Advancing Utility of OncoBEAM™ in Clinical Practice

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Advancing Utility of OncoBEAM™

in Clinical Practice

EQA - May 12, 2017, Napoli Frederick S. Jones, Ph.D.

Director, Medical Scientific Affairs - Sysmex Inostics

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What Does Sysmex Inostics Do?

Pharma/CRO Services (over 40,000 samples tested)

Biomarker Assay Development CDx Kit Development

Regulatory Registration & Approval cGMP Manufacturing

Commercialization

Clinical Products and Services

Assist in Therapy Selection Assessment of Drug Response Resistance and Recurrence Monitoring

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BEAMing Digital PCR

• 3 Flow Cytometry

Wild-type

Mutant

Pre-Amplification Emulsion PCR

Flow Cytometry Hybridization

»

BEAMing (Beads, Emulsions, Amplification, Magnetics) has shown efficacy in several therapeutic clinical trials as well as in oncology patient testing

applications.

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Sysmex Inostics OncoBEAM™ Assays for Cancer Therapy Selection and Monitoring

• 4 6/14/2017

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Concordance Between Tissue and Cell-Free DNA on Clinically Actionable Mutations

OncoBEAM™ Clinical Snapshot: Published Performance

Sources: Jeffers et al. (2013): Cancer Res. 73. SY 11 – 02; Thress et al. (2015): Lung Cancer. 90(3) : 509 – 15.; Jones et al. (2016): J Clin Oncol 34 (suppl; Abstract 11538); Higgins et al. (2012): Clin Cancer Res. 18(12) : 3462-9; Schadendorf, et al. (2015): Eur J Cancer. 51 : S685.

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Publications

0 10 20 30 40 50 60

2009 2010 2011 2012 2013 2014 2015 2016

# cumulative publications

Van Cutsem et al. 2015 Journal of Clinical Oncology

Tabernero et al.

2015 Lancet Oncology

Dawson et al. 2013 New England Journal of Medicine

Morelli et al. 2015 Annals of Oncology

Karlovich et al. 2016 Clinical Cancer Research

Diaz et al. 2012 Nature

Misale et al. 2012 Nature

Ciardiello et al. 2014 Journal of Clinical Oncology Sorich et al. 2015

Annals of Oncology Thress et al. 2015

Lung Cancer Oxnard et al. 2016

JCO

Spoerke et al. 2016 Nat Comun.

Toledo et al. 2016 Oncotarget

• 6 Schmiegel et al.

2017 Mol. Oncol.

Grasselli et al. 2017 Ann. Oncol.

Vidal et al. 2017 Ann. Oncol.

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Thank you!

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OncoBEAM™ Testing Centers

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USA

GCP, CLIA testing facility Baltimore

EMEA

33 IVD testing centers

JAPAN

GCP testing facility, Kobe 1 IVD testing center GERMANY

GCP testing facility Hamburg

LATIN AMERICA 2 IVD testing centers

ASIA PACIFIC

4 IVD testing centers CHINA

GCP testing facility, Shanghai 1 IVD testing center

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Sysmex Inostics OncoBEAM™ RAS Kit (Joint Collaboration: Sysmex | Merck)

Bringing Service based Assays to Hospitals Globally

LDT to IVD

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Applications in Metastatic Colorectal Cancer

NRAS

• Codon 12

• Codon 13

• Codon 59

• Codon 61

• Codon 117

• Codon 146 KRAS

• Codon 12

• Codon 13

• Codon 59

• Codon 61

• Codon 117

• Codon 146

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34 mutation expanded RAS panel

• 10 6/14/2017

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RAS mutation status

Anti-EGFR therapy

Tissue

Blood

WT

Chemotherapy (e.g. FOLFIRI)

MUT

Monitoring of RAS mutation status

T0 T1 T2

MUT

No tissue

Therapy Selection

Anti-EGFR Re-challenge?

Blood-based RAS Testing mCRC Therapy Selection and Detection of Resistance

RAS Resistance Detection

»

Concordance of RAS status in blood vs tissue

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Concordance Study Results

Tissue SOC RAS result

OncoBEAM™

RAS CRC Plasma RAS

Result

Mutation detected

No mutation

detected Total

Mutation detected 112 7 119

No mutation detected 9 110 119

Total 121 117 238

Overall Agreement = 93.3%

Positive Percent Agreement = 92.6%

Negative Percent Agreement = 94.0%

Cutoff Setting

» RAS Tissue Mutation Rate: 50.8%

» RAS OncoBEAM^TM Blood Mutation Rate: 50.0%

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» Ref: OncoBEAM RAS CRC CE-IVD kit Instructions for use (IfU)

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Schmiegel & Scott et al, (2017) Mol Oncol. 11, 208-219

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PFS RAS WT by BEAMing plasma PFS RAS WT by tissue testing

10.3m (95% CI 7.7-25) 10.3m (95% CI 7.7-19.8)

Clinical Relevance: PFS 1^st line RAS wild-type population (N=34)

Vidal et al., 2017 Ann. Oncol. Manuscript in press

Clinical Performance: Blood versus Tissue

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Clinical Performance: Blood versus Tissue

• 15 Graselli et al. (2017) Ann. Oncol. Manuscript in press

Clinical Relevance: PFS and OS in RAS wild-type RAS population

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Summary of OncoBEAM plasma testing at Baseline

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Next Steps: Monitoring

1. Is the therapy working?

2. Is the cancer progressing?

- Compare to radiologic:

Faster?

More reliable in some cases?

Less expensive?

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» Prospective trial to monitor 25 treatment-naïve KRAS tissue wt patients undergoing first-line cetuximab-FOLFIRI therapy

» 22 mutations in KRAS/NRAS/BRAF/PIK3CA genes were monitored (2,178 analyses in total)

» Results:

‒ 100% concordance of BEAMing plasma and tissue mutation results at baseline using FDA-approved tumor tissue tests (Ion Torrent and Cobas)

‒ BEAMing results provide the earliest indication of patient outcome (which is confirmed later by imaging)

Longitudinal Mutation Analyses Correlated with Clinical Outcome (Toledo et al. 2016)

Toledo et al. (2016) Oncotarget, 5.

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Close Monitoring of Plasma Mutational Status Reveals Dramatic Differences in Outcomes

»

1. An abrupt increase in cfDNA mutation levels precedes clinical deterioration 2. Continued wt status or low mutation levels are favorable

1 Toledo et al. (2016) Oncotarget, 5.

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Plasma Monitoring by BEAMing Reveals

Disease Progression in Advance of Imaging

surgery

alive Rx

surgery

» Abrupt increase of KRAS mutation 6 months prior to evidence of metastases from imaging

» PIK3CA mutation profile mirrors tumor burden, predicts recurrence 3 months in advance of imaging

1 Toledo et al. (2016) Oncotarget, 5.

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Vidal & Muinelo et al., 2017 Ann. Oncol. Manuscript in press

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Anti-EGFR Different Therapy

Weeks of treatment

ctDNA

..patients with RAS- WT mCRC…

…who progress and have

detectable RAS mutations during therapy…

…which

decrease during a pause in anti- EGFR therapy …

…who may respond to anti-EGFR re-challenge?

Emerging Application: Patient Selection for Re-challenge with Anti-EGFR Therapy

Can Liquid Biopsy identify…

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Longitudinal analysis of RAS mutations in serial plasma samples of 18 patients that progressed on anti- EGFR therapy showed emergence of acquired RAS mutations in 7 patients (39%) at time of progression

Vidal & Muinelo et al., 2017 Ann. Oncol. Manuscript in press

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KRAS Exon 3 mutation

Low frequency RAS first detected

Imaging:

2 year tracking of plasma RAS status during anti-EGFR and anti-VEGF therapy with OncoBEAM

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- OncoBEAM RAS testing is a less invasive, highly sensitive alternative to tissue-based RAS testing to determine therapy selection.

- OncoBEAM RAS is useful to monitor emergence of resistance in mCRC patients treated with anti-EGFR.

- OncoBEAM RAS is useful to evaluate early response to treatment and to gauge when treament might be interrupted and/or

switched.

- Data generated from Testing Centers using RAS kit IVD workflow shows harmonized of performance.

Conclusions - OncoBEAM in CRC

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Applications in Lung Cancer

»

multiplexed to run with 2 mL of plasma EGFR

• Deletion 19

• L858R

• T790M

• C797S

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EGFR mutation status

Tissue

Blood

Emerging Mutation Detection Directs Therapy in NSCLC

TKI therapy

WT

Chemotherapy

MUT

Monitoring for emerging T790M resistance mutation

T0 T1 T2

Blood

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• 28 02/04/2015

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Performance of different EGFR plasma assays

• 29 Source: Thress et al, Lung Cancer 2015

Cobas® Therascreen™ ddPCR™ OncoBEAM™

Exon 19 deletion

Sensitivity 86% 82% - 93%

Concordance 89% 87% - 95%

L858R

Sensitivity 90% 78% 90% 100%

Concordance 97% 95% 97% 95%

T790M

Sensitivity 41% 29% 71% 71%

Concordance 57% 48% 74% 70%

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• 30 02/04/2015

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OncoBEAM Identifies Timing of C797S Mediated Acquired Resistance - Astellas (ASP8273) Project

• 31 02/04/2015

» Emergence of EGFR C797S coincided with the re-emergence of EGFR T790M and/or activating mutations in plasma in patients with acquired resistance

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Blood based testing first…

FFPE, formalin-fixed paraffin- embedded

A. Conventional paradigm

Acquired resistance to EGFR-TKI

All patients undergo biopsy, FDA approved FFPE assay

for T790M

Third gen. EGFR-TKI T790M

positive T790M

negative Chemotherapy

B. Proposed paradigm for use of plasma diagnostics

Acquired resistance to EGFR-TKI

FDA approved plasma assay for T790M and sensitising mutations

T790M negative

T790M positive

Skip biopsy, start 3^rd gen.

EGFR-TKI

Biopsy, FDA approved FFPE assay for

T790M

T790M positive

T790M negative

3^rd gen.

EGFR-TKI Chemotherapy

Paradigm Shift is Occurring

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High Sensitivity Matters

• 33 Sources: Schmiegel et al. (2017): Mol Oncol. 11(2) : 208 – 219; Saunders et al. (2016): Annals of Oncology 27 (6) : 149 – 206; Vidal et al. (2017):

J Clin Oncol 35 (suppl 4S; Abstract 607); Oxnard et al. (2016) J Clin Oncol 34(28):3375-3382; Baselga et al. (2015): Oral presentation. SABCS, Abstract S 6 – 01

48% of patients with MAFs <1% 42% of patients with MAFs <1%

15%

27%

22%

36%

Distribution of EGFR MAFs in EGFR-mutant NSCLC patients

with T790M+ resistance

0.02-0.1% 0.1-1% >1% >5%

22%

23%

32%

Distribution of PIK3CA MAFs in HR+/HER- recurrent breast

cancer patients

0.02-0.1% 0.1-1% >1% >5%

45% of patients with MAFs <1%

13%

35%

14%

38%

Distribution of RAS MAFs

in mCRC patients

0.02-0.1% >0.1-1% >1% >5%

Distribution of RAS MAFs in mCRC patients

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Refine the management of metastatic disease and hone clinical decision points to rapidly determine therapy efficacy

»

Utility of OncoBEAM