Abstract

•  Rearrangements in NTRK1, NTRK2, and NTRK3 that lead to constitutively-active TRKA, TRKB, and TRKC receptors are oncogenic and prevalent in a wide array of tumor types, including lung adenocarcinoma, thyroid, head and neck cancer, glioblastoma, and others

•  NTRK1 and NTRK3 fusions with various partner genes have been described in 2-3% of papillary thyroid carcinomas and are mutually exclusive of other known oncogenic mutations

•  LOXO-101 demonstrates potent and highly-selective inhibition of TRKA, TRKB, and TRKC over other kinase- and non-kinase targets

•  LOXO-101 demonstrated robust inhibition of tumor growth in xenograft models, acceptable pharmaceutical properties, and safety in nonclinical models

•  LOXO-101 was generally well tolerated with the most common adverse events being Grade 1 and 2 fatigue, dizziness and anemia; no study drug related SAEs have been reported; the MTD has not yet been reached

•  As of 29 June 2015, one patient with a known LMNA-NTRK1 fusion has shown a dramatic and sustained response after treatment at 100mg BID

Summary

Study Objectives

To determine the safety of oral LOXO-101, including dose-

limiting toxicity (DLT), in adult patients with an advanced solid

tumor, characterize the pharmacokinetic (PK) properties, and to

identify the maximum tolerated dose (MTD) and/or the

appropriate dose of LOXO‑101 for further clinical investigation.

LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models.

LOXO-101

Introduction: The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3, respectively), and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Gene rearrangements resulting in mis-expression of fusion products that include the TRK kinase domain have been observed in diverse tumor types and may contribute to tumorigenesis (Vaishnavi, Cancer Discov 5:25, 2015). NTRK1 and NTRK3 fusions with various partner genes have been described in 2-3% of papillary thyroid carcinomas and are mutually exclusive of other known oncogenic mutations (TCGA, 2014 and data on file). LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in preclinical models. Methods: We are performing a Phase 1, multicenter, open-label, 3+3 dose-escalation study of LOXO-101 to assess safety and tolerability. Results: Data from 15 patients evaluated across 3 dose cohorts were reviewed. LOXO-101 was generally well tolerated with the most common adverse events being Grade 1 and 2 fatigue, dizziness and anemia. Pharmacokinetic assessment demonstrated that maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. Exposure increased in approximate proportion with dose and was similar on Day 1 and Day 8 of repeated dosing in all subjects, and biologically relevant plasma levels have been achieved. Conclusions: LOXO-101 is well tolerated at doses for which biologically relevant plasma levels are achieved. The activity of LOXO-101 will be assessed in thyroid cancer patients with NTRK gene fusions in ongoing studies.

LOXO-101 is highly selective for TRKA, TRKB, and TRKC

•  No inhibition of >200

other kinases at 1000

nM

•  Weak inhibition of TNK2

(IC50 > 1000 nM)

•  >100-fold selective for

other kinases

•  1,000-fold selective for

>75 non-kinase targets

(A) LOXO-101 caused inhibition of tumor growth at doses of 20 to 200 mg/kg/day; (B) Inhibition of tumor growth was associated with dose-dependent reduction in pTRKA and pERK

Time (Days)

Tum

or V

olum

e (m

m3)

0 7 14 21

0

1000

2000

3000

10 mg/kg BID

20 mg/kg QD

30 mg/kg BID

60 mg/kg QD

100 mg/kg BID

200 mg/kg QD

Vehicle Control

LOXO-101 Treatment

A

0

50

100

0.01

0.1

1

10

Dose of LOXO-101 (mg/kg, PO)

pTR

KA

or

pER

K(P

erce

nt o

f C

ontr

ol, m

ean±

SEM

)

Concentration of LO

XO

-101 in Plasm

a andTum

or (µ g/mL or

µ g/g, mean

± SEM)

pTRKApERK

Vehicle 10

Plasma Level (µg/mL)Tumor Level (µg/g)

20 60 200

B

Methods

Study Design Phase 1, multicenter, open-label, 3+3 dose-escalation and safety study, with expansion cohorts for TRK-selected patients Drug Treatment LOXO-101 administered either QD or BID doses for continuous 28-day cycles. Individual patients will continue daily LOXO-101 dosing until disease progression, unacceptable toxicity, or other reason for treatment discontinuation Pharmacokinetics LOXO-101 concentrations quantified in plasma by a validated LC-MS/MS on Days 1 and 8 of Cycle 1

Dose Escalation Relapsed/refractory

Solid Tumors Progressed on SOC

ECOG 0-2

TRK Fusion positive

TRK Mutation / Alteration

Locally Confirmed TRK Status

Phase I Dose Escalation Phase I Dose Expansion

3+3 Design

RP2D

LOXO-101, A Selective Pan-TRK Inhibitor for patients with TRK-alterations

Marcia Brose1, Todd M. Bauer2,3, Howard A. Burris, III2,3, Robert C. Doebele4, Anna F. Farago5, Alice T. Shaw5, Brian B. Tuch6, Michael C. Cox6, David S. Hong7 1University of Pennsylvania, Philadelphia, PA 2Sarah Cannon Research Institute, Nashville, TN; 3Tenessee Oncology, PLLC, Nashville, TN; 4University of Colorado, Aurora, CO; 5Massachusetts General Hospital, Boston, MA; 6Loxo Oncology, South San Francisco, CA; 7MD Anderson Cancer Center, Houston, TX

386

Selection of Identified TRK Fusions

Characterization of Trk Fusions in Papillary Thyroid Cancer

NTRK  Gene   Fusion  Partner  (N=13)  NTRK1   IRF2BP2  (n=2),  TFG  (n=1),  TPM3  (n=1),  

SQSTM1  (n=1)  &  SSBP2  (n=1)  

NTRK2   none  

NTRK3   ETV6  (n=6)  &  RBPMS  (n=1)  

An analysis of publically-available TCGA gene expression data (RNA-Seq) from 513 papillary thyroid cancer tumors was

performed with Omicsoft’s OncoLand software. The analysis revealed 13 in-frame fusion transcripts putatively harboring the

full kinase domain of NTRK1, NTRK2 or NTRK3.

Dose- and Schedule-Dependent Inhibition of Tumor Growth and pTRKA in 3T3-TRKA Allografts

Dose- and Schedule-Dependent Inhibition of Tumor Growth in KM-12 Allografts

LOXO-101 caused inhibition of tumor growth at doses of 200 mg/kg/day in either single dose or split dosing

Baseline Characteristics

Characteristics Subjects (n=15) Median age (range), years 57, (38-76)

Sex Male 8

Female 7

Race White 12

Black 3

Tumor Type

Colorectal carcinoma 2

Head and neck (MASC, synovial sarcoma, squamous cell) 3 (1,1,1)

Lung (NSCLC, mesothelioma) 3 (2,1)

Appendiceal peritoneal carcinomatosis 1

Anal 1

Thyroid (follicular) 1

Thymus 1

Pancreatic 1

Melanoma 1

Soft tissue sarcoma 1

ECOG Status 0 7

1 8

Prior systemic anticancer therapy alone, n (%) 10 (67%)

Prior radiation and systemic anticancer therapy, n (%)* 4 (27%)

Median number of regimens (range)* 3 (0-6)

TRK-fusion positive 1 (LMNA-NTRK1 fusion soft tissue sarcoma)

*One patient received radiation therapy alone

Interim Results (Data as of 25 March 2015)

Seven SAEs were reported in four patients and were considered unrelated to study drug: pneumonia, bile duct obstruction, malignant neoplasm progression, pleural effusion, syncope

At the 100-mg BID dose level, one DLT occurred, delirium (Grade 3, deemed unrelated to study drug), which resolved within 72 hours; dose was reduced to 100 mg QD without recurrence

Summary of Treatment-Emergent Adverse Events

Dose: Total

(n=15)

Adverse Events (AEs)*

All Grades Grade 3-4

n (%) n (%) Fatigue 7 (47%) 1 (7%)

Dizziness 4 (27%) 0

Anemia 5 (33%) 2 (13%)

Constipation 3 (20%) 0

Dry mouth 3 (20%) 0

Diarrhea 2 (13%) 0

Nausea 2 (13%) 0

Vomiting 2 (13%) 0

Chills 2 (13%) 0

Pyrexia 2 (13%) 0

ALP increased 2 (13%) 0

Hyper-glycemia 2 (13%) 0

Hypokalemia 2 (13%) 0

Peripheral edema 2 (13%) 0

Syncope 2 (13%) 2 (13%)

Cough 2 (13%) 0

Rash 2 (13%) 0

AST increased 1 (7%) 1 (7%)

Delirium 1 (7%) 1 (7%)

Pneumonia 1 (7%) 1 (7%)

*Treatment-emergent adverse events (reported by > 10% of total subjects) or any Grade 3-4 events; patients were on study between 8 to 64 days

Study baseline Study cycle 3 day 1

LMNA-NTRK1 Fusion Soft Tissue Sarcoma Response (Scans as of 29 June 2015)

MP  

Doebele et al, Cancer Discovery. July 2015. Published OnlineFirst July 27, 2015; doi: 10.1158/2159-8290.CD-15-0443

Study cycle 5 day 1