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

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Presentation on theme: "Más es posible: Cáncer diferenciado de tiroides refractario a radioyodo Jaume Capdevila, MD GI and Endocrine Tumor Unit Vall d’Hebron University Hospital."— Presentation transcript:

1 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

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

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

4  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

5 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

6 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

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

8 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 (http://www.eisai.com/news/news html; 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

9 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

10 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

11 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

12 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

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

14 Reduction in Tumor Size with Sorafenib Treatment

15 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

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

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

18 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

19 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

20 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)

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

22 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

23 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%

24 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

25 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

26 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

27 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

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

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

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

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

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

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

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

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

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

37 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

38 GRACIAS POR VUESTRA ATENCIÓN


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