1293TiP

Axl family

MET family

PDGFR family

• In xenograft models of NSCLC where METex14del and MET amplification are putative oncogenic drivers, MGCD265 induces robust tumor regression

• Amethyst NSCLC is a global, open-label, parallel arm, Phase 2 trial evaluating the tumor response to MGCD265 in patients with locally advanced, or metastatic NSCLC exhibiting an activating genetic alteration of MET

• This Phase 2 parallel-arm study will be conducted in four cohorts of patients having genetic tumor alterations activating MET:

mutations in tissue amplification in tissue mutations in ctDNA amplification in ctDNA

• The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1

• A Bayesian Predictive Probability Design is applied independently to each cohort of up to 45 patients, assuming p0=0.20 and p1=0.40

KEY INCLUSION CRITERIA:

• Histologically-confirmed NSCLC with metastatic or unresectable, locally advanced disease

• Receipt of at least one prior platinum-containing chemotherapy regimen in the advanced disease setting

• Genetic MET alteration in tumor tissue or blood

• ECOG performance status 0, 1, or 2

• Adequate bone marrow and organ function

METHODSBACKGROUND• MET is a receptor tyrosine kinase for hepatocyte growth factor (HGF) and activates cellular signalling pathways that are important for tissue homeostasis

• Genetic alterations in MET, including mutations and/or gene amplification, occur in approximately 7% of NSCLC and function as oncogenic drivers that promote cancer development and progression1

• Various mutations located at or near the exon 14 splice site of the MET gene (METex14del) result in loss of expression

This non-expressed region encodes the Y1003 CBL ubiquitin ligase regulatory binding site that is required for CBL-dependent MET degradation and signal attenuation

Absence of this receptor domain results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC

STUDY OBJECTIVESPRIMARY OBJECTIVE:

• To determine the tumor response to MGCD265 in selected patient population

SECONDARY OBJECTIVES:

• To evaluate the safety and tolerability of MGCD265 in selected population

• To evaluate secondary efficacy endpoints with MGCD265 treatment in selected population

• To assess correlation between selected tumor gene alterations using different analytical techniques in tumor tissue and ctDNA

• To assess change in genetic alteration status in ctDNA with MGCD265 treatment over time in the selected population

Anti-Tumor Activity in Xenograft Models

KEY EXCLUSION CRITERIA:

• Prior treatment with a small molecule or antibody inhibitor of MET or HGF

• Prior positive test for EGFR mutation or ALK gene rearrangement

• Symptomatic or uncontrolled brain metastases

• Unstable angina pectoris, congestive heart failure of NYHA Class ≥ 3, or QTc > 480 msec

DOSING REGIMEN AND ASSESSMENTS:

• Patients receive oral MGCD265 twice daily (BID) in cycles of 21 days

• Routine safety assessments performed throughout the study

• Disease assessments using RECIST version 1.1

• PK parameters evaluated after single and repeated administration

• ctDNA collection at key time points throughout study

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Gastric Cancer PDX Model with METex14del gene and MET Amplification

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Lung Adenocarcinoma PDX Models with METex14del gene and increased MET Copy Number

Amethyst NSCLC Trial: Phase 2 Trial of MGCD265 in Patients (pts) with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with Activating Genetic Alterations in Mesenchymal-Epithelial Transition Factor (MET)

SUMMARY• MGCD265 is a potent and selective inhibitor of MET

• MGCD265’s unique binding mode resulting in inhibition of wild-type and a broad range of mutant MET species may be clinically advantageous

• The Amethyst NSCLC trial

evaluates the activity of MGCD265 in patients with NSCLC with genetic alterations in MET

provides clinical trial evidence for the potential use of ctDNA in patient selection

• Enrollment began in April 2016 and is ongoing in the United States, Canada, South Korea, Taiwan, Australia, Hungary, Poland and Italy

REFERENCES1. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225(1):1-26. doi:10.1016/j.canlet.2004.09.044

2. Phase I study of receptor tyrosine kinase (RTK) inhibitor, MGCD265, in patients (pts) with advanced solid tumors. J Clin Oncol 33, 2015 (suppl; abstr 2589)

Amethyst NSCLC Trial (265-109) NCT02544633

L. Bazhenova1, R. Mehra2, T. Nagy3, L. Cavanna4, J.-S. Lee5, J.-Y. Han6, H.K. Kim7, B. Halmos8, M. Shum9, M. Schreeder10, I. Rybkin11, F. Badin12, R. Mena13, P. Jänne14, J. Christensen15, V. Tassell15, R. Chao15, D. Faltaos15, D.-W. Kim16 1University of California San Diego, La Jolla, CA, USA; 2Fox Chase Cancer Center, Philadephia, PA, USA; 3Országos Onkológiai Intézet, Budapest, HU; 4Azienda Unità Sanitaria Locale di Piacenza-Ospedale Guglielmo da Saliceto, Piacenza, IT; 5Seoul National University Bundang Hospital, Seongnam-si, KR; 6National Cancer Center, Goyang, KR; 7Saint Vincent Hospital, Suwon-si, KR; 8Montefiore Medical Center, Bronx, NY, USA; 9Innovative Clinical Research Institute, Whittier, CA, USA; 10Clearview Cancer Institute, Huntsville, AL, USA; 11Henry Ford Health System, Detroit, MI, USA; 12 Baptist Health Lexington, Lexington, KY, USA; 13Providence Health and Services, Burbank, CA, USA; 14Dana Farber Cancer Institute, Boston, MA, USA; 15Mirati Therapeutics, Inc., San Diego, CA, USA; 16Seoul National University Hospital, Seoul, KR.

Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster

Study Trial Information: www.mirati.com

• MGCD265 is a potent, orally available, small molecule RTK inhibitor

• MGCD265 inhibits mutant and wild type forms MET and of Axl, both of which mediate signals for cell growth, survival, and migration

• Binding of MGCD265 to MET occurs within a hydrophobic pocket induced in the DFG “out” conformation and thus inhibits both wild-type and mutant species including those harboring mutations in the activation loop

• MGCD265 has induced confirmed tumor responses in patients with MET-altered NSCLC treated with MGCD265 in the Phase 1 setting2

Gen

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Pre-

Scre

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A: MET mut (tissue) Initial n=10

B: MET amp (tissue) Initial n=10

C: MET mut (ctDNA) Initial n=10

D: MET amp (ctDNA) Initial n=10

Continuous Reassessment:

Up to 45 Patients Per Arm

Expansionn~55

Expansionn~55

Amethyst NSCLC Study Design

MGCD265

MGCD265 Target Profile