New Aspects of Tyrosine Kinase Inhibitors Marcia S. Brose MD PhD Associate Professor

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1 New Aspects of Tyrosine Kinase Inhibitors Marcia S. Brose MD PhD Associate Professor Department of Otorhinolaryngology: Head and Neck Cancer Department of Medicine, Division of Hematology/Oncology Abramson Cancer Center The University of Pennsylvania Philadelphia, PA

2 Disclosures Companies: AstraZeneca, Bayer/Onyx, Eisai, Exelixis, Novartis, Roche/Genentech, Loxo, Oxigene Relationships: Advisory board consultant, honoraria, research grants, and primary investigator As there are currently two FDA approved agents for progressive DTC other than doxorubicin and sorafenib, all the remaining agents I will mention will be in the context of a clinical trials 2

3 Genetics of Differentiated Thyroid Cancer: aberrant intracellular signaling Poorly differentiated RAS (25 30%) TP53 (20 30%) CTNNB1 (10 20%) BRAF (10 15%) Follicular Mutations in 70 75% RAS (40 50%; lower in oncocytic) PAX8/PPARγ (30 35%; lower in oncocytic) TP53 (21%) PTEN (8%) PIK3CA (7%) BRAF (2%) Oncocytic Conventional Papillary DTC Anaplastic Medullary Papillary Mutations identified in ~70% BRAF a (40 50%) RAS b (7 20%) RET/PTC (clonal; 10 20%) EGFR (5%) TRK (<5%) PIK3CA (2%) a BRAF mutations are mostly V600E; 1 2% are K601E and others b RAS includes N-, H-, and K-RAS (predominantly NRAS and HRAS codon 61) Nikiforov YE et al. Arch Pathol Lab Med 2011;135:569 77; COSMIC database Catalog of Somatic Mutations in Cancer

4 Kinase Inhibitors ATP KI KI ATP Y P Activated pathway Cancer Y Activated Pathway Cancer RET, BRAF.. inhibition VEGFR inhibition Tumor growth Tumor angiogenesis

5 Targets of Kinase Inhibitors Compound Name VEGFR BRAF PDGFR KIT RET Other Sorafenib FLT-3 Sunitinib FLT-3 Axitinib Pazopanib Vandetanib + + EGFR Cabozantinib + + C-MET Lenvatinib FGFR Vemurafenib BRAF V600E DTC, differentiated thyroid cancer; EGFR, endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. 1. Perez CA, et al. Biologics. 2012;6: Pacini F. Expert Rev Endocrinol Metab. 2012;7:

6 DECISION and SELECT: Next Steps Patients on the SELECT had a much shorter PFS on the placebo arm than DECISION, suggesting that the populations are not the same in growth rate. A direct comparison in the same population would be useful to compare efficacy. Use of RECIST 1.1 vs 1.0 for study entry Use of central review on SELECT resulted in almost 1/3 rd of patients deemed eligible by investigators being deemed ineligible (selection for more aggressive disease) Central review of pathology to determine number of Poorly Differentiated subtype was done on DECISION but not on SELECT Lenvatinib had significantly higher number of deaths related to drug and incidence of thromboembolic events and hemorrhages. If FDA approved, safety and efficacy of the two agents when used sequentially will need to be determined, ideally by a sequencing study (A then B vs B then A)

7 Rational for the Addition of Everolimus to Sorafenib in Sorafenib Failures Radiographically, patients progression is not uniform and many nodules are stable. At the tissue level, there is heterogeniety, suggesting that sorafenib is controlling some of the tumor growth, even at the time of progression. Patients who are progressing say they feel better if they stay on the sorafenib. One patient switched to mtor inhibitor responded in the progressing nodules but failed due to progression of nodules previously stabilized on sorafenib Development of underlying resistance pathways likely differ based on heterogeneity among disease sites

8 Analysis of 40 pts on UPCC0330 Yarchoan et al: Low nuclear pakt staining was associated with decreased response (paper submitted)

9 100% Response by Nuclear pakt Expression Percent of Patients 80% 60% 40% 20% P<0.01 Partial Response Stable Disease Progressive Disease 0% Above Average Below Average Partial Response 18.2% 70.6% Stable Disease 72.7% 29.4% Progressive Disease 9.1% 0.0% Nuclear pakt Expression

10 UPCC 19309: Everolimus Plus Sorafenib for DTC Patients Who Progress on Sorafenib Alone Eligibility criteria Metastatic, iodinerefractory thyroid cancer Life expectancy > 3 months PD on sorafenib ECOG PS 0-2 Good organ and bone marrow function n = 35 Sorafenib + everolimus Intrapatient dose escalation Primary endpoints RECIST PFS Response rate 35 Patients accrued PFS 13.9 months (embargoed) DTC, differentiated thyroid cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; PD, progressive disease; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors. ClinicalTrials.gov identifier # NCT

11 UPCC 19309: Everolimus + sorafenib for patient that progressed on sorafenib alone PFS 13.9 months Series Months

12 UPCC 19309: Everolimus + sorafenib for patient that progressed on sorafenib alone Study ID Date on Study Drug End of study Date End of Study Visit Date Total time On Studydays Time in months Highest Dose of Highest Dose of Everolimus Sorafenib /27/2011 7/10/2012 7/10/2012 PD mg 800 mg /27/2011 9/8/2011 9/8/2011 PD mg 800 mg /4/2011 4/10/2011 4/28/ WD mg 600 mg /4/2011 6/19/2014 6/19/2014 PD mg 800 mg /4/2011 7/10/ /10/2014 PD mg 800 mg /17/2011 3/24/2011 4/14/2011 AE mg 600 mg /18/ /24/ /25/2012 PD mg 600 mg /18/2011 9/27/2012 4/4/2013 PD mg 800 mg /17/2011 7/10/2011 EOS ND - AE mg 800 mg /29/2011 8/25/2011 8/25/2011 PD mg 600 mg /9/ /3/ /26/2013 PD mg 800 mg /23/2011 7/28/2011 EOS ND- PD mg 600 mg /14/2011 1/4/2012 1/5/2012 PD mg 600 mg /16/ /19/2013 1/16/2014 PD mg 800 mg /1/2012 3/21/2012 4/5/2012 AE mg 600 mg /22/2012 7/6/2012 7/12/2012 PD mg 600 mg /8/ /28/2014 ACTIVE mg 600 mg /22/ /28/2012 1/24/2013 PD mg 800 mg /22/2012 5/16/2013 5/16/2013 PD mg 800 mg /24/ /1/ /01/2013 PD mg 600 mg /23/2012 4/2/2013 4/4/2013 PD mg 600 mg /11/2012 8/14/ /14/2014 PD mg 600 mg /6/2012 4/17/ /17/2014 PD mg 800 mg (Re- Screen) 10/24/ /29/ mg 800mg /2/ /28/2014 ACTIVE mg 800 mg /10/2013 5/2/2014 6/19/2014 PD mg 400mg /29/2013 9/25/2014 9/25/2014 PD /3/ /28/2014 ACTIVE /3/ /28/2014 ACTIVE mg /21/2013 5/29/2014 5/29/2014 PD mg QD /27/2014 9/25/ /25/2014 PD mg

13 UPCC 18310: Vemurafenib in patients with Progressive PTC with BRAF V600E Key Eligibility Criteria Recurrent, unresectable or metastatic PTC BRAF V600 mutation positive by cobas RAI refractory Evidence of progression within 14 months Prior chemotherapy allowed Cohort 1: VEGFR2i-naive (n = 26) Cohort 2: VEGFR2i-pretreated (n = 25) Vemurafenib 960 mg bid until disease progression or unacceptable toxicity Primary end point: response rate per investigator in VEGFR2i-naive patients. Secondary end points: safety, duration of response, PFS, OS, PK, response rate in VEGFR2 inhibitor pretreated patients bid, 2 times a day; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; VEGFR, vascular endothelial growth factor receptor; VEGFR2i, vascular endothelial growth factor receptor 2 inhibitor.

14 NO25530 Waterfall plot: Cohort 1 (TKI-naïve) # * Patients who had not discontinued treatment at time of data cut Cohort 1 (Tki naïve) BORR-evaluable 1 N= 26 # 1 patient missing baseline scan 9 Objective Responders 2 (Rate; 95% CI) Best Response (confirmed) Clinical Benefit Response (CR, PR, SD 6 mos) PR SD PD 10 (38.5%; ) 10 (38.5%; ) 15 (57.7%; ) 1 (3.8%: ) 19 (73.1%; ) 1 Patients with at least 2 post-bl tumor scan or PD/WD from for death or AE within first two cycles. 2 Confirmed PR/CR

15 PFS KM Curve: Cohort 1 Median PFS 18.2 mos (95% CI: )* *6 patients continue on therapy without progression 15

16 PFS KM Curve: Cohort 2 Median PFS: 8.9 months (95% CI: 5.4 NE)* *5 patients continue on therapy without progression 16

17 Cabozantinib: A Phase 1 Study Metastatic or surgically unresectable DTC Failed standard therapy Cabozantinib 140mg N=15 Adequate organ function and ECOG 0-2

18 UPCC 28313: Cabozanitib for patients with progressive RAI refractory DTC Eligibility criteria Metastatic, iodinerefractory thyroid cancer Life expectancy > 3 months ECOG PS 0-2 Good organ and bone marrow function n = 35 Primary endpoints cabozantinib RECIST 140mg daily PFS Response rate 18 patients accrued

19 Summary: RAI-Refractory DTC DTC is a vascular tumor that has been associated with increased activity of the MAPK pathways, and iodine-refractory patients have an average survival of 3 years Results of phase 3 trials with sorafenib (DECISION) were positive, This was approved in November 2013 and was the first agent since doxorubicin in Two additional phase 3 trials of lenvatinib (SELECT) and vandetanib (VERIFY) are ongoing Additional MKIs are also now in development, many of which target VEGFR-2, but also mtor, MEK, MET and BRAF and clinical trials will be needed to help us determine sequencing of approved agents and second- and third-line treatments going forward. DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; mtor, mammalian target of rapamycin; RAI, radioactive iodine; VEGFR, vascular endothelial growth factor.

20 Trials on the Runway RIFTOS Study to determine what are the indicators for starting treatment for patients with DTC and who does the best and why Lenvatinib+everolimus in patients with DTC who progressed on lenvatinib alone Lenvatinib+everolimus For patients with MTC who have progressed on Cabozantinib and vandetanib

21 2014 / 2015 DTC Activities Summary Phase II Sorafenib in advanced thyroid cancer including ATC, DTC and MTC JCO Sorafenib Phase II reported early: met primary endpoint as of interim analysis Phase II: vemurafenib in BRAFmutated DTC Phase II: Vemurafenib in BRAF mutated DTC results ESMO 2013 Phase II: Cabretastatin in ATC Phase II: Everolimus+sorafenib in pts who progress on sorafenib Phase II: Cabozantinib in DTC Phase II: Everolimus+sorafenib: abstract submitted ASCO DECISION: Phase III sorafenib in DTC DECISION: Phase III results ASCO 2013 Sorafenib First FDA approved drug RAIrefractory DTC November 2013 EXAM: Phase III Cabozantinib in MTC EXAM: Phase III Cabozantinib in MTC results ASCO 2012 EXAM: FDA approves Cabozantinib in MTC- Nov 2012 SELECT: Phase III Lenvatinib in DTC Phase III: ASTRA Solumetanib Adjuvant study with RAI for high risk DTC SELECT: FDA Approves Lenvatinib in DTC February 2015 Phase III: VERIFY Vandetanib for DTC

22 Working together we can access new treatments and leverage resources. Coming together is a beginning; keeping together is progress; working together is success. -Henry Ford Thank You For Your Support!

23 Center for Rare Cancers What we hope to offer Cooperation among groups with different expertise Possible monthly meeting among Pis Sharing Industry Contacts to help facilitate access to trials and drugs Availability of translational research lab to facilitated translational work Full tissue IHC and Genetics Core available with staff who can help guide residents and techs Clinical Trial Research Staffing Economy of scale, sharing FTEs where needed Sharing GCP and centralized approach to decrease burden for clinical trial data collection Sharing insight and staff to aid in budget negotiations and regulatory Focus on capturing ALL eligible patients

24 And Personalized Therapy What we can offer Partnership with CPD to obtain solid tumor testing on all our patients Developing Basket trials aimed to catch patients with specific genetic and non-genetic pathway activation across tumor types. Ex, Trial of Tipifarnib for HRAS mutated solid tumors Partnership with Industry Partners with similar goals Genetech Novartis Exelixis Eisai Identify novel therapeutic markers for new targeted approaches Learn from other tumor types how targeted therapies may be applied in new contexts

25 Center for Rare Cancers and Personalized Therapies Initial Groups Sarcoma Neurooncology Gyn Onc Neuroendocrine Vet School Thyroid Mesothelioma Trials Cabozantinib in GBM and Other (mesothelioma) Loxo TRAK 1,2,3 inhibitor (solid tumors) Tipifarnib in HRAS mutated tumors (thyrid and other) More thyroid trials

26 University of Pennsylvania Thyroid Cancer Therapeutics Program Brose Translational Research Lab Mark Yarchoan MD Aaron Cohen MD Christian Squillante MD Waixing Tang, MD Zakkiyya Posey Thyroid Cancer Clinical Trials Unit Yvette Cruz, RN Carolyn Grande, RN, CRNP Kathleen Harlacker Thelma McCloskey Diane Foglia Experimental Therapeutics Program Andrea Troxel, PhD Peter O Dwyer, MD Pathology/Imaging Michael Feldman, MD, PhD Laurie Loevner, MD Thyroid Cancer Interest Group Susan Mandel, MD Ara Chalian, MD Douglas Fraker, MD Robert Lustig, MD Virginia LiVolsi, MD Zubair Baloch, MD Daniel Pryma MD Marcia Simpson Brose is a Damon Runyon-Siemens Clinical Investigator Many community endocrinologists who have referred their patients, and the patients who have agreed to participate in our trials