Evolution and Revolution of Radioiodine Refractory Differentiated Thyroid Cancer

Transcription

1 Evolution and Revolution of Radioiodine Refractory Differentiated Thyroid Cancer Steven I. Sherman, M.D. Associate Vice Provost, Clinical Research Naguib Samaan Distinguished Professor Chair, Department of Endocrine Neoplasia and Hormonal Disorders

2 Disclosures I have received honoraria or consulting fees from the following companies: BristolMyersSquibb Eisai Genzyme LOXO NovoNordisk Veracyte

3 Evolution of RAI-refractory thyroid carcinoma

4 Objectives Definition and characterization of radioiodine-refractory differentiated thyroid cancer Current standard therapies TSH suppressive thyroid hormone Multitargeted kinase inhibitors Investigational therapies Multitargeted kinase inhibitors Selective kinase inhibitors Immunotherapy Redifferentiation therapy

5 Classic model of DTC treatment Surgery Radioactive iodine TSH-suppressive thyroid hormone therapy

6 The original molecular targeted therapy: RAI the first person known to be cured of metastatic cancer: by drinking 4 doses of radioactive iodine. Life, 1949

7 The original molecular targeted therapy: RAI

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9 Classic model of DTC treatment Surgery Radioactive iodine TSH-suppressive thyroid hormone therapy

10 RAI uptake can be heterogeneous Maloof, Vickery, & Rapp, J Clin Endocrinol Metab 1956

11 And RAI doesn t always work The results of therapy of thyroid cancer with radioactive iodine have been disappointing [due to] the spotty nature of iodine concentration. Trunnell & Brayer, J Clin Endocrinol Metab 1953

12 Patterns of RAI-refractory DTC Cabanillas, McFadden & Durante, Lancet 2016

13 How do you define RAI-refractory DTC? Strength of Evidence Structural lesions that are not RAI avid on nuclear imaging Structural lesions that do not shrink or are growing within 6-12 months of RAI treatment despite uptake Cumulative treatment with 600 mci Lesions that are 14 FDG avid on PET imaging Persistently abnormal biomarker (thyroglobulin, anti-tg Ab) Others?

14 ATA guidelines: Defining RAI-refractory DTC In the setting of structural disease outside the thyroid bed, any of the following: Never any uptake on initial posttherapy scan or subsequent diagnostic scan Loss of previous RAI avidity Uptake in some but not all lesions Progression despite RAI uptake Further RAI therapy is never indicated Haugen et al., Thyroid 2016

15 Patterns of RAI-refractory DTC Cabanillas, McFadden & Durante, Lancet 2016

16 Evaluating the patient with RAI-refractory DTC Imaging CT, 18 FDG-PET/CT, MRI, other structural/functional imaging studies Rate of progression Serial imaging, lesion growth rates Balance burden of disease with rate of progression Risk of progression Assess current and potential future symptoms and morbidities from progression Risk of therapy Consider co-morbidities and how they might influence choice of therapy Haugen et al., Thyroid 2016

17 ATA guidelines: Treatment for RAI refractory DTC Consider focal therapy when appropriate (surgery, radiation, ablative procedures, etc.) TSH suppressive thyroid hormone therapy Consider clinical trials Kinase inhibitors for rapidly progressive, symptomatic, or threatening disease Approved kinase inhibitors Others available preferably in trial Upon progression, consider another kinase inhibitor Haugen et al., Thyroid 2016

18 TSH suppression and distant metastases Percent survival P= yr survival: ~65% vs. ~ 25% Years Aggressive M oderate Non-supp. Carhill et al., J Clin Endocrinol Metab 2015

19 Signaling pathway inhibitors relevant to DTC Haugen & Sherman, Endocr Rev 2013

20 Multitargeted antiangiogenic TKIs improve PFS Lenvatinib Sorafenib Median PFS Sor 10.8 mo Pl 5.8 mo HR 0.59 ( ) P< Schlumberger, et al., N Engl J Med 2015; Brose, et al., Lancet Oncol 2014

21 Multitargeted antiangiogenic TKIs shrink tumors Lenvatinib Overall response rate: 65% Sorafenib Overall response rate: 12.6% Schlumberger, et al., N Engl J Med 2015; Brose, et al., Lancet Oncol 2014

22 Second line TKI therapy may also be helpful PR 44% PFS 12.8 mos Shah, et al., Int l Thyroid Congress, 2015

23 Do antiangiogenic TKIs improve survival? Lenvatinib Sorafenib HR (95% CI): 0.80 ( ); P = 0.14 Guo, et al., ECCO 2015; Brose, et al., Lancet Oncol 2014

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25 ATA guidelines: Treatment for RAI refractory DTC Haugen et al., Thyroid 2016

26 Spectrum of oncogenic mutations in PTC 1% 1% BRAF 1% 14% RAS 2% 7% 1% RET/PTC EIF1AX 13% 62% NTRK PAX8/PPARg ALK PTEN Other/unknown Low mutation density: 0.41 nonsynonymous mutations/mb Adapted from Giordano, et al., Cell 2014

27 Signaling pathway inhibitors relevant to DTC Haugen & Sherman, Endocr Rev 2013

28 Brose, et al., Lancet Oncol 2016; Falchook, et al., Thyroid 2014 BRAF inhibitors are active in BRAF mutant PTC Vemurafenib Dabrafenib PR 38.5% mpfs 18.2 mos PR 27.3% mpfs 8.9 mos PR 30.8%

29 Selective inhibition of NTRK: Larotrectinib Hong, et al., ESMO 2016

30 Immunotherapy Drake et al., Nat Rev Clin Oncol 2014

31 Immunotherapy: Pembrolizumab cpr 9.1% PFS 6.8 mos Mehnert, et al., ASCO 2016

32 ITOG trial: Pembrolizumab + Lenvatinib Cohort 1 (n=30) Progressive RR-DTC No prior Lenvatinib Lenvatinib 20 mg qd Pembrolizumab 200 mg q3wk Primary endpoint: Complete response Cohort 2 (n=30) Progressive RR-DTC on Lenvatinib Lenvatinib at last dose Pembrolizumab 200 mg q3wk Primary endpoint: Objective response

33 Chakravarty, et al., J Clin Invest 2011 BRAF V600E mutation causes loss of RAI avidity Mouse expressing BRAF wild type BRAF V600E expression induced BRAF wild type restored

34 Chakravarty, et al., J Clin Invest 2011 MAPK inhibitors restore RAI uptake BRAF inhibitor MEK inhibitor

35 Selumetinib may restore responsiveness to RAI Ho, et al., New Engl J Med 2013

36 Selumetinib may restore responsiveness to RAI 20 patients with RAI refractory PTC or PDTC RAI therapy following dosimetry via 124 I-PET after 5 wks of selumetinib 60% with uptake 25% PR (overall) RAS mutation predictive? Ho, et al., New Engl J Med 2013

37 Redifferentiation therapy Pre-Ki Post-Ki Pre-Ki Post-Ki Pre-Ki Post-Ki Pre-Ki Post-Ki X Jaber, et al., ENDO2017

38 Selumetinib + RAI trial: augment avid disease Patients with recurrent or metastatic DTC - RAI avid lesion within 24 months - No therapeutic RAI < 6 mos - Cumulative therapeutic 131-I received < 800 mci. - No previous exposure to MEK/RAS/RAF inhibitors - Systemic therapy completed < 28 days prior to registration. Primary endpoint: Response rate at 6 months R a n d o m i z e 28 pts 28 pts Secondary endpoints: Best overall response, progression-free survival, Tg response, safety/tolerability. Exploratory endpoint: Correlate genomic/transcriptomic analysis of RAI-avid tumors to clinical outcomes. ARM A: RAI + Placebo ARM B: RAI + selumetinib (75 mg po bid) SITES 1. Dana Farber/MGH 2. Duke 3. MD Anderson 4. Medstar Washington 5. Memorial Sloan Kettering 6. Mayo Rochester 7. Ohio State 8. U Colorado 9. UC San Diego

39 Traditional radioiodine therapy

40 Radioiodine therapy after redifferentiation

41 First line therapy of progressive RAI-refractory DTC Mutation testing: BRAF, RAS, etc. BRAF wild type BRAF mutant Rare mutation, e.g., NTRK No contraindication to anti-vegfr TKI Contraindication to anti-vegfr TKI Contraindication to anti-vegfr TKI No contraindication to anti-vegfr TKI Clinical trial of selective inhibitor Lenvatinib > Sorafenib Sorafenib > Lenvatinib RAS mutant Clinical trial BRAF inhibitor +/- MEK inhibitor Lenvatinib > Sorafenib MEK inhibitor Consider RAI

42 Investigational treatments of RAI refractory DTC Angiogenesis/multikinase inhibitors Anlotinib Apatanib Donafenib Everolimus/Sorafenib Everolimus/Pasireotide Nindetanib Pazopanib Sulfatinib Temsirolimus/Sorafenib Vandetanib MAPK targeting + RAI Selumetinib + RAI Dabrafenib + RAI Trametinib + RAI Vemurafenib + RAI Vemurafenib/KTN RAI Oncogene targeting Larotrectinib RXDX-105, LOXO-292, BLU-667 Tipifarnib Immunotherapy +/- targeted agent

43 Conclusions Consensus defintions of RAI-refractory DTC can aid patient identification and evaluation Antiangiogenic kinase inhibitors can improve progression-free survival, but effects on overall survival are yet uncertain Highly selective MAPK pathway inhibitors may be effective to alter the malignant phenotype Further clinical trials essential to identify potentially curative, better tolerated therapies

44 MDA Oncologic Endocrinology Fellowship Program First of its kind; established in 2012 Develop expertise in evaluation & management of endocrine neoplasias Understand the research developments in thyroid cancer & other endocrine neoplasias Expand the understanding of managing endocrine complications of cancer patients Program Director Mimi Hu, MD

45 Acknowledgements MD Anderson Collaborators Naifa Busaidy Maria Cabanillas Aubrey Carhill Ramona Dadu Robert Gagel Mouhammed Habra Mimi Hu Tania Jaber Camilo Jimenez Steven Waguespack Steven Weitzman Anita Ying Gil Cote Marie-Claude Hofmann International Thyroid Oncology Group National Thyroid Cancer Treatment Cooperative Study Group Ohio State University/MD Anderson Cancer Center Thyroid Cancer SPORE