Development of LOXO-101 in Adult and Pediatric Patients With Cancer

Transcription

1 Development of LOXO-101 in Adult and Pediatric Patients With Cancer Michael Craig Cox, PharmD, MHSc, BCOP Director, Clinical Development & Medical Affairs Loxo Oncology, Inc. 1

2 Thematic Convergence Underscores Loxo Oncology Strategy Growing data sugges/ng drug specificity leads to be6er pa/ent outcomes Clinical adop/on of mul/plex gene/c tes/ng to triage cancer pa/ents 2

3 What Is a Gene Fusion? (e.g., ETV6) (e.g., NTRK3) h6p:// /pancanfusv2/

4 How Can We Detect Gene Fusions? 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.

5 LOXO-101 is Highly Specific for TRK Receptors LOXO-101 has favorable TRK inhibitor properties: 1. High potency for TRKA, TRKB, TRKC Enzyme IC 50 of 11 nm, 5 nm, and 6 nm Excellent cell-based potency Proliferation IC 50 of 8 nm and 2 nm in MPRIP-NTRK1 and CD74-NTRK1 fusion cell lines Proliferation IC 50 of 6 nm in KM12 cell line (TMP3-NTRK1 fusion) LOXO-101 TRK 1 2. Limited inhibition of other kinases No inhibition of 229 other kinases at 1000 nm Weak inhibition of TNK2 (IC 50 > 1000 nm) 3. >100x selective for other kinases 4. >1,000x selective for other off targets IC 50 >10,000 nm for 75 diverse mammalian targets 1 TRKA and TRKB shown. Upstate kinase panel shown does not include TRKC. LOXO-101 shown to be equipotent for TRKC in other assays. 5

6 LOXO-101 In Vitro and In Vivo Activity IN VITRO: POTENCY IN TRK FUSION CELL MODELS; SPARES UNSELECTED CELL MODELS 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 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) Courtesy of the Doebele lab. Doebele et al. Cancer Discov Oct;5(10):

7 Partial List of Identified TRK Fusions 7

8 LOXO-101 Adult Phase 1 Study Design Ongoing dose escalation 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 DOSE COHORT PATIENTS ENROLLED 50mg QD 4 100mg QD 5 100mg BID mg QD 5 Data 150mg cutoff BID October 20, TOTAL 43 Data cutoff March 25, 2016 Hong D et al. Proc AACR Annual Meeting Abstr CT008 8

9 LOXO-101 Adult Phase 1 Interim Treatment-Emergent AEs, Regardless of Attribution to Study Drug DOSE 100 MG BID (N=24) TOTAL (N=43) Adverse Gr 3/4 All Gr Gr 3/4 All Gr Events (AEs)* n (%) n (%) n (%) n (%) Fatigue 0 5 (21%) 2 (5%) 14 (33%) Constipation 0 3 (13%) 1 (2%) 10 (23%) Dizziness 0 6 (25%) 0 10 (23%) Anemia 1 (4%) 4 (17%) 3 (7%) 8 (19%) Increased AST 1 (4%) 5 (21%) 4 (9%) 8 (19%) Cough 0 4 (17%) 0 8 (19%) Diarrhea 0 4 (17%) 0 8 (19%) Increased ALP 0 5 (21%) 1 (2%) 7 (16%) Dyspnea 1 (4%) 3 (13%) 1 (2%) 7 (16%) Nausea 0 4 (17%) 0 7 (16%) Abdominal pain 0 3 (13%) 1 (2%) 6 (14%) Increased ALT 1 (4%) 4 (17%) 2 (5%) 6 (14%) Anxiety 0 2 (8%) 0 5 (12%) Hypertension 0 4 (17%) 1 (2%) 5 (12%) Peripheral edema 0 2 (8%) 0 5 (12%) Pyrexia 0 2 (8%) 0 5 (12%) Vomiting 0 2 (8%) 0 5 (12%) Hyperkalemia 1 (4%) 1 (4%) 2 (5%) 3 (7%) Delirium 1 (4%) 1 (4%) 2 (5%) 2 (5%) Pleural effusion 1 (4%) 1 (4%) 2 (5%) 2 (5%) Syncope (5%) 2 (5%) *Treatment-emergent adverse events (reported by > 10% of total subjects) or any Grade 3-4 events that occurred in at least 2 patients. Hong D et al. Proc AACR Annual Meeting Abstr CT008 9

10 Best Response to LOXO-101 for Patients with TRK Fusions 100% 80% Stable disease Confirmed partial response Maximum Change in Tumor Size (%) 60% 40% 20% 0% -20% -40% -60% NSCLC TPR- NTRK % MASC ETV6- NTRK3 7+ MASC ETV6- NTRK3 10+ GIST ETV6- NTRK3 10+ Papillary Thyroid Cancer ETV6- NTRK3 Undifferen/ated SoY Tissue Sarcoma LMNA-NTRK1-80% -100% Note: Ongoing cycle number noted for each patient below each bar; 28-day cycles Hong D et al. Proc AACR Annual Meeting Abstr CT008 10

11 Patient #1: LMNA-NTRK1 fusion soft tissue sarcoma 42 yo female with undifferentiated sarcoma progressed through epirubicin, ifosfamide, sorafenib, and doxorubicin 100mg BID Rapid resolution of dyspnea and hypoxemia Confirmed partial response Currently on study in cycle 14 Study baseline Study cycle 3 day 1 Study cycle 13 day 1 Hong D et al. Proc AACR Annual Meeting Abstr CT008 11

12 Enriching for TRK Fusions DIPG and other High-Grade Gliomas 1 4% of DIPG and 10% of HGGs reported to have NTRK-1, -2, -3 fusions 40% (4/10) HGG in infants <3 Papillary thyroid cancer 2 7 of 28 younger pa&ents (25%) tested TRK fusion posi&ve Ages 6-18 yo 6 of 7 ages Infan&le Fibrosarcoma 3,4 >85% of tumors have ETV6-NTRK3 fusion Case reports of other NTRK fusion partners Congenital Mesoblas&c Nephroma 5 100% of cellular subtype exhibit ETV6-NTRK3 Sarcoma 6 TRK fusions may share myopericy&c/ haemangiopericy&c pasern seen by rou&ne histologic assessment 1 Wu G et al. Nat Genetics Prasad ML et al. Cancer Orbach D. E Journal Cancer Wong V. J Natl Cancer Inst Demellawy Pathology Haller F et al. J Pathol. 2016

13 LOXO-TRK Pediatric Phase 1 Objec/ves: Safety, PK Pa/ents: 1 month old 21 years old Solid tumors (allcomers), Primary CNS tumors, prior standard therapy AED - 75mg BID AED - 100mg BID AED 150mg BID AED 200mg BID Expansion cohorts at MTD to further characterize PK across age groups AED 50mg BID AED = Adult Equivalent Dose Rolling-6 Dose Escala/on Study Ini/ated 21 December 2015 Nagasubramanian R et al. Proc ASCO Abstr TPS10583

14 Patient #1: ETV6-NTRK3 Infantile Fibrosarcoma 16 mo female with infantile fibrosarcoma Dx in Feb 2015 S/P Vincristine, Dactinomycin, Clyclophosphamide ; Ifosfamide, Doxorubicin; Etoposide, Ifosfamide, Neupogen; Ifosfamide, Doxorubicin S/p Surgery x 3 100mg AED BID - liquid Improved engagement/ playfullness in cycle 1 Confirmed partial response Currently on study in cycle 5 Study baseline Study cycle 2 day 1 Study cycle 3 day 1 14 Nagasubramanian R et al. Ped Blood Cancer. 2016