Disclosures Novartis thyroid cancer research funding 1 Outline - - PDF document

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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

Disclosures

• Novartis – thyroid cancer research funding

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Outline

• Pathology and epidemiology of thyroid cancer
• Newly established treatment approaches for

advanced thyroid cancer

• Emerging approaches within the thyroid oncology

program at the Winship Cancer Institute

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.

http://www.ouhsc.edu/histology/

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Cancer Statistics 2013

Siegel R. et al. CA CANCER J CLIN 2013;63:11–30 Davies, L. et al. JAMA 2006;295:2164‐2167.

US Incidence of Thyroid Cancer by Size and Histology

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Survival in differentiated thyroid carcinoma 2936 patients (1987-2001)

Jonklass J, et al, Thyroid 2006

I II III IV

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Surviving 2 4 6 8 10 12 14 16 18 FuTimeFINAL

Time to Death, Yrs

Management of Progressive or Metastatic Disease

• Multidisciplinary approach

– Endocrinology – continuing management of thyroid hormone replacement and TSH suppression – Surgeons – resection of amenable solitary lesions – Radiation oncologist – Irradiation for local control or symptom palliation – Nuclear medicine physician – dosimetry-based I131 therapy – Medical Oncologist – targeted biologic agents; cytotoxics??

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Systemic therapy

• Cytotoxic chemotherapy currently plays no significant role in the

management of advanced DTC and MTC

• Considerations for initiation of biologic therapy

– Symptom – Disease burden – Objective progression (biomarker doubling time and anatomic imaging) – Tumor histology – tall cell, insular and poorly differentiated histology – I131 avidity and response

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

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Gemcitabine/Oxaliplatin in refractory thyroid cancer

Spano et al. Med Oncol 2012 29:1421‐1428

Molecular understanding of thyroid tumor development

Thyroid Follicular Cell

Hyperfunctioning Adenoma

Follicular Carcinoma Follicular Adenoma Papillary Thyroid Carcinoma Anaplastic Carcinoma

TSH-R G-protein Ras Signaling Epigenetic Changes RET/PTC Ras BRAF Trk Met Pax8-PPARγ 3p (TRβ) p53 PI3K β catenin p53 PI3K β catenin

Abbosh and Nephew, Thyroid:15, 551‐561, 2005

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Aberrant signaling pathway in thyroid cancer

Abbosh and Nephew, Thyroid:15, 551‐561, 2005

PDTC

PTC FTC

Tumor growth, dedifferentiation

βcatenin AKT PI3K Ras Ras RET/PTC Pax8-PPARγ BRAF MEK-ERK p53

15-20% 15-20% 40-60% 20-30% 20-30%

PDTC, ATC

NIS

PDTC, ATC

Multikinase inhibitors

Thyroid carcinoma

Drug IC50 (nm) VEGFR1 VEGFR2 VEGFR3 RET RET/PTC3 RAF Other Axitinib 1.2 0.25 0.29

• PDGFR 1.7

Lenvatinib 22 4 5.2 35

• FGFR 46

Motesanib 2 3 6 59

• PDGFR 84

Pazopanib 10 30 47 2800

• PDGFR 74

Sorafenib

• 90

20 49 50 6 PDGFR 58 Sunitinib 2 9 17 41 224

• Vandetanib

1600 40 110 100 50-100

• EGFR 500

Carbozantinib

• 0.035
• 4.5
• C-MET 1.8

Sherman SI, JCEM, 2009

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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; Angiogenesis; 91 2%/81%/83% 11

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):4708‐13, 2008; Bible KC et al. J Clin Oncol 27:15s, #3521 2009

Phase II evaluation of biologic agents in thyroid cancer

Drug Patients RR / SD / CBR PFS (months) Molecular and Biologic Target Sunitinib Sunitinib 43 13%/68%/81% NR Angiogenesis; RET tyrosine kinase 33 34%/48%/82% 6.5 Sorafenib Sorafenib 41 15%/56%/71% 15 B-Raf VEGFR 1, 2, 3 30 23%/53%/76% 19

Kloos et al. J Clin Oncol 1675‐84. 2009; Gupta‐Abramson et al. J Clin Oncol 2008

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Phase III clinical trial of vandetanib versus placebo in MTC

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

Phase III clinical trial of vandetanib versus placebo in MTC

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

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Meaningful benefit but potential cardiac toxicity

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%) Rash 8 (3%) 1 (1%) Asthenia 6 (3%) 1 (1%) Dyspnea 4 (2%) 3 (3%) Back pain 1 (0.4%) 3 (3%) Syncope 2 (2%)

Most common grade 3+ adverse events (>2% incidence in either arm)

Wells et al. Proc. ASCO Annual Meeting June 2010

Efficacy of Cabozantinib (Cabo) in Medullary Thyroid Cancer (MTC) Patients with RAS or RET Mutations: Results from a Phase 3 Study Steven I. Sherman1, Ezra E. W. Cohen2, Patrick Schöffski3, Rossella Elisei4, Martin Schlumberger5, Lori Wirth6, Milan Mangeshkar7, Dana T. Aftab7, Douglas O. Clary7, and Marcia S. Brose8

1University of Texas MD Anderson Cancer Center; 2University of Chicago; 3University Hospitals

Leuven, KU Leuven; 4University of Pisa; 5Institut Gustave Roussy, University Paris-Sud;

6Massachusetts General Hospital; 7Exelixis Inc; 8University of Pennsylvania Health System

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MTC and Cabozantinib

• MTC is a rare form of thyroid cancer1

– Patients with distant metastases have a median survival of ~2 years2

• 75% of cases occur sporadically, 25% are hereditary3,4

– Up to 65% of sporadic cases have somatic RET mutations3 – >95% of hereditary cases have germline RET mutations4

• RET M918T mutation associated with poor prognosis5
• Cabozantinib is a potent inhibitor of receptor tyrosine kinases MET,

VEGFR2, and RET6

• Cabozantinib treatment resulted in significant prolongation in PFS in

pts with progressive, metastatic MTC in Phase 3 evaluation7

1Schlumberger et al. (2008) Nat Clin Prac, v4(1); 2Modigliani et al. (1998) Clin Endocrinol, v48; 3Moura et

• al. (2009) Br J Cancer, v100; ; 4Kouvaraki et al. (2005) Thyroid, v15(6); 5Schilling et al. (2001) Int J Canc

v95; 6Yakes et al. (2011) Mol Canc Ther v10(12); 7Schöffski et al. J Clin Onc 2012 30 Suppl:5508

Phase 3 Trial Design

Treatment until progression

• r unacceptable toxicity

Locally advanced

• r metastatic

MTC with documented RECIST progression (N=330) Cabozantinib 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

* mRECIST: modified Response Evaluation Criteria in Solid Tumors

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PFS and ORR per IRC

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)

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 cabozantinib arm vs 0% in placebo arm1
• Median tumor response duration of 14.7 months

1Determined in patients with measurable disease

RET Mutation Study Results

RET Mutational Analysis Results

RET Mutation Positive M918T1 126 C611-C634 mutations 33 A883F 7 Y791F 1 V804M 1 S891A 1 RET Mutation Negative 46 RET Mutation Unknown 115 Total 330

Unknown RET Status

Insufficient Sample 57 Assay Failure 33 Novel RET Mutation2 21 Small Deletions 16 Point Mutations 5 Sample Discrepancies 4 Total 115

• M918T is the predominant RET mutation in this patient population

1 Includes 4 compound M918T mutations 2 Mutations not listed in ATA Guidelines (Kloos et al, 2009)

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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

Similar Effect of Cabozantinib on PFS in Hereditary and Sporadic MTC

Median PFS Cabozantinib 36 weeks Placebo 24 weeks Median PFS Cabozantinib 48 weeks Placebo 17 weeks Fraction event free

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Effect of RET Mutation Status on PFS

Median PFS Cabozantinib 60 weeks Placebo 20 weeks HR (95%CI) = 0.23 (0.14, 0.38) Median PFS Cabozantinib 25 weeks Placebo 23 weeks Hazards not proportional

Patients with RET M918T Demonstrate Prolonged PFS Relative to Patients with Other RET Mutations

Note: RET M918T negative group includes RET mutation negative patients

Median PFS Cabozantinib 61 weeks Placebo 17 weeks HR (95%CI) = 0.15 (0.08, 0.28) Median PFS Cabozantinib 36 weeks Placebo 24 weeks HR (95%CI) = 0.70 (0.26, 1.87)

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Patients with Unknown RET Status Show Prolongation of PFS on Cabozantinib

Fraction survival

Median PFS Cabozantinib 48 weeks Placebo 13 weeks HR (95%CI) 0.30 (0.16, 0.57)

Conclusion

• Cabozantinib treatment resulted in significant prolongation of PFS in

pts with progressive, metastatic MTC in Phase 3 evaluation

– Median PFS: 11.2 months (cabozantinib) versus 4.0 months (placebo)

• Pts with activating RET or RAS mutations show greatest PFS benefit
• The RET unknown group shows PFS prolongation consistent with

the RET positive group

– Likely due to undetected RET or RAS mutations

• The RET negative group is small and heterogeneous

– Pts with RET-/RAS+ mutation status had prolonged PFS with cabozantinib – Undetected RET and RAS mutations may also contribute to clinical activity in this subgroup

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

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Study 303: Study Schema Patient Characteristics

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Primary Endpoint:<br />Kaplan-Meier Estimate of PFS PFS by Previous VEGF-Targeted Therapy

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PFS Subgroup Analyses Response Rates

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Best Tumor Response Overall Survival, ITT population

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Study Medication Exposure Treatment-emergent Adverse Events (TEAEs)

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Most Frequent Treatment-related Adverse Events (> 20%) TEAEs of Special Interest

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Conclusions

Efficacy summary for established agents in MTC and DTC

Drug # of patients RR (%) PFS (months) Indication Vandetanib 331 45 30.5 vs. 19.3 MTC Carbozantinib 330 27 11.2 vs. 4 MTC Sorafenib 397 24 10.8 vs. 5.8 DTC Lenvatinib (Phase II data) 59 36 9 MTC Orphan drug designation 58 50 12.6 DTC Orphan drug designation Lenvatinib 392 65 v. 2 18.3 vs. 3.6 Phase III data in DTC

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Thyroid Oncology Research Program Winship Cancer Institute Emory University

Research Questions

• Optimal selection strategy for surveillance and systemic

therapy

• Development of biomarkers of prognosis and

response

• Novel treatment approaches
• Single versus combination therapy
• Role of biologic agents post progression

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Owonikoko et al. Cancer 2013 Apr 15;119(8):1503‐11

mTOR signaling and thyroid cancer

mTOR activated by Goitrogen Proposed mechanism

Brewer et al. Cancer Research 67, 8002, 2007 Furuya F et al. Steroids 74, (7): 628‐634 , 2009

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SSR 1 SSR 2 SSR 3 SSR 4 SSR 5 Actin

TPC-1 BCPAP CAL-62 C643 U-Hth7 U-Hth74-cl-7

Surface expression of somatostatin receptors (SSR) on thyroid cancer cell lines Everolimus (RAD001) and Pasireotide (SOM230) in TPC-1 xenograft

1000 2000 3000 4000 5000 6000 5 8 11 14 18 21 25 28

RAD Control(QD) SOM Control(Once) RAD 1mg/kg(QD) SOM 10mg/kg(Once) RAD1mg/kg(QD)+SOM10mg/kg(Once)

Tumor Volume (mm3 )+/- SEM

Days

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WCI-1777: Phase II Trial of Everolimus and Pasireotide

90 Eligible Patients

Stratify by histology, age and sex Randomize

Arm C – 30 patients Start both Everolimus and Pasireotide Continue until disease progression Arm B – 30 patients Start with Pasireotide Add Everolimus at progression Arm A – 30 patients Start with Everolimus Add Pasireotide at progression

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

31 Comparing frontline and post-frontline efficacy of biologic agents in advanced thyroid cancer

Owonikoko et al. Oncologist. 2013;18(12):1262‐9.

Comparison by gender (A) and histology (B)

Owonikoko et al. Oncologist. 2013;18(12):1262‐9.

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Comparison by single/combination regimen and by vascular/non vascular targeted agents

Owonikoko et al. Oncologist. 2013;18(12):1262‐9.

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