An update on systemic treatment of differentiated and medullary thyroid cancers: What to do after AI Disclosures: clinical trial support: - Exelixis, BI, Bayer, ECOG, TOG, GSK - Actogenix, Proacta, BMS, NCI, oche regular cash payments and subsidies: Stanford University: salary, tuition plan, retirement A. Dimitrios Colevas, MD Division of Oncology Stanford School of Medicine A. Dimitrios Colevas, MD Division of Oncology Stanford School of Medicine ET activation in DTC: ET/PTC oncogenic rearrangement: 5-30% of spontaneous PTC 60-70% of radiation induced PTC Signaling via AS/ BA/ MEK/ EK Lanzi et al,. Biochemical pharmacology 77(2009) 297-309 1
Kinases and TKI s What are they? Kinases are enzymes TKI= tyrosine kinase inhibitor TKIs stop phosphate addition to specific proteins Mostly act at the ATP binding site. New targeted agents in thyroid cancer G V E G P D G B A c K I T L T 3 c M E T T I E2 sorafenib x x x x x sunitinib x x x x x XL 184 ( cabozantinib) x x x x x x vandetanib x x x Lenvatinib (E7080) x x x lenalidomide X* axitinib x x motesanib x x x x pazopanib x x x vemurafenib X E G E T H D A C The IC 50s for inhibition of ET autophosphorylation of each TKI against Wild-Type (WT) ET and ET mutants Inhibitor ET wildtype IC 50 [nm] ET C634 ET V804L ET M918T Axitinib 50 130 >5000 2300 Motesanib 150 250 >5000 1900 Sorafenib 30 70 390 430 Sunitinib 10 70 40 360 Vandetanib 60 110 >5000 560 XL-184 3.8 27 DP 2490 <1 10 30 90 DP 3636 <1 <1 1 10 Modified with permission from AW Gramza et al. Abstract poster #5559, ASCO 2010 Prognosis in DTC: PET matters, AI doesn t obbins,. J. et al. J Clin Endocrinol Metab 2006;91:498-505 2
Medullary Thyroid Carcinoma (MTC) Medullary thyroid cancer Comprises 3 5% of all thyroid cancers and occurs in a hereditary (25%) or sporadic (75%) pattern Activating ET mutations occur in ~100% of hereditary MTCs (germline) and in >50% of sporadic MTCs (somatic) MET is commonly overexpressed in MTC, often in association with phosphorylated ET Status of TKIs: ecent phase 2 trials in MTC Drug Target(s) # patients Activity Available? Sunitinib in MTC, Phase 2 J. A. De Souza et al., J Clin Oncol 28:15s, 2010 (suppl; abstr 5504) Sorafenib 1 Sunitinib 5 ET, VEG, BA, PDG, KIT, LT-3 PDG, KIT, VEG, ET, LT3 Hereditary 5 Sporadic 16 One P Durable eduction 50% YES 7? YES Vandetanib 2 ET, VEG, EG Hereditary 30 ECIST P 20% Durable eduction 73% Motesanib 3 Axitinib 4 XL184 6 VEG 1,2,3, KIT, ET VEG 1,2,3, PDG, KIT, ET ET, VEG2, MET, KIT, TIE2 Hereditary 6 Sporadic 76 ECIST P 2% Durable eduction 48% YES NO 11 ECIST P 18% NO 28 ECIST P 29% eduction 93% NO This trial confirms activity in same range as with other relevant TKIs, independent of ET status. All patients in this trial PD in <6 months prior to enrollment. Pre versus post treatment progression as evidence of benefit. efs: 1 J Clin Oncol 28:2323-2330. 2010. 2 J Clin Oncol 28:767-772. 2010. 3 J Clin Oncol 27:3794-3801.2009 4 J Clin Oncol 26:4708-4713.2008 5 J Clin Oncol 27:15s, 2009 (suppl; abstr 6056) 6 http://www.exelixis.com/sites/default/files/pdf/eotc08_379_xl184-001.pdf 3
% Tumor Change MTC patient responses in a Phase 1 Study of XL184 azelle Kurzrock et al., ASCO 2010 # 5502 40 a 30 20 10 0-10 -20-30 -40-50 -60 * * * * * * * * * * * Tumor shrinkage was observed regardless of ET mutation status. esponses in patients with prior Vandetanib exposure. No activating ET mutations Activating ET mutations ET status unknown Median response duration not met after 17 months median f/u. Vandetanib in locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind Phase III trial (ZETA) Sam Wells et al. J Clin Oncol. 2012 Jan 10;30(2):134-41. Epub 2011 Oct 24. 13 Study design Locally advanced or metastatic MTC (N=331) 195 pts tested for ET, 95% mutant Vandetanib 300 mg/day n=231 2:1 randomization Progression Optional open-label Vandetanib 300 mg/day Placebo n=100 Study objectives Primary endpoint: progression-free survival (PS) Secondary assessments included: Overall survival Time to worsening of pain Safety and tolerability (CTCAE 3.0) ollow for survival J Clin Oncol. 2012 Jan 10;30(2):134-41 4
PS (primary endpoint) Vandetanib in MTC: Ph 3 PS by ET mutation status 1.0 Hazard ratio <1 favors Vandetanib avors vandetanib avors placebo 0.9 Vandetanib 300 mg Progression-free survival 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 Placebo Hazard ratio = 0.46 (0.31 0.69); P<0.0001 Median: not reached (Vandetanib); 19.3 months (placebo) 6 12 18 24 30 36 Time (months) Partial responders ECIST J Clin Oncol. 2012 Jan 10;30(2):134-41 V:45% (104) P:13% (13) (12/13 after x- over to V) J Clin Oncol. 2012 Jan 10;30(2):134-41 Overall survival (there was crossover) Living better? G 3: > 7 stools/day rom J Clin Oncol. 2012 Jan 10;30(2):134-41 5
Cabozantanib (XL184 by Exelixis) EXAM trial P Schöffski et al, ASCO 2012. P Schöffski et al, ASCO 2012. EXAM trial P Schöffski et al, ASCO 2012. P Schöffski et al, ASCO 2012. 6
Timeline for a MTC patient Bosnian war Arab spring alive and well! 2 nd recurrence ecurrence - vandetanib 1959 1 st recurrence 1981 1989 1992 2005 2011 2012 diagnosed Kim Jong-Il Kim Jong-un MTC 2010 take home message We can shrink tumors and extend PS in MTC with Vandetanib and XL184 Unclear if this is clinically meaningful. Motesanib and XL184 are promising but Sorafenib and Sunitinib are available now. Is ET really the relevant target? Is best in class biochemically predictable? Tianamen square When do these patients need treatment? with permission rom Lori Wirth MD Is XL184 better or inferior to Vandetanib? Will we ever know? Papillary and follicular thyroid cancer Differentiated Thyroid Carcinoma (DTC) incidence doubled in past decade Mortality rise of 33% 1600 deaths in US, 2009 No meaningful benefit from cytotoxic chemotherapy Subsets of note: BA mutant in PTC ET/ PTC fusion in PTC 7
Which agent is leading the pack in DTC? Axitinib in thyroid cancer ph 2 Cohen et al. J Clin Oncol 26:4708-4713.2008 Motesanib in thyroid cancer ph 2 Sherman et al. N Engl J Med 2008;359:31-42. axitinib Yttrium conj. sorafenib sorafenib thalidomide motesanib IN +Doxo celecoxib vorinostat gefitinib Yes pazopanib <6 months 18/37 (49%) 12 >20 Modified from Bible et al, www.thelancet.com/oncology Vol 11 October 2010 Sorafenib in thyroid cancer ph 2 Gupta- Abramson et al. J Clin Oncol 26:4714-4719.2008 Sorafenib in thyroid cancer ph 2 Kloos et al. J Clin Oncol 27:1675-1684. 2009 Efficacy of pazopanib in progressive, radioiodinerefractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Bible et al, www.thelancet.com/oncology Vol 11 October 2010 Pazopanib in DTC: reversal of growth slopes Pasopanib 800 mg daily in 39 patients with PD in less than 6 months OS PS esponses Survival 8
Sorafenib in thyroid: educed doses and BA V600E mutant Vandetanib late breaking news 2012: not just for MTC!. Lancet Oncol 2012; 13: 897 905 P=0.017 for H.. 0.63 76% dose reduced in first month to 400 mg QD. One patient with PTC, BA V600E mutant had a dramatic P European Journal of Endocrinology 165 315 322 Thyroid. 2011 eb;21(2):119-24. But. Sophie Leboulleux et al. Lancet Oncol 2012; 13: 897 905 And Sophie Leboulleux et al. Lancet Oncol 2012; 13: 897 905 9
And AND CT in progress: Phase 3 Trial of Lenvatinib (E7080) in 131I-efractory Differentiated Thyroid Cancer 50% in DTC, 36% in MTC PS endpoint, placebo controlled Must have progression within past year Open March 2011, 360 patients sought One prior TKI allowed ecruitment ongoing CT in progress: Sorafenib Versus Placebo in AI- efractory Differentiated Thyroid Cancer Open October 2009 Sorafenib versus placebo 419 patients, accrual complete Progression in prior 14 months Crossover to sorafenib permitted PS primary endpoint 10
Differentiated Thyroid Carcinoma take home messages: There is hope after radioactive iodine. Many TKIs are active. Sorafenib, Sunitinib, Pazopanib, Vandetanib are all available but not DA approved.????survival??? Sorafenib, E7080 studies END What is the target? VEG? Emerging biological targets BA V600E mutant: PLX 4032 trials? ET/ PTC fusion: Worth the investment? MEK inhibitors may convert AI refractory to AI sensitive rom Alan Ho oral presentation ASCO 2012 11