SCOUTing a Path to NAVIGATE Expedited Pediatric Development

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1 SCOUTing a Path to NAVIGATE Expedited Pediatric Development Michael Craig Cox, PharmD, MHSc, BCOP Senior Director, Clinical Development and Medical Affairs Loxo Oncology, Inc. 1

2 Disclosures I am an employee and stockholder of Loxo Oncology, Inc. I hold a patent, 62/318,041, issued to Loxo Oncology, Inc. I will discuss off-label, investigational use of larotrectinib In November 2017, Loxo Oncology and Bayer entered into an exclusive global collaboration for the development and commercialization of larotrectinib and LOXO-195, a next-generation TRK inhibitor. Loxo Oncology leads worldwide development and U.S. regulatory activities. Bayer leads ex-u.s. regulatory activities and worldwide commercial activities. In the U.S., Loxo Oncology and Bayer will co-promote the products. 2

3 Patient samples (%) Clinically actionable alterations in cancer Frequency of all reported actionable alterations in solid tumors, N=2112 Head 8% 17% 8% 3% 33% Gene amplification Mutation hotspots Truncation Gene deletion Long tail 31% Short insertion, deletion Rearrangement 1,579 unique gene alterations Adapted from Frampson et al. Nature Biotech Current clinical testing paradigms comprising mutation hotspots may capture less than a third of total actionable alterations Comprehensive genomic profiling using an optimized NGS diagnostic testing can identify more targets for treatment Loxo Oncology focuses on the long tail of clinically actionable alterations, genetically defined cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect Reference: Frampson et al. Nat Biotechnol November ; 31(11): doi: /nbt

4 Gene fusions and their detection NGS, Next-Generation Sequencing Detects known and novel fusions with arbitrary breakpoints in DNA or RNA Exact capabilities depend on enrichment strategy RT-PCR, Reverse Transcription Polymerase Chain Reaction Detects known fusion transcripts in RNA Detects 5 /3 imbalance as a fusion signature, but can not determine novel partner FISH, Fluorescence In Situ Hybridization Detects gene rearrangements in DNA that may generate a fusion transcript IHC, Immunohistochemistry Detects protein expression, which may be attributable to a fusion event 4

5 The History of Oncogenic NTRK Genes 5

6 TRK fusions are found in diverse cancer histologies 6

7 Estimated frequency of TRK fusions across tumor types 5% 5%-25% 75% CNS Astrocytoma 1 Low-grade glioma 2 Glioblastoma 3 GI Colorectal cancer 2,4 Cholangiocarcinoma 5 Pancreatic cancer 6 Head and Neck Squamous cell carcinoma 2 Lung Adenocarcinoma 2,7 Large cell neuroendocrine carcinoma 8 Other Acute myeloid leukemia 9 Breast-invasive carcinoma 2 Melanoma 2 Sarcoma 2 Congenital mesoblastic nephroma 10,11 Recurrent papillary thyroid cancer 12 Pontine glioma 13 Spitzoid melanoma 14 Pediatric and young adult soft tissue sarcomas 15 Pan-negative gastrointestinal stromal tumors (GIST) 16 Mammary analogue secretory carcinoma (MASC) of the salivary gland 17 Secretory breast carcinoma 18 Infantile fibrosarcoma 19 References: 1. Jones DT, et al. Nat Genet. 2013;45: Stransky N, et al. Nat Commun. 2014;5: Kim J, et al. PLoS One. 2014;9:3. 4. DeBraud F, et al. ASCO (abstr 2502). 5. Ross JS, et al. Oncologist. 2014;19: Bailey P, et al. Nature 2016;531: Vaishnavi A, et al. Nat Med. 2013;19: Fernandez-Cuesta L, et al. AACR (abstr 1531). 9. Kralik JM, et al. Diag Path. 2011;6: Argani P, et al. Mod Path. 2000;13: Rubin BP, et al. Amer J Path. 1998;153: Leeman-Neill RJ, et al. Cancer. 2014;120: Wu G, et al. Nat Genet. 2014;46: Wiesner T, et al. Nat Commun. 2014;5: Morosini D, et al. ASCO (abstr 11020). 16. Brenca M, et al. J Path. 2016;238: Bishop JA, et al. Hum Pathol. 2013;44: Tognon C, et al. Cancer Cell. 2002;2: Bourgeois JM, et al. Am J Surg Pathol. 2000;24:

8 Tyr Tyr Tyr Tyr Tyr Tyr TRK fusions are rare but recurrent oncogenic drivers Beyond the embryo, tropomyosin receptor kinase (TRK) proteins are primarily limited to the nervous system 1 3 neurotrophin receptors encoded by 3 distinct genes that regulate specific normal functions 2-6 NTRK1 TRKA Pain, thermoregulation NTRK2 TRKB Movement, memory, mood, appetite, body weight NTRK3 TRKC Proprioception Recurrent chromosomal fusion events have been identified across diverse pediatric and adult cancers 7-13 NTRK1/2/3 Promoter 5 partner LBD kinase domain ERK 5 partner NTRK kinase domain AKT 5 partner NTRK kinase domain 5 partner NTRK kinase domain References:1. Vaishnavi et al. Cancer Discovery. 2014;5(1): Crowley et al. Cell. 1994;76(6): Smeyne et al. Nature. 1994;368(6468): Skaper. CNS Neurol Disord Drug Targets. 2008;7(1): Ammendrup-Johnsen I et al. J Neurosci. 2015;35(36): Huang et al. Annu Rev Neurosci. 2001;24: Chen et al. Anticancer Res. 2014;34(4): Fujimoto J et al. Proc Natl Acad Sci U S A. 1996;93(9): Dupain C et al. Mol Ther Nucleic Acids. 2017;6: Wang D et al. Comput Math Methods Med. 2015;2015: Tognon C et al. Cancer Res. 2001;61(24): Roccato E et al. Br J Cancer. 2002;87(6): Ardini E, et al. Mol Oncol. 2014;8(8):

9 Larotrectinib (LOXO-101) Larotrectinib is the first and only selective pan- TRK inhibitor in clinical development TRKA/B/C 2 Highly potent against TRKA, TRKB, TRKC (5 11 nm IC 50 in cellular assays) 1 Highly selective, with limited inhibition of other kinases and >1,000x selective over other off targets 1 References: 1. Doebele et al. Cancer Discov Oct;5(10): Chartier et al Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. PeerJ 1:e126. 9

10 Larotrectinib in Vitro and in Vivo activity In Vitro: Potency in TRK Fusion Cell Models; Spares Unselected Cell Models 1,2 Percent of Control LOXO-101 (nm) Fusion Lines KM12 (TPM3-NTRK1) CUTO3.29 (MPRIP-NTRK1) MO91 (ETV6-NTRK3) Percent of Control LOXO-101 (nm) Non-Fusion Lines H1650 H3122 HCC78 A549 H1299 SW837 HT29 HCT116 HCT15 In Vivo: Tumor Regressions in TRK Fusion Xenografts 1,2 Tumor Volume Change (%) KM12 Line (TPM3-NTRK1; colon cancer) Tumor Volume Change (%) CUTO-3.29 Line (MPRIP-NTRK1; lung cancer) Tumor Volume Change (%) MO-91 Line (ETV6-NTRK3; AML) Vehicle Control 60 mg/kg/day 200 mg/kg/day Time (Days) Time (Days) Time (Days) References: 1. Courtesy of the Doebele lab. Doebele et al. Cancer Discov Oct;5(10): Hong D et al. Proc AACR-NCI-EORTC Molecular Targets Meeting

11 Larotrectinib phase I study: LOXO-TRK Ongoing study Advanced or metastatic solid tumors ECOG 0/1, normal organ function QD or BID oral fixed, continuous dosing, 28-day cycles Outcome measures Safety and tolerability Pharmacokinetics measured at cycle 1, days 1 and 8 Efficacy assessments conducted every other cycle starting C3D1 200mg QD 100mg QD RP2D 100mg BID 150mg BID 200mg BID April 2014: Study opened 50mg QD March 2015: First TRK fusion patient enrolled Hong et al. AACR-NCI- EORTC N=30, dose escalation cohorts n=3 TRK fusion responses/6 enrolled

12 First TRK fusion patient treated with larotrectinib Baseline Cycle 3, day1 Cycle 13, day1 41 year old female with LMNA- NTRK1 fusion undifferentiated sarcoma previously treated with epirubicin, ifosfamide, sorafenib and doxorubicin Rapid resolution of dyspnea and hypoxemia with larotrectinib 100mg BID Confirmed PR by cycle 3, DOR >25 months at data cutoff of April 14, 2017 Reference: Doebele et al. Cancer Discov Oct;5(10):

13 NAVIGATE: Larotrectinib Phase 2 Basket Study October Simon 2-stage design Stage 1: 1/7 Stage 2: 4/18 Primary endpoint Best overall response of confirmed CR or PR as measured by RECIST 1.1 or RANO criteria, as appropriate to tumor type Secondary endpoints Duration of response Confirmed best response Progression free survival Overall survival Safety 13

14 Unmet need in TRK fusion cancers and evolving clinical solutions Kit formulation Liquid formulation Need to dose children that can not swallow a capsule Explore a pediatric study Pediatric advisory board Great drug Currently available therapies manage disease appropriately Inhibiting TRK in a child may cause more harm Chemotherapy will cause less developmental issues TRK fusion pediatric cancers are an extremely rare occurrence 14

15 The path to SCOUT, pediatric phase I trial Nemours Children s Hospital Loxo Oncology FDA Nov 14-month-old girl, ETV6- NTRK3 rearranged IFS, refractory to chemotherapy and surgical procedures Compassionate use? Do what it takes to get access to therapy Expedite trial opening 20, Nov File pediatric IND 9, Dec Permission to Proceed 14, Dec Phase I trial open 21, Dec Treat first patient with kit formulation; starting dose based on SimCYP PK model 15

16 SCOUT: First case study publication 16 month old female with infantile fibrosarcoma who had failed all standard chemotherapy regimens and had undergone 3 surgical resections Started on 100mg AED BID liquid formulation of larotrectinib > 90% reduction in tumor mass by end of cycle 1 Baseline End of cycle 1 End of cycle 2 Reference: Nagasubramanian et al. Pediatric Blood Cancer DOI /pbc 16

17 The path to SCOUT, pediatric phase I trial Nemours Children s Hospital Loxo Oncology FDA Nov 14-month-old girl, ETV6- NTRK3 rearranged IFS, refractory to chemotherapy and surgical procedures Compassionate use? Do what it takes to get access to therapy Expedite trial opening 20, Nov File pediatric IND 9, Dec Permission to Proceed 14, Dec Phase I trial open 21, Dec Treat first patient with kit formulation; starting dose based on SimCYP PK model Progressed/nonresponsive to available therapies; No standard or available curative therapy exists Subsequently granted request to waive exception three times Exhausted chemotherapy options; Available curative therapy would amputate or cause significant loss of function in an extremity 17

18 Pre-surgical use of larotrectinib in TRK fusion sarcoma 2 year old girl with progressive ETV6-NTRK3 infantile fibrosarcoma previously treated with 2 cycles of vincristine/ actinomycin-d/ cyclophosphamide progression amputation was only alternative cycles larotrectinib PR referred for surgery Baseline Start of Cycle 3 Pathologic CR with clear margins (R0 resection); >98% necrosis No functional deficit post-surgery Off larotrectinib x 8 months and no evidence of disease Data cut-off: 17 th July 2017 Courtesy of L. Mascarenhas, CHLA 18

19 SCOUT: Trial design Phase I Dose Escalation Refractory advanced solid and primary CNS tumors Rolling 6 dose escalation scheme RP2D Dose Expansion Phase 2 Locally Confirmed TRK Status Infantile fibrosarcoma Other extra-cranial, TRK fusion positive Primary CNS, TRK fusion positive Clinical trials travel service provides travel assistance for patients and caregivers 19

20 Maximum change in tumor size (%) Larotrectinib is highly effective in children with TRK fusions (INV) Non-TRK fusion TRK fusion non-trk fusion patients not shown due to clinical disease progression without post-baseline tumor measurements 2 TRK fusion patients not shown due to having non-measurable disease at baseline *Locally advanced patients who underwent surgery; INV = assessed by investigators * * * IFS Soft tissue sarcoma * Reference: Turpin et al. Pediatric Cancer Research: From Basic Science to the Clinic 2017 annual meeting, 4 th Dec

21 Larotrectinib is highly effective in children with TRK fusions TRK fusions IRC (n=17)* TRK fusions INV (n=17)* Non-fusions INV (n=7) Objective response rate (95% CI) 93% (68 100%) 93% (68 100%) 0 Partial response 80% 67%** 0 Complete response 13% 27% 0 Stable disease 7% 7% 0 Progressive disease % *2 patients not evaluable due to having non-measurable disease at baseline **Includes 2 patients with unconfirmed partial responses as of July 17, 2017, which were subsequently confirmed IRC = assessed by blinded independent review committee; INV = assessed by investigators Reference: Turpin et al. Pediatric Cancer Research: From Basic Science to the Clinic 2017 annual meeting, 4 th Dec

22 Non-TRK fusion TRK fusion Larotrectinib responses in children occur early and are durable # # # Treatment ongoing Surgery Pathologic complete response Post-surgery observation Start of complete response Start of partial response Treatment after surgery Non-measurable disease only Overall treatment duration (months) Reference: Turpin et al. Pediatric Cancer Research: From Basic Science to the Clinic 2017 annual meeting, 4 th Dec

23 SCOUT trial sites: Geographic footprint 18 sites open GR FR 9 sites open SP IT 1 site open AUS US US US 23

24 Larotrectinib clinical development in adult and pediatric TRK fusion cancers Adult phase I Age 18 years Advanced solid tumors TRK fusion status determined by local CLIA (or similarly accredited) laboratories Primary endpoint Best objective response rate (ORR) SCOUT: pediatric phase I/II Age 21 years Advanced solid tumors n=12 N=55 TRK fusion patients RECIST v1.1 per investigator assessment Secondary endpoints Duration of response (DOR) Progression-free survival (PFS) NAVIGATE: adult/adolescent phase II basket trial Age 12 years Advanced solid tumors TRK fusion positive Data cut-off: April 14, 2017 Safety Dosing Single-agent larotrectinib, administered predominantly at 100 mg BID continuously Treatment beyond progression permitted if patient continuing to benefit Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

25 Maximum change in tumor size (%) Efficacy of larotrectinib in TRK fusion cancers * *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; # Pathologic CR Note: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recorded. Patients with confirmatory response data available (n=50) Objective response rate (95% CI) 76% (62 87%) Partial response 64% Complete response 12% Stable disease 12% Progressive disease 12% # # Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

26 Maximum change in tumor size (%) Efficacy of larotrectinib regardless of age * *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; # Pathologic CR Note: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recorded. Adult patients Pediatric patients # # Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

27 Maximum change in tumor size (%) Efficacy of larotrectinib regardless of tumor type * Thyroid Colon Melanoma Soft tissue sarcoma Lung GIST Appendix IFS Breast Salivary gland Cholangiocarcinoma Pancreas *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; # Pathologic CR Note: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recorded. # # Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

28 Maximum change in tumor size (%) Efficacy of larotrectinib regardless of fusion partner * NTRK1 NTRK2 NTRK3 LMNA STRN ETV6 TPM3 TPM4 TPR CTRC PDE4DIP IRF2BP2 SQSTM1 PPL TRIM63 *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; # Pathologic CR Note: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recorded. # # Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

29 Duration of larotrectinib therapy Treatment after progression Treatment after surgery Treatment ongoing Time to first response Surgery Pathologic CR 93% of responding patients and 75% of all patients remain on treatment or underwent surgery with curative intent 0 Median time to response Overall treatment duration (months) = 1.8 months No progressions in central nervous system observed Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

30 Adverse events with larotrectinib therapy Treatment-emergent AEs (%)* Treatment-related AEs (%) Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total Fatigue Dizziness Nausea Anemia Vomiting Increased AST Constipation Cough Increased ALT Diarrhea Dyspnea (13%) patients required dose reductions all maintained tumor regression (1 CR, 5 PR, 1 SD) on reduced dose No discontinuations for adverse events Reference: Hyman et al. American Society of Clinical Oncology 2017 annual meeting, 3 rd June

31 LOXO-195 Larotrectinib LOXO-195 to Address TRK Acquired Resistance TRKA G595R Tumor type Fusion Resistance mutation LMNA-NTRK1 fusion colorectal Colorectal TPM3-NTRK1 TRKA G595R Colorectal LMNA-NTRK1 TRKA G595R NSCLC TPR-NTRK1 TRKA G595R Sarcoma TPM3-NTRK1 TRKA G595R IFS ETV6-NTRK3 TRKC G623R ETV6-NTRK3 IFS Cholangio LMNA-NTRK1 TRKA F589L * + GNAS Q227H TRK solvent front mutations detected in 5 of 6 patients with acquired resistance. First 2 patients successfully treated with LOXO-195. Baseline On LOXO-195 Treatment Oligometastatic progression, continue on larotrectinib * Gatekeeper mutation Reference: Drilon al. Cancer Discovery. 2017;7(9):

32 Larotrectinib: Achievements st Oncology Breakthrough Designation awarded for adults and pediatrics by the US FDA Oncology Breakthrough Designation awarded for a molecularly defined population by the US FDA Oncology Orphan Drug awarded for a molecularly defined population by the US FDA Real-time development of resistance mutation targeted salvage therapy 32

33 Larotrectinib: Sequence of events Breakthrough Therapy Designation Phase 1 study open Rare Pediatric Designation for infantile fibrosarcoma NAVIGATE open SCOUT open EMA PIP approval SCOUT: First EU site opened NDA rolling submission start First TRK fusion patient enrolled NDA dataset complete Hong et al. AACR-NCI- EORTC N=6 adult patients, 3 confirmed PR Hong et al. AACR N=7 adult patients, 6 confirmed PR Hong et al. ESMO-Asia N=8 adult patients, 7 confirmed PR Hyman et al. ASCO, combined analysis, N=55 Laetsch et al. ASCO, Pediatric Phase 1 analysis, N=17 DuBois et al. CTOS Pre-surgical use in locally advanced sarcoma Turpin et al. AACR-Pediatrics Updated pediatric P1 analysis, N=17 33

34 Larotrectinib: Lessons learned An effective drug has an easier path to tread, even when targeting a rare patient population Regulatory Agencies are highly collaborative when a new agent shows promise in areas of unmet medical need Comprehensive genomic tumor profiling can allow us to realize the long tail of precision medicine 34

35 Acknowledgements Patients and their families, many of whom traveled long distances to participate in these studies Avera Cancer Institute Lucile Packard Children's Hospital Sydney Children s Hospital Barts Health NHS Trust Royal London Hospital Massachusetts General Hospital The Finsen Centre Centro Integral Oncologico Clara Campal MD Anderson Cancer Center The Ohio State University Children's Hospital Boston MedStar Health Research Institute Thomas Jefferson University Children's Hospital of Los Angeles Memorial Hospital Universitaetsklinikum Heidelberg - Zentrum fuer Kinder- und Jugendmedizin ZIPO Cincinnati Children's Hospital Medical Center Memorial Sloan Kettering Cancer Center Universitätsmedizin Berlin Charite Campus Virchow-Klinikum Medizinische Klinik mit Schwerpunkt Kardiologie City of Hope National Medical Center National Cancer Centre University College Hospital Cleveland Clinic Nemours Children's Hospital University Hospital Southampton NHS Foundation Trust Dana-Farber Cancer Institute Olgahospital University Hospitals of Cleveland Dartmouth Hitchcock Medical Center Oregon Health and Science University UCLA Jonsson Comprehensive Cancer Center Fondazione IRCCS Istituto Nazionale dei Tumori Roswell Park Cancer Institute UCLA Medical Center Fox Chase Cancer Center Samsung Medical Center University of Chicago Fundacion Jimenez Diaz Sarah Cannon Research Institute University of Colorado Hospital Universitario Vall d'hebron Seattle Children's Hospital University of North Carolina Inova Health Care Services Seoul National University Hospital University of Pennsylvania Institut Bergonie Severance Hospital, Yonsei University Health System University of Pittsburgh Medical Center Institut Curie - Oncologie Medicale South Texas Accelerated Research Therapeutics Midwest University of Washington - Seattle Cancer Care Alliance Institut Gustave Roussy St. Jude Children's Research Hospital UT Southwestern - Medical Center Instituto Portugues de Oncologia do Porto Francisco Gentil St. Vincent's University Hospital Vanderbilt University School of Medicine John Theurer Cancer Center Stanford Cancer Center Wake Forest Baptist Medical Center West Virginia University Cancer Institute 35