Más es posible: Cáncer diferenciado de tiroides refractario a radioyodo Jaume Capdevila, MD GI and Endocrine Tumor Unit Vall d’Hebron University Hospital Developmental Therapeutics Unit Vall d’Hebron Institute of Oncology

Thyroid Cancer: Cell Type and Histology Follicular cells Anaplastic Differentiated Papillary Hürthle cell Follicular Medullary thyroid carcinoma (MTC) Parafollicular cells (3-5%) (90-95%)

Thyroid Cancer: Cell Type and Histology Follicular cells Anaplastic Differentiated Papillary Hürthle cell Follicular Medullary thyroid carcinoma (MTC) Parafollicular cells (3-5%) (90-95%)

 INITIAL TREATMENT  Total thyroidectomy +/- lymphadenectomy, except in unifocal microcarcinoma (individualized to patient)  ADJUVANT TREATMENT  Radioactive iodine ( 131 I) (RAI) therapy  FOLLOW-UP TREATMENT  Levothyroxine to suppress TSH to <0.1 mU/L  RECURRENT OR METASTATIC DISEASE TREATMENT  Local therapy (re-operation, external radiation)  Systemic therapy  RAI therapy  Patients with refractory advanced disease Chemotherapy (limited efficacy and considerable toxicity) Participation in clinical trials with small molecule tyrosine kinase inhibitors is recommended Mazzaferri EL, et al J Clin Endocrinol Metab 2001 Cooper DS, et al. Thyroid 2009 Management of Differentiated Thyroid Cancer (DTC): ATA 2009

Gottlieb JA, et al. NEJM, 1974; Shimaoka K, et al. Cancer, 1985 Chemotherapy of Thyroid Cancer with Adriamycin — Experience with 30 Patients Jeffrey A. Gottlieb, M.D., and C. Stratton Hill, Jr., M.D. N Engl J Med 1974; 290: months 7-8 months

Genetics of Thyroid Cancer Papillary Mutations identified in ~70%  BRAF a (40–50%)  RAS b (7–20%) RET/PTC (clonal; 10–20%) EGFR (5%) TRK (<5%) PIK3CA (2%) Follicular Mutations identified in 70–75%  RAS (40–50%; lower in oncocytic) PAX8/PPAR  (30–35%; lower in oncocytic) TP53 (21%) PTEN (8%) PIK3CA (7%)  BRAF (2%) Poorly differentiated  RAS (25–30%) TP53 (20–30%) CTNNB1 (10–20%)  BRAF (10–15%) Anaplastic Medullary DTC Papillary Conventional Oncocytic

Capdevila J, et al. Target Oncol, 2009 Targeted Therapies in Thyroid Cancer LENVATINIB SORAFENIB VANDETANIB CABOZANTINIB SUNITINIB LENVATINIB

MKIs of Angiogenesis BRAF Inhibitors mTOR InhibitorsMEK Inhibitors Other (MoA) Sorafenib [Nexavar] Vemurafenib [Zelboraf] Temsirolimus [Toricel] Selumetinib [AZD6244] Lenalidomide (Inhibitor of angiogenesis) Axitinib [AG ] Dabrafenib [GSK ] Everolimus [Afinitor] Trametinib [GSK ] Tanespimycin [17-AAG] (Heat shock protein 90 [HSP90] inhibitor) Pazopanib [GW786034, Votrient] VEGF trap [Aflibercept] (Inhibitor of angiogenesis) Motesanib [AMG 706] Fosbretabulin tromethamine [CA4P] (Microtubule destabilizing agent, vascular- targeting agent) Sunitinib [SU011248, Sutent] Bortezomib [Velcade] (Proteasome inhibitor) Vandetanib [ZD6474, Caprelsa] Panobinostat [LBH589] (Histone deacetylase inhibitor) Lenvatinib [E7080] Gefitinib [ZD1839, Iressa] Cabozantinib [XL-184, Cometriq] Cediranib [AZD2171] Summary of Agents Being Investigated in Thyroid Cancer* * Includes DTC and MTC DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; MoA, mechanism of action; MTC, medullary thyroid cancer; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network; TKI, tyrosine kinase inhibitor. NCCN evidence category 1 = based upon high-level evidence; category 2B = based on lower-level evidence. 1.NCCN Guidelines: Thyroid Carcinoma. v US Prescribing Information. Nexavar. November Eisai press release, Feb ; available at ( accessed March 2014 Two TKIs are FDA/EMA-approved for progressive, metastatic MTC –Vandetanib [NCCN evidence category 1] 1 –Cabozantinib [NCCN evidence category 1] 1 Sorafenib is FDA/EMA-approved for locally recurrent or metastatic, progressive, DTC that is RAI-refractory 2 [NCCN evidence category 1] 1 Other agents are being investigated for first- and second-line treatment of DTC –Positive Phase 3 results reported for lenvatinib; FDA/EMA-submitted for approval in RAI-refractory DTC –Vandetanib Phase 3 trial just finished recruitment

ADVANCES IN RAI-REFRACTORY DTC  Two new drugs for systemic therapy in RAI-refractory setting  SORAFENIB (FDA & EMA approval)  LENVATINIB (FDA & EMA submitted)  Targeting MAPK pathway in DTC  BRAF inhibitors  “Redifferentiation” with MAPK inhibitors

ADVANCES IN RAI-REFRACTORY DTC  Two new drugs for systemic therapy in RAI-refractory setting  SORAFENIB (FDA & EMA approval)  LENVATINIB (FDA & EMA submitted)  Targeting MAPK pathway in DTC  BRAF inhibitors  “Redifferentiation” with MAPK inhibitors

DECISION: Study Design Locally advanced or metastatic, RAI-refractory DTC Progression (RECIST) within the previous 14 months No prior chemotherapy, targeted therapy, or thalidomide 417 patients randomized from November 2009 to August 2011 Stratified by: –Geographical region (North America or Europe or Asia) –Age (<60 or ≥60 years) Progression assessed by independent central review every 8 weeks At progression –Patients on placebo allowed to cross over at the investigator’s discretion –Patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion Sorafenib 400 mg orally twice daily Placebo Orally twice daily Randomization 1:1 Primary endpoint Secondary endpoints Overall survival Response rate Safety Time to progression Disease control rate Duration of response Sorafenib exposure (AUC 0-12 ) Progression-free survival Brose M, et al. Lancet 2014

DECISION: Progression-free Survival (by Independent Central Review) Brose M, et al. Lancet 2014 n Median PFS, days (months) Sorafenib (10.8) Placebo (5.8) PFS Probability (%) Days From Randomization HR, 0.59; 95% CI, ; P<0.0001

DECISION: PFS in Predefined Subgroups Brose M, et al. Lancet 2014

Reduction in Tumor Size with Sorafenib Treatment

DECISION: Most Common TEAEs AE*, %Sorafenib (n = 207)Placebo (n = 209) Any GradeGrade 3/4Any GradeGrade 3/4 Hand-foot skin reaction Diarrhea Alopecia Rash/desquamation Fatigue Weight loss Hypertension Metabolic – lab (other) † Serum TSH increase † Anorexia Oral mucositis Pruritus Nausea Hypocalcemia Brose M, et al. Lancet 2014

A Post-Hoc Subgroup Analysis by Maximum Tumor Size Brose M et al. Lancet 2014

A Post-Hoc Subgroup Analysis by Thyroid Carcinoma Symptoms at Baseline Brose M et al. Lancet 2014

ADVANCES IN RAI-REFRACTORY DTC  Two new drugs for systemic therapy in RAI-refractory setting  SORAFENIB (FDA & EMA approval)  LENVATINIB (FDA & EMA submitted)  Targeting MAPK pathway in DTC  BRAF inhibitors  “Redifferentiation” with MAPK inhibitors

Study 303 (SELECT): Study Schema Patients with DTC (N = 392) IRR evidence of progression within previous 13 months 131 I-refractory disease Measurable disease Up to 1 prior VEGF or VEGFR- targeted therapy Placebo (n = 131) 24 mg daily PO Lenvatinib (n = 261) 24 mg daily PO Stratification Geographic region (Europe, N. America, Other) Prior VEGF/ VEGFR- targeted therapy (0,1) Age (≤ 65 years, > 65 years) Treatment until disease progression confirmed by IRR (RECIST v1.1) Lenvatinib (Optional, open-label) Randomization 2:1 DTC, differentiated thyroid cancer; 131 I, radioiodine; IRR, independent radiologic review, ORR, objective response rate; OS, overall survival; PO, by mouth; RECIST, response evaluation criteria in solid tumors. Primary endpoint PFS Secondary endpoints ORR OS Safety Schlumberger M, et al. ASCO 2014

Primary Endpoint: Kaplan-Meier Estimate of PFS Schlumberger M, et al. ASCO 2014 Placebo vs Lenvatinib HR = 0.20 (95% CI 0.15–0.27), P < mo (2.2–3.7) vs 18.3 mo (15.1–NA)

PFS by Previous VEGF-Targeted Therapy Schlumberger M, et al. ASCO 2014

PFS Subgroup Analyses Schlumberger M, et al. ASCO 2014 CI, confidence interval; HR, hazard ratio; NR, not reached; PFS, progression-free survival. Events/NMedian (Months) Lenvatinib 14/65 31/72 31/63 31/61 61/141 14/28 32/92 60/157 47/104 17/35 90/226 Placebo 21/28 31/32 31/34 30/37 60/71 18/19 35/41 74/83 39/48 7/7 106/124 Baseline Tumor Burden (mm) ≤35 35−60 60−92 >92 Histology Papillary Poorly differentiated Follicular Bone Metastasis No Yes Lung Metastasis No Yes Lenvatinib NR NR Placebo HR (95% CI) 0.14 ( 0.06, 0.33) 0.19 ( 0.10, 0.36) 0.24 ( 0.13, 0.43) 0.21 ( 0.11, 0.42) 0.30 ( 0.20, 0.44) 0.21 ( 0.08, 0.56) 0.10 ( 0.05, 0.19) 0.18 (0.12, 0.27) 0.26 (0.16, 0.42) 0.24 ( 0.08, 0.77) 0.21 ( 0.15, 0.29) Favors PlaceboFavors Lenvatinib HR and 95% CI

Best Tumor Response Schlumberger M, et al. ASCO 2014 CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Median tumor shrinkage for responders (range): -52% (-100%, -30%) Median tumor shrinkage for all patients (range): +2% (-53%, +54%) RR: 65% RR: 2%

Study Medication Exposure Lenvatinib (n = 261) Placebo (n = 131) Duration of treatment, months, median (range) 13.8 (0–27)3.9 (0–24) Dose intensity, mg/day, median (range) 16.8 (6–25)24.0 (15–24) Time to first dose reduction, months, median (95% CI) a 3.0 (2.0–3.2)NR Presented by: Martin Schlumberger, MD Schlumberger M, et al. ASCO 2014

Most Frequent Treatment-Related Adverse Events (> 20%) Adverse Event, % Lenvatinib (n = 261)Placebo (n = 131) Any GradeGrade ≥ 3Any GradeGrade ≥ 3 Hypertension Diarrhea60880 Fatigue / asthenia Decreased appetite Nausea / vomiting Decreased weight Stomatitis36440 Palmar-plantar erythrodysesthesia syndrome Proteinuria Headache28360 Dysphonia /20 lenvatinib treatment-emergent deaths were considered by investigator as treatment-related: Pulmonary embolism (n = 1) Hemorrhagic stroke (n = 1) General health deterioration (n = 4) Schlumberger M, et al. ASCO 2014

ADVANCES IN RAI-REFRACTORY DTC  Two new drugs for systemic therapy in RAI-refractory setting  SORAFENIB (FDA & EMA approval)  LENVATINIB (FDA & EMA submitted)  Targeting MAPK pathway in DTC  BRAF inhibitors  “Redifferentiation” with MAPK inhibitorsinhibitors

Genetics of Thyroid Cancer Papillary Mutations identified in ~70%  BRAF a (40–50%)  RAS b (7–20%) RET/PTC (clonal; 10–20%) EGFR (5%) TRK (<5%) PIK3CA (2%) Follicular Mutations identified in 70–75%  RAS (40–50%; lower in oncocytic) PAX8/PPAR  (30–35%; lower in oncocytic) TP53 (21%) PTEN (8%) PIK3CA (7%)  BRAF (2%) Poorly differentiated  RAS (25–30%) TP53 (20–30%) CTNNB1 (10–20%)  BRAF (10–15%) Anaplastic Medullary DTC Papillary Conventional Oncocytic

Phase II Study of Vemurafenib in BRAF Mutant RAI-Refractory DTC Brose M, et al. ESMO 2013

Best Objective Response & PFS Brose M, et al. ESMO 2013

Lonard, DM, et al. Nat Rev Endocrinol 2012 Role of NIS Protein in DTC

Chakravarty D, et al. J Clin Invest 2011 Inhibition of BRAF Signaling Increases RAI Incorporation in inducible BRAF V600E Mouse Model

Protocol Schema Ho AL, et al. N Engl J Med t 2013

Efficacy in Increasing Uptake of 124 I Ho AL, et al. N Engl J Med t 2013

Best Responses for RAI-Treated Patients Ho AL, et al. N Engl J Med t 2013

Class-Effect: Same Experience with Dabrafenib Rothenberg SM, et al. Clin Cancer Res 2015

Class-Effect: Same Experience with Dabrafenib Rothenberg SM, et al. Clin Cancer Res 2015

Current Treatment Options in RAI- Refractory DTC & Near Future  Drug approved for systemic therapy in first-line advanced DTC  SORAFENIB (FDA & EMA approval)  New drug waiting for being approved (data in first & second-line)  LENVATINIB (FDA & EMA submitted)  Phase III trial recruited with Vandetanib in first-line (similar design as DECISION)  Future data on molecularly selected patients (BRAF, MEK…)  Increasing interest in “redifferentiation” process with MAPK inh

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