placebo (n=99) Diarrhea 25 (11%) 2 (2%) Hypertension 20 (9%) 1 (1%) ECG QT prolonged 18 (8%) 1 (1%) Fatigue 13 (6%) 1 (1%) Decreased appetite 10 (4%) 0 Rash 8 (3%) 1 (1%) Asthenia 6 (3%) 1 (1%) Dyspnea 4 (2%) 3 (3%) Back pain 1 (0.4%) 3 (3%) Syncope 0 2 (2%)

23 Efficacy of Cabozantinib (Cabo) in Medullary Thyroid Cancer (MTC) Patients with RAS or RET Mutations: Results from a Phase 3 Study Steven I. Sherman 1, Ezra E. W. Cohen 2, Patrick Schöffski 3, Rossella Elisei 4, Martin Schlumberger 5, Lori Wirth 6, Milan Mangeshkar 7, Dana T. Aftab 7, Douglas O. Clary 7, and Marcia S. Brose 8 1 University of Texas MD Anderson Cancer Center; 2 University of Chicago; 3 University Hospitals Leuven, KU Leuven; 4 University of Pisa; 5 Institut Gustave Roussy, University Paris-Sud; 6 Massachusetts General Hospital; 7 Exelixis Inc; 8 University of Pennsylvania Health System

24 MTC and Cabozantinib MTC is a rare form of thyroid cancer 1 Patients with distant metastases have a median survival of ~2 years 2 75% of cases occur sporadically, 25% are hereditary 3,4 Up to 65% of sporadic cases have somatic RET mutations 3 >95% of hereditary cases have germline RET mutations 4 RET M918T mutation associated with poor prognosis 5 Cabozantinib is a potent inhibitor of receptor tyrosine kinases MET, VEGFR2, and RET 6 Cabozantinib treatment resulted in significant prolongation in PFS in pts with progressive, metastatic MTC in Phase 3 evaluation 7 1 Schlumberger et al. (2008) Nat Clin Prac, v4(1); 2 Modigliani et al. (1998) Clin Endocrinol, v48; 3 Moura et al. (2009) Br J Cancer, v100; ; 4 Kouvaraki et al. (2005) Thyroid, v15(6); 5 Schilling et al. (2001) Int J Canc v95; 6 Yakes et al. (2011) Mol Canc Ther v10(12); 7 Schöffski et al. J Clin Onc Suppl:5508

25 Phase 3 Trial Design Treatment until progression or unacceptable toxicity Locally advanced or metastatic MTC with documented RECIST progression (N=330) Cabozantinib 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 * mrecist: modified Response Evaluation Criteria in Solid Tumors

26 PFS and ORR per IRC Probability Cabozantinib 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 cabozantinib arm vs 0% in placebo arm 1 Median tumor response duration of 14.7 months Determined in patients with measurable disease

27 RET Mutational Subgroups Assessed for Relationship to PFS and Response Rate Sporadic versus Hereditary MTC Hereditary MTC: patients with RET mutation detected in blood Sporadic MTC: blood sample lacks RET mutation Tumor mutational status: RET positive vs RET negative RET mutation type: M918T vs other RET mutations RET M918T is most common and associated with poor prognosis

28 Similar Effect of Cabozantinib 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 Cabozantinib 36 weeks Cabozantinib 48 weeks Placebo 24 weeks Placebo 17 weeks

29 Effect of RET Mutation Status on PFS RET Mutation Positive (N=169) RET Mutation Negative (N=46) 1.0 Cabozantinib 1.0 Cabozantinib Fraction survival Placebo Fraction survival Placebo p< Time (weeks) p= Time (weeks) Median PFS Median PFS Cabozantinib 60 weeks Cabozantinib 25 weeks Placebo 20 weeks Placebo 23 weeks HR (95%CI) = 0.23 (0.14, 0.38) Hazards not proportional

30 Patients with Unknown RET Status Show Prolongation of PFS on Cabozantinib RET Mutation Unknown (N=115) Fraction survival Median PFS Cabozantinib 48 weeks Placebo 13 weeks HR (95%CI) 0.30 (0.16, 0.57) p= Time (weeks)

31

32

33

34

35 Brose M et al. The Lancet, 384, Issue 9940, 2014,

36

37

38 A phase 3, multicenter, randomized, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT)

39 Study 303: Study Schema

40 Patient Characteristics

41 Primary Endpoint:<br />Kaplan-Meier Estimate of PFS

42 PFS by Previous VEGF-Targeted Therapy

43 Best Tumor Response

44 Overall Survival, ITT population

45 Treatment-emergent Adverse Events (TEAEs)

46 Efficacy summary for established agents in MTC and DTC Drug # of patients RR (%) PFS (months) Indication Vandetanib vs MTC Carbozantinib vs. 4 MTC Sorafenib vs. 5.8 DTC Lenvatinib (Phase II data) MTC Orphan drug designation Lenvatinib v vs. 3.6 Phase III data in DTC

47 Emerging approaches in thyroid cancer management

48 mtor signaling and thyroid mtor activated by Goitrogen cancer Cross talk between mtor and SSR pathways TPC-1 BCPAP CAL-62 C643 U-Hth7 U-Hth74-cl-7 SSR 1 SSR 2 SSR 3 SSR 4 SSR 5 Actin Brewer et al. Cancer Research 67, 8002, 2007 Owonikoko et al. unpublished data

49 Everolimus (RAD001) and Pasireotide (SOM230) in TPC-1 xenograft RAD Control(QD) RAD 1mg/kg(QD) SOM Control(Once) SOM 10mg/kg(Once) 6000 RAD1mg/kg(QD)+SOM10mg/kg(Once) Tumor Volume (mm 3 )+/- SEM Days

50 WCI-1777: Phase II Trial of Everolimus and Pasireotide 90 Eligible Patients Stratify by histology, age and sex Randomize Arm A 30 patients Start with Everolimus Add Pasireotide at progression Arm B 30 patients Start with Pasireotide Add Everolimus at progression Arm C 30 patients Start both Everolimus and Pasireotide Continue until disease progression

51 Salvage TKI therapy in thyroid cancer Retrospective analysis of outcome of salvage therapy in thyroid cancer patients treated at the Winship Cancer Institute 39 eligible patients identified Comparison of frontline and post frontline efficacy of biologic agents

52 Comparing frontline and post-frontline efficacy of biologic agents in advanced thyroid cancer Owonikoko et al. Oncologist. 2013;18(12):

53 Other emerging strategies under evaluation B-Raf and Ras specific inhibitors, vemurafenib, selumetinib and dabrafenib now in phase II clinical trials Combined B-Raf and MEK inhibitor in B-Raf mutant thyroid cancer Combination of B-Raf inhibitor and Iodine therapy as a resensitization strategy in iodine refractory disease

54 Conclusions Biologic agents have established efficacy leading to FDA approval of several agents Sorafenib, Levantinib, Carbozantinib and Vandetanib have shown objective efficacy over placebo in the phase III setting Treatment related adverse events and early treatment failure are important limitations of this treatment strategy Combination of biologic agents in the frontline and salvage therapy with TKI are areas of future research Optimal selection of patients likely to benefit from TKI and molecular selection are under active investigation