JIOINO AMDP,

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Disclaimer
The views and opinions expressed in thispresentation are those of the presenter and should
not necessarily represent the views and opinions ofthe PMDA.

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From CDx Era to Oncology Panel Era
The first time approval of
oncology panel in Japan?
Report of Cancer
Genome medicalconsortium

Approval of
Trastuzumab
2000

Approval of
Gefitinib for EGFRNotification on CDx
TK positive NSCLC& relevant drugs

2005
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2010


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2015
Nature 2014 507: 294

20183

Approved CDxs in JapanCDx Trade Name

Corresponding drug

Biomarker

POTELIGEO TEST IHC/POTELIGEO TEST FCM mogamulizumab

CCR4 protein

Cobas BRAF V600 mutation test

vemurafenib

BRAF mutation

Histofine ALK iAEP kit

alectinib

ALK protein

Vysis ALK Break Apart FISH probe kit

crizotinib and alectinib

ALK fusion

THxID BRAF kit

dabrafenib/trametinib

BRAF mutation

Cobas EGFR mutation test v2.0

osimertinib

EGFR mutation

OncoGuide AmoyDx ROS1 Gene Fusions
Detection Kit

crizotinib

ROS1 fusion (RNA)

PD-L1 IHC 22C3 pharmDx [Dako]pembrolizumab

PD-L1 proteinVentana OptiView ALK (D5F3)

crizotinib and ceritinib

ALK protein

MEBGEN RASKET-B kit

cetuximab and panitumumab

KRAS and NRAS mutation

BRACAnalyis CDxolaparib

BRCA1 and BRCA2
mutation

Oncomine Dx Target test

dabrafenib/trametinib

BRAF mutation

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What is the essence of CDx?
Post Market of Drug

Clinical trial of DrugLab test1

Lab test2

Lab test3

Clinical validation via aconcordance study
Reference standard
Dx system in JapanLab test4

Reimbursement
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What is the essence of CDx?
Post Market of Drug

Clinical trial of DrugLab test1

Lab test2

Follow-on CDx

Clinical validation via a concordance study

Lab test3

Reference standard
Dx system in JapanLab test4

Reimbursement
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Issues of CDx in Japan
lOne CDx corresponds to One clinical trial.
üNot “One CDx to One drug”, nor “One CDx to Onebiomarker”.
üe.g. ALK, BRAF, etcüDevelopment of “Follow-on CDx for multiple drugs”
based on the external concordance study is encouraged.

lIs it the lab-test for subtype diagnostics or
identification of the therapeutic responder?
üAs the biomarker for drug response is established inlong-term clinical use, it could be a test item in a routine
medical practice.
üe.g. HER2 for breast cancer
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From One Gene test to Multiplex NGS
test – Benefits for Patients
Commercialization of NGS is making the followingchanges:lEnabling to obtain a lot of genome information on
driver genes including SNV, Ins/Dels, CNA andstructural variants.
lEnabling precision medicine based on therapeutic
response factors and prognostic factors in additionto CDx.

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From One Gene test to Multiplex NGS
test – Challenges in Lab tests
Clinical implementation of NGS is making thefollowing changes:
lDrastic increase of information for annotation andinterpretation of variants requisites the reference
databases.
lEstablishment of clinical field for the genome
precision medicine which interprets the genome
profile and selects optimal medication.
lEmergence of various type of diagnostic system, i.e.
single-site assay performed at marketing
authorization holder’s lab.
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9Case1: BRACAnalysis CDxTM

BRACAnalysis

lThis assay identifies breast cancer patients with deleterious
or suspected deleterious germline BRCA mutation from
more than 19,000 variants.
lApproved as CDx system for Olaparib in 2018 in the categoryof software as a medical device.
lAnnual postmarketing report on
summary of newly
variant classificationis requested.

)A
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B4RC
M
: 0. 2 5: 104/. 01 4/1

8. 410Case2: Oncomine





TM

Dx Target Test

Dx Target Test CDx

lThis assay is indicated to CDx on 3 genes (BRAF, ROS1, EGFR).
Also indicated to qualitative diagnostic tests of 23 genes forpatients who have already been considered for all
appropriate therapies in US SSED.
lApproved as CDx system for Tafinlar/Mekinist in Japan in
2018. The test result of other genes on the panel could beprovided for clinical research use only.
lFirst NGS-based CDx in Japan.

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Case3: NCC Oncopanel
lThis NGS-based IVD system is developed mainly by theNational Cancer Center, and has received designation underthe Sakigake Designation System in 2017.
lThis assay detects SNV, Ins/Dels, CNA and generearrangements of 114 driver genes.
114 mutationamplification (whole exon)
ABL1
ACTN4
AKT1
AKT2
AKT3
ALK
APC
ARAF
ARID1AARID2ATM
AXIN1
AXL
BAP1
BARD1
BCL2L11/BIM
BRAF
BRCA1
BRCA2
CCND1
CD274/PD-L1
CDK4
CDKN2ACHEK2CRKLCREBBPCTNNB1/b-catenin
CUL3
DDR2
EGFR
ENO1
EP300
ERBB2/HER2
ERBB3
ERBB4
ESR1/ER
EZH2
FBXW7
FGFR1
FGFR2
FGFR3
FGFR4FLT3
GNA11
GNAQ
GNAS
HRAS
IDH1IDH2
IGF1R
IGF2
IL7R
JAK1
JAK2
JAK3KDM6A/UTX
KEAP1KITKRAS
MAP2K1/MEK1MAP2K2/MEK2MAP2K4MAP3K1MAP3K4MDM2MDM4MET
MLH1MTOR
MSH2MYC
MYCN

NF1NFE2L2/Nrf2
NOTCH1NOTCH2NOTCH3NRAS
NRG1NTRK1NTRK2
NTRK3
NT5C2PALB2PBRM1PDGFRAPDGFRBPIK3CAPIK3R1PIK3R2
POLD1POLEPRKCIPTCH1PTEN
RAC113 fusion genes
RAC2RAD51C
RAF1/CRAF
RB1RETRHOAROS1SETBP1SETD2SMAD4SMARCA4/BRG1SMARCB1SMO
STAT3STK11/LKB1TP53
TSC1VHLALKAKT2AKT3BRAFERBB4FGFR2
FGFR3
NRG1
NTRK1
NTRK2
PDGFRARETROS1

G
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10412Case4: FoundationOne CDx

TMlThis assay is NGS-based IVD test that can detect genetic
mutations in 324 genes and two genomic signatures i.e. MSIand TMB in any solid tumor type.
lThis assay provides the information of 6 CDx genes and canidentify which patients with any of five tumor types may
benefit from 17 different FDA-approved targeted treatment
options.
lSubmitted to MHLW in March2018 and under the review ofPMDA.

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Framework of cancer genome precision
medicine in Japan
11 core hospitals for cancer
genome precision medicine

obtain the genome variants
data using the oncology panel
annotation of variants using
databases and report thecomprehensive genome profile

Approx. 100 associate
hospitals for cancer genome
precision medicine

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Finalizing the report of theevidence-based categorizationof variants by expert panel

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CDx vs Comprehensive Gene
Profile (CGP)
Indication for use
CDx
Assumed Medication Established medication
with strong evidence
Output of theDirectly judge thediagnostics systemeligibility forcorresponding
approved drug
Assumed medical
institutes ofimplementation
Major Regulatory
evaluation points

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Positive and negative
predictive values



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CGP
Medication with potential
evidence
Interpreted by the expert panel
for the clinical significance
Medical institutes with expert
panels, i.e. core hospitals forcancer genome precision
medicine
Analytical performance based on
validated accuracy,
reproducibility, repeatability etc.
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Typical Schematic Flow of Medication
using Oncology Panels
DNA sequencing

Variant call

Annotation

Oncology Panel

GeneX: c.2611C>TGeneY: c.1652A>G
GeneZ: ............

Software

DNA sequencer

Bioinformatics Pipeline

Mutation
Database

SNV, Ins/Del, CNV,
Rearrangements

ReportGeneA:
SNV: xxxx
GeneB:
Indel: xxxx…

Approved as IVD Device

Knowledge
Database

ReportPatient
GeneA:#:
Tier1:xxxxxxxx
SNV: xxxx
Tier2:xxxx….
GeneB:
Indel: xxxx…

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Interpretation
by Expert Panel16

Points to Consider in Reviewing
Oncology Panels
DNA sequencing

Variant call

Oncology Panel

GeneX: c.2611C>TGeneY: c.1652A>G
GeneZ: ............

Annotation
552Software
52DNA
5 sequencer
52
SNV, Ins/Del, CNV,
Bioinformatics Pipeline
55Rearrangements
225552 25Report
5GeneA:
SNV: xxxx
5GeneB:

Approved as IVD Device

5 52018/6/30

225525

ReportPatient
2GeneA:#:Tier1:xxxxxxxx
SNV: xxxx
Tier2:xxxx
22GeneB: ….

Indel: xxxx…

52
5 552525

Indel: xxxx…

H

MJDA?

2552

Mutation
Database
5Knowledge
Database
2Interpretation
by Expert Panel
17

Review Policies

5 -55 5 ---. 5-

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D-

55518

Analytical Validity
lAccuracy should be stated in terms of Positive
Percentage Agreement and Positive Predictive
Value using reference samples or reference
methods for each mutation type (e.g. SNVs,Ins/Dels, CNAs, structural variants) .
lHow to select the reference method (orthogonalmethod) in Japan?
Example: FoundationOne CDx SSED Table 6

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What would happen after the clinicalimplementation of Oncology Panels?
Marker X-positive patients were selected for the phase 3 study
in the development of new drug. Marker X has already beenmeasured using approved oncology panel to obtain thecomprehensive gene profile (CGP). Is it required to apply newCDx for marker X for approval application of the new drug?
New CDx for marker X is approved to identify thepatients for the new drug. Marker X has already beenmeasured using approved oncology panel to obtain theCGP. Is it possible to identify the patients for the new
drug based on the result report of the CGP without using
CDx for marker X?
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CDx vs Comprehensive Gene
Profile (CGP)
Indication for use
CDx
Assumed Medication Established medication
with strong evidence
Output of theDirectly judge thediagnostics systemeligibility forcorresponding
approved drug
Assumed medical
institutes ofimplementation
Major Regulatory
evaluation points

2018/6/30

Positive and negative
predictive values

CGP
Medication with potential
evidence
Interpreted by the expert panelfor the clinical significance
Medical institutes with expert
panels, i.e. core hospitals forcancer genome precision
medicine
Analytical performance based on
validated accuracy,reproducibility, repeatability etc.
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After the clinical implementation ofOncology Panels
The concept of CDx never changes
Post Market of Drug
Clinical trial of DrugLab test1

Lab test2

Lab test3

Clinical validation via aconcordance study
Reference standard
Dx system in JapanLab test4

Reimbursement
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CDx in the Oncology Panel Era?
Post Market of Drug

Clinical trial of DrugNGS 1

NGS 2

NGS 3

Clinical validation via aconcordance study?

NGS 4?

AdditionalReimbursement 
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Near Future World With No More CDx
NGS-1

Clinical trial of Drug
NGS-1

NGS-2

NGS-2

NGS-3

Post Market NGS-4

NGS-3

NGS-5

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Conclusion
lAlong with the promotion of the cancer genome
precision medicine, movement to provide theapproved oncology panel in medical practice isprogressing.
lReview policies for evaluation of the oncology
panel in PMDA are being established.
lThe emergence of oncology panels does notchange the regulatory need for CDx system in Japan,
however the standardization of panels in the future
could lead to the equivalence of NGS-based tests
and possibly the shift in CDx-based regulatory
framework.
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