Presentation on theme: "New Approaches in the Treatment for the Advanced Thyroid Cancer"— Presentation transcript:
1 New Approaches in the Treatment for the Advanced Thyroid Cancer Sun Wook Kim, MD PhDDivision of Endocrinology and Metabolism,Sungkyunkwan University School of Medicine,Samsung Medical Center,Seoul, Korea
2 Objectives Conventional treatment in advanced thyroid cancers (differentiated thyroid cancers, DTCs)Genetic alterations in DTCsRECISTNewer molecular targeted therapies
3 Background DTCs comprise most of thyroid cancers RAI refractory DTCs have poorer prognosisFirst, let me begin with short background story.DTC accounts more than 90% of all thyroid cancers and therapeutic approach will be quite different from DTC and other type of thyroid cancers.Today’s talk for newer therapies will be focused on advanced DTC.
4 Classification of Thyroid Cancers Parafollicular cellsFollicular cellsDifferentiatedMedullaryFollicularAnaplastic (Undifferentiated)PapillaryHürthleSporadic (80%)Hereditary (20%)As you know, Differentiated thyroid cancer is originated from follicular cells and it’s biologic behavior is different from anaplastic or undifferentiated carcinomaOr Medullary carcinoma which is derived from parafollicular C cells.
5 Classification of Thyroid Cancers Cancer typeClinical characteristicsPapillary~80% of thyroid cancers10-year survival: 74–93%FollicularConstitute ~10% of thyroid cancers10-year survival 43–94%Hürthle cellConstitute ~4% of thyroid cancers10-year survival: ~76%AnaplasticConstitute ~2% of thyroid cancersAggressive, rapidly invasiveMedian survival: 4–5 months from diagnosisDifferentiatedDTC is comprised of papillary, follicular and hurthl cell cancers.It accounts for more than 90% of all thyroid cancers with variable prognosis with 50% to 95% 10 year survival rate.
6 Background DTCs comprise most of thyroid cancers RAI refractory DTCs have poorer prognosisSecond background is that RAI refractory DTCs have poor prognosis.
7 Initial disease stage predicts overall survival in patients with DTC Stage I1008060402075% of all tumoursStage IIStage IIISurvival (%)25% of all tumoursAlthough over 75% of DTCs do well after conventional treatment comprised of surgery, RAI and TSH suppression, 25% of DTC do not respond to conventional therapy and shows poor prognosis.Stage IVp<0.0011084621214YearsJonklaas J, et al. Thyroid 2006;16:1229–42
8 18FDG PET-CTApproved for detection of occult thyroid cancer when serum thyroglobulin>10ng/ml and negative RAI scan(Sensitivity 60-95%, specificity 50-90%accuracy 75%)Flip-flop phenomenon between FDG and RAI uptakeIn these patients with advanced DTC, FDG-PET has a crucial role in the diagnosis and evaluation of prognosis.It is approved for detection of occult thyroid cancer when thyroglobulin is over 10ng/ml and RAI scan is negative. Its sensitivity is around 68%, specificity 82% and overall accuracy is around 75%.There is a flip – flop phenomenon between FDG and RAI uptake.
9 FDG Uptake Is a Marker of Resistance to 131I Treatment and of Poor Prognosis Estimated 60 months survivalRAI +, FDG -: 95%RAI -, FDG +: 45%RAI +, FDG +: 45%Presence of FDG uptake is related toAge >40 yearsLarge metastasesPoorly differentiated orpapillary/follicular disease with necrosis and mitosisRAI- FDG -- - -RAI + FDG -- - -RAI - FDG +- - -RAI + FDG +Thus FDG uptake in the metastatic lesion is a marker of resistance to RAI treatment and poor prognosis.You can see in this figure that if FDG uptake is positive, the overall prognosis is poor regardless of RAI uptake and it reached about 50% 5YSR compare to 95% when FDG uptake was negative.These patients with FDG positive will be the patients who needs novel therapeutic modalities.Robbins RJ, et al. J Clin Endocrinol Metab. 2006
10 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCsRECISTNewer molecular targeted therapies
11 Therapeutic modalities for RAI refractory recurrent DTCs IndicationProsConsSurgerySurgically resectable local recurrences or metastatectomyPotential for curePotential significant morbidityExternal beam radiationAdjuvant: neckTherapeutic and palliative: metastatic sitesDecrease in recurrences, progression and painMay preclude future neck surgery; dysphagia and xerostomia; secondary malignancyPEIT and RFALocally recurrent disease in patients at high risk for morbidity and mortality from surgeryPotential for avoidance of surgeryLocal pain; injury to local structure; unknown effect on survival and recurrenceSystemic chemotherapyUnresectable, RAI-refractory, metastatic diseaseMay slow progression of disease; may alleviated disease symptomSignificant adverse events; unknown effect on survivalThere are 4 conventional modalities which have each pros and cons.First, Surgical resection is indicated in resectable local recurrence and metastasis for cure but accompanies potential morbidity caused by surgery.External Beam radiation therapy is indicated as adjuvant setting after surgery or palliative to metastatic site. It may decrease recurrences, progression and pain but may preclude future surgery and associated with dysphagia, xerostomia and secondary malignancy.PEIT or RFA is for local treatment when the patients’ condition does not allow surgical approach. However, its effect on overall survival is unknown.Finally, systemic chemotherapy can be considered in unresectable , RAI refractory disease in the hope that it may slow progression and alleviate symptoms but accompanies significant side effects.Busaidy and Cabanillas et al. J Thy Res 2012
12 FDA approval of doxorubicin for treatment of metastatic thyroid cancer (1974) Matuszczyk A, et al. Horm Metab Res 2008Epithelial origin, 5% PRFDA = Food and Drug Administration; PR = partial responseFor chemotherapeutic approach, FDA approved doxorubicin for treatment of DTC in However, it has very low response rate around 5%. Thus patients with progressive DTC have had unmet clinical need for over three decades.Thus, patients with progressive DTC have had an unmet clinical need for over three decades
13 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCsRECISTNewer molecular targeted therapies
14 Thyroid cancer is associated with aberrant cell signaling Genetic alterationPapillary thyroid cancer (%)Follicular thyroid cancer (%)B-Raf V600E44─45%B-Raf copy gain335RET/PTC (1 and 3)~20RAS~1040–50PI3KCA mutations<10PI3KCA copy gain1228PTEN2Pax8/PPARγTotal>70>65MAP kinasePI3K/AKTMost common genetic alterations in Papillary thyroid cancer are point mutations of BRAF and RAS and rearrangement of RET proto-oncogene.In follicular cancers, mutations in RAS and rearrangement of the PPARr and PAX8 genes are common changes.These genetic changes involves MAP Kinase pathway or PI3K/AKT pathways and gives us a basis for using molecular drugs targeting these pathways.Nikiforov YE. Mod Path 2008;21 Suppl 2:S37–43 Xing M. Endocr Relat Cancer 2005;12:245–62 Wang HM, et al. Ann Surg Oncol 2007;14:3011–8
15 Cell signalling in differentiated thyroid cancer Tumor CellEndothelial CellRET/PTCEGFRVEGFR-2RasRasB-RafPI3KRafPI3KAKTMEKAKTMEKmTORERKmTORERKIntracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis.In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types.In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt.Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer.S6KS6K• Growth• Survival• Proliferation• HIF1a• Inhibition of apoptosis• Migration• Growth• Survival• Proliferation• Migration• AngiogenesisGraphic adapted fromKeefe SM, et al. Clin Cancer Res. 2010;16:
16 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCsRECISTNewer molecular targeted therapies
17 RECIST (1) Response Evaluation Criteria In Solid Tumors Defines when cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progression") during treatments.Published in February, 2000 by an international collaboration EORTC, NCI of US and NCI of CanadaResponse Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that definewhen cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progression")during treatments. The criteria were published in February, 2000 by an international collaborationincluding the European Organisation for Research and Treatment of Cancer (EORTC), NationalCancer Institute of the United States, and the National Cancer Institute of Canada Clinical TrialsGroup.
18 RECIST (2)Eligibility- Only patients with measurable disease at baseline (longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan)Response Criteria- CR: disappearance of target lesion- PR: >30% decrease in longest diameter of target- SD: neither PR nor PD- PD: >20% increase in longest diameter of targetor appearance of one or more new lesionsFrequency of tumor re-evaluation- usually every other cycle (6-8 weeks) is reasonable
20 Objectives Conventional treatment in advanced DTCs Genetic alterations in DTCsRECISTNewer molecular targeted therapiesFinally, let’s review about Newer molecular targeted therapies
21 Kinase inhibitor activities relevant to advanced thyroid carcinomas IC50(nm)DrugVEGFR1VEGFR2VEGFR3RETBRAFOther targetsSorafenib9020496Sunitinib291741Motesanib359PDGFR, C-KITVandetanib40110100EGFRLenvatinib(E7080)224535PDGFR, FGFR-1Axitinib188.8.131.52Pazopanib103047Sorafenib, sunitinib, motesanib, vandetanib and lenvatinib is multikinase inhibitors that share the ability of inhibiting RET and VEGFR along with other kinases.It have been used in advanced DTCs with the aim of inhibiting MAPK and angiogenesis.In contrast, the main role of axitinib and pazopanib see to act only in antiangiogenic effect.Schlumberger and Sherman, 2012 Eur J Endocrinology
22 Motesanib (AMG 706)First large, international trial for progressive DTC was a phase II study of motesanib (125mg/day) on 93 patients- PR: 13 (14%)- SD: 33 (35%) (>24 weeks)- PFS (Progression Free Survival): 40 weeks
23 VandetanibRandomized phase II in 145 patients with refractory DTC treated with vandetanib (300mg/day) vs placebo on PFSObjective tumor response rate: <5% in vandetanib groupPFS: 11.1 mos (vandetabnib) vs 5.8 mos (placebo) (HR=0.63, 95% CI )Leboulleux S et al, 2012 Lancet Oncol
24 Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial11.1 (vandetabnib) vs 5.8 (placebo) mos. (HR=0.63, 95% CI ) (P=0.008)Leboulleux S et al, 2012 Lancet Oncol
25 SunitinibFirst phase II (37.5mg qd) in 28 DTC patients with FDG-avid disease on FDG-PET scan- One CR, 7 PR and 14 SD- Decrease in FDG uptake at 7 days of medication predicts better response to therapySecond phase II with 31 DTCs with progressive disease (50mg/day 4wks, 2wks off)- PR 13%- SD 68%
26 Lenvatinib (E7080) Phase II (24mg of lenvatinib) in 58 DTCs - PR 45% (53% of naïve patients and 42% of pretreated patients)- SD 46%- PFS (median) 13.3 mos- Dose reduction 39%- Withdrawal 29%Phase III comparing the effect of lenvatinib vs placebo on PFS in progressive refractory DTC is on-going.
27 Axitinib Phase II (5mg twice daily) in 45 DTCs - PR: 14 - SD: 19 2nd phase II is ongoing (NCT )
28 Pazopanib Multi-targeted TKI (VEGFR, PDGFR and c-Kit) Approved for renal cell cancer and soft tissue sarcoma in USFDAPhase II (800mg daily) in 37 DTCs- PR 49%
29 Dose reduction for toxicity (%) SorafenibReported in four phase II trials (400mg bid)DrugsYearnPR(%)SD>6 mo.(%)PFS,medianDose reduction for toxicity (%)Sorafenib20083023532047200941 PTC15565232253413.5662011191882>2479Effect of sorafenib was reported in 4 phase II trials. First trial included 30 patients with advanced thyroid cancer.75% showed Partial response or stable disease and progression free survival was 20 month.In another trial with 41 PTC patients, also about 70% showed partial response or stable disease.In a third trial in 32 patients, 25% PR and 34% SD was observed.In a fourth trial, 3 patients showed PR and the rest showed stable disease.However, half of the patients in all trial need to reduce the dose because of toxicity.Efficacy of sorafenib seems better on lung than bone metastases and with BRAF mutation.Sorafenib also proved to be active in children with DTC.Better in PTCs, on lung than on bone metastses and among PTCs, with BRAF mutationAlso, active in children with PTC
30 Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trialComparing the effect of sorafenib vs placebo on PFS in treatment of naïve patients with RAI refractory, progressive metastatic DTCCrossover or Continue Sorafenib400 mg PO BIDProgressionOff StudyDoctor’s DecisionDisease ProgressionEligibility Criteria:Locally advanced or metastatic DTCProgression within 14 monthsRAI refractoryNo prior targeted therapy, chemotherapy or thalidomidePlaceboRandomisation (1:1) (n=380)Sorafenib 400 mg PO BIDThere is on-going DECISION trial which finished enrollment.DECISION is phase III study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancersIt is going to compare the effect of sorafenib vs placebo on PFS in the patients with RAI refractory progressive DTCs.It finished enrollment of 380 eligible patients and on-going. In case of progression in patients on placebo, they can be switched to sorafenib treatment according to physicians decision.NCT
31 Agents to restore RAI uptake 13 cis-retinoic acidBexarotene (synthetic agonist of RXR)RosiglitazoneSelumetinib (AZD6244)- MEK ½ inhibitor- 11(65%) of 17 RAI refractory DTC restoredRAI uptake- 6/7(86%) had PR to RAI (only in patients whose information on best response was available)
32 Side effects of molecular targeted therapies Fatigue, Hypertension, Anorexia, DiarrheaCytopenia, Skin toxicities- Dose reduction in 11-73%- Withdrawal in 7-25%Serum TSH should be monitored- T4 dose increase is needed sometimesCutaneous squamous cell cancers and keratoacanthomas in up-to 21% of patients treated with BRAF inhibitors
33 Take home messagesPatients with advanced DTC require novel therapies and should be considered in prospective trials of molecular targeted agents when the disease burden is large and when progression has been documented.DECISION (sorafenib) and Phase III E7080 trial will provide evidence that kinase inhibitors are more effective in patients with DTC with metastatic disease refractory to RAI treatment.