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NGS Testing Helps to Identify New Treatment Opportunities for Advanced Solid Tumor Cancers Driven by Molecular Alterations
Audrey Thacker, Jessica Templer, Hany Magharyous, Pratik Multani, Jason Christiansen, Jennifer Lamoureux
Ignyta, Inc., 4545 Towne Centre Ct., San Diego, CA 92121 ASCLS 2017
NTRK, ROS1, ALK and RET fusions have been identified as oncogenic drivers in multiple solid tumors. Ingeneral, these gene alterations are rare, but targeted therapies are being developed that may provide newtherapeutic options for patients whose tumors harbor these alterations. However, in order to develop thesenew drugs, new methods must also be developed to efficiently and comprehensively identify appropriatepatients.Two clinical stage investigational small molecule tyrosine kinase inhibitors, entrectinib (RXDX-101) and RXDX-105, target TRK/ROS1/ALK and RET, respectively. The anti-tumor effects of entrectinib and RXDX-105 havebeen demonstrated in multiple preclinical models, including in cell lines and in murine patient-derived tumormodels, driven by NTRK, ROS1, ALK or RET fusions. Entrectinib and RXDX-105 exerted these potent inhibitoryeffects, in vitro and in vivo, in cancer models driven by NTRK, ROS1, ALK or RET alterations, irrespective oftheir histologies.Based upon these data, clinical trials are underway to study these two investigational agents and determinetheir safety and efficacy in molecularly selected patients. Patients with solid tumors containing NTRK, ROS1or ALK fusions are being enrolled in the ongoing STARTRK-2 trial of entrectinib (NCT02568267) and patientswith RET fusions are being enrolled in the ongoing Phase1/1b RXDX-105-01 trial of RXDX-105(NCT01877811). To date, both entrectinib and RXDX-105 have demonstrated durable RECIST responses in ahigh proportion of molecularly selected patients.Utilization of Next Generation Sequencing testing for alterations in NTRK, ROS1, ALK and RET has proven tobe a valuable tool in selecting patients with solid tumor malignancies, for whom promising new treatmentopportunities (such as entrectinib and RXDX-105) are being developed.
Abstract
Targeted Therapy Approach for Gene Fusions Leading to Cancer
Tumor Histology NTRK1 NTRK2 NTRK3 ROS1 ALK RET
Astrocytoma 3%a
Breast (Secretory) 92%b 0.1%
Breast (NOS) 2%
Cholangiocarcinoma4%c 9% 2%
CML <1%
Congenital Fibrosarcoma 90-100%d, e
Colorectal Cancer (CRC) <1%f, g, h <1%i 1-2% 1-2% 0.2%
Glioblastoma 1-3%j, k 1%
Head and Neck Cancer <1%i <1%i
Inflammatory MyofibroblasticTumor (IMT)
3%l
Melanoma (Spitz) 16%m 17% 10%
Mesoblastic Nephroma 90%d
Myelofibrosis <1%
Myosarcoma 1%i
Non-small cell lung cancer <1%h,n,o <1%i 1-2% 3-7% 1-2%
Papillary Thyroid 5-13%p 2-24%q,r,s 7% 6%
Pediatric Glioma 7% combinedt
Pediatric Sarcomas <1%u
Salivary Gland: Mammary Analog Secretory Carcinoma (MASC)
90-100%e,v
Salivary Gland-Not Otherwise Specified (NOS)
2%w
Sarcomas (including GIST) 1-9% 2-11% 2-3% 1-5%
Targeted Gene Alterations by Tumor Type
Target TRKA TRKB TRKC ROS1 ALK
IC50* (nM) 1.7 0.1 0.1 0.2 1.6
Entrectinib is an Investigational, CNS-active TRK, ROS1, and ALK Inhibitor
♦ Most potent, orally available pan-TRK-inhibitor in clinical development; active against most known TRK-resistant
mutants
♦ ~30x more potent against ROS1 than crizotinib
♦ Designed to cross blood-brain barrier (BBB) to address primary brain tumors and secondary CNS metastases
♦ Demonstrated rapid tumor response in preclinical models and molecularly selected patient populations
NGS Process Overview
The most frequent ( > 10% incidence) treatment-related adverse events were fatigue (44%), dysgeusia (41%),
paresthesia (28%), nausea (24%), and myalgia (22%)
The vast majority of treatment-related adverse events were Grade 1 or 2 in severity
The most frequent ( > 2% incidence) Grade 3 treatment-related adverse events were fatigue (4%) and anemia (3%)
Adverse events were reversible with dose modification
There was no evidence of cumulative toxicity, hepatic toxicity, or QTc prolongation
No responding patient has discontinued due to intolerability
Entrectinib Phase 1 Data
• RECIST responses were noted across 63% of patients (5 out of 8) with primary or metastatic TRK, ROS1, or ALK fusion-positive disease involving the brain
• 1 additional patient with BCAN-NTRK1glioneuronal tumor
• SD by RECIST (not validated for primary brain tumors)
• 60% by exploratory 3-D volumetric assessment by P. Brastianos MD, MGH
Best Response in TKI treatment-naïve NTRK-, ROS1-, and ALK fusion positive tumors (n=24)
Drilon, Siena at el, Cancer Discovery 2017
FusionConfirmed
Responses (n)ORR (%)
NTRK1/3 3/3 100%
ROS1 12/14 86%
ALK 4/7 57%
RXDX-105 Phase 1 Data
Baseline
Week 3
♦ 33 year old female patient with newly diagnosed EML4-RET Fusion-Positive NSCLC
♦ Target Lesion Response to RXDX-105
♦ 48% tumor reduction after 3 weeks on RXDX-105
♦ As of Cycle 8, patient continued to respond to RXDX-105 and was ongoing treatment with 78% reduction in tumor measurements from baseline
RXDX-105 Case Study
Source: Images provided by Memorial Sloan Kettering Cancer Center
Baseline Cycle 2
Conclusions
a: Jones-2013; b: Tognon-2002; c: Ross-2014; d: Rubin-1998; e: Knezevich-1998; f: Martin-Zanca-1986, g: Ardini-2014, h: Vaishnavi-2013; i: Stransky-2014, j: Fratini-2013, k: Kim-2014; l: Yamamoto-2015; m: Wiesner-2014; n: Zheng-2014; o: Farago-2015; p: Greco-2010; q: Leeman-Neill-2014; r: Ricarte-Filho-2013; s: Prasad-2016; t: Wu-2014; u: Morosini-2015; v: Bishop-2013; w: Weinreb-2013
RXDX-105 is a VEGFR-Sparing, Potent RET Inhibitor♦ RXDX-105 exhibits high potency against wild-type RET (biochemical IC50: 0.3 nM), RET fusions (IC50: 0.3-0.8
nM) and RET mutations (IC50: 5-15 nM)
♦ RXDX-105 has demonstrated potent antitumor activity in multiple patient-derived xenograft (PDX) models of RET fusion-positive cancers
♦ The Phase 1 dose escalation portion of the study has been completed with 55 patients enrolled across 8 dose cohorts; doses up to 350 mg, PO, QD were tested; an MTD based on DLTs was not determined
♦ Target efficacious exposures for RET inhibition based on animal models have been achieved in the clinical setting at doses at or above 150 mg, PO, QD
Best Response N = 9a Histology
Complete Response 1 mCRC
Partial Response 3 NSCLC
Unconfirmed PR 1 NSCLC
Stable Disease 1 NSCLC
Progressive Disease 2a NSCLC; mCRCa
Not Evaluable 1 NSCLC
Objective Response Rateb
NSCLC RET fusions 57%
mCRC RET fusions 50%
All RET fusions 56%
Best Objective Response of RECIST-Evaluable, RET Inhibitor-Naïve Patients with
RET Fusion-Positive Solid Tumors in Ph 1/1b
a1 patient with RET fusion-positive mCRC was treated in Phase 1, in addition to the 8 patients treated in Phase 1bbORR includes patients who received at least 1 study scan (including one patient with an uPR) or discontinued RXDX-105 due to PD or AE
Best Response to RXDX-105 in Ph 1/1b RET Inhibitor-Naïve Patients with RET Fusion-Positive Solid Tumors
Note: All patients received a starting dose of 275mg or 350mg, PO, QD, in the fed state.
* FISH positive, NGS pending** Early discontinuation due to adverse effects (AE)*** Unconfirmed partial response (PR)
Entrectinib Case Study
♦ 46 year old male patient with metastatic NSCLC, first diagnosed in November 2013
♦ 30 pack-year smoking history
♦ Prior therapies
♦ carboplatin/pemetrexed
♦ pembrolizumab
♦ docetaxel
♦ vinorelbine
♦ ECOG performance status of 2
♦ Required supplemental O2
♦ Significant pain and dyspnea due to widely metastatic disease
♦ Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases
♦ In hospice care
♦ Identified to have tumor harboring SQSTM1-NTRK1 fusion enrolled in Ignyta’s STARTRK-1 study at MGH in March 2015
Baseline(15-20 mets)
Day 26(CR)
Day 155(CR)
Images: Farago and Shaw, MGH♦ Next Generation Sequencing testing for alterations in NTRK, ROS1, ALK and RET has been shown to be an effective
method of selecting patients with solid tumor malignancies that are driven by fusions in these genes which allows fortreatment with molecularly targeted therapies.
♦ Both entrectinib and RXDX-105 are clinical stage investigational small molecule tyrosine kinase inhibitors that havedemonstrated rapid tumor response in molecularly selected patient populations.
♦ Entrectinib is a CNS-active TRK, ROS1, and ALK inhibitor that exhibits potent anti-tumor effects in patients withNTRK, ROS1, or ALK fusions.
♦ Clinical evidence of lung and brain tumor reduction in a male patient with metastatic NSCLCidentified as having an NTRK1 fusion.
♦ RXDX-105 is a RET inhibitor that has demonstrated potent anti-tumor activity in patients with RET fusions.
♦ Clinical evidence of tumor reduction in a female patient with NSCLC identified as having a RET fusion.
Total Nucleic Acid Extraction: Agencourt Formapure KitFFPE Slides
Sequencing on MiSeqCustom Informatics
Sample Extraction
Library Preparation
Sequencing/Analysis
Microdissection
RNA