Regulatory Perspectives on ctDNA-Based DrugDevelopment（ctDNAによる患者選択への期待と課題）
Office of In Vitro Diagnostics
Pharmaceuticals and Medical Devices Agency

Naoyuki YABANA

2021/6/12

第28回抗悪性腫瘍薬開発フォーラム

Disclaimer
The views and opinions expressed in this presentation are those of thepresenter and should not necessarily represent the views and opinionsof the PMDA.

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ctDNA assays are implemented in medical practice

Early Detectionof Resistance

Early Diagnosis
Nature Reviews Cancer 17 pp 223-238 (2017)

Detection of Molecular
Residual Disease2021/6/12

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CDx and/or CGP

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FoundationOne Liquid CDx (F1CDxL) was approvedin March 2021

MHLW
APPROVED

Modified from https://www.foundationmedicine.in/foundationone-liquid-cdx.html

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Critical Issues in Review of F1CDxL (1)⚫It was required to provide appropriate information to
the medical community on when and in whatsituations the use of liquid biopsy is recommended
for testing for solid tumors instead of tissue biopsy.
⚫Joint taskforce of JSMO, JSCO and JCA released “Policy
recommendations for the appropriate use of ctDNA-basedgenome profiling tests” in Jan 2021 .
⚫There are no restrictions on intended use compared to F1CDx,
and it is possible to use F1CDx and F1CDxL at the discretion of
the physician based on guidance and policy recommendationsof joint TF.
Product photos from https://www.foundationmedicine.in/foundationone-liquid-cdx.html

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Critical Issues in Review of F1CDxL (2)SNV

Approved

Approved

IndelsApproved

Approved

Copy number
Amplification

Approved

Not Approved

Rearrangement

Approved

Approved

MSI

Approved

Not Approved

TMBApproved

Not Approved• Not included in the scope ofapproval, but can bereported for research use at
the request of a physician.
• Further accumulation ofclinical data using liquidbiopsy is awaited to establish
the clinical validity.
Product photos from https://www.foundationmedicine.in/foundationone-liquid-cdx.html

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Approved CDx using Liquid Biopsy
CDx

BM (drug)

Major evaluated studies in the review

Cobas EGFR Mutation
Test v2

EGFR (Osimertinib)

Efficacy of ctDNA-positive sub-population of AURA2 study.
Comparison with paired tissue biopsy test results of AURA2 study.

EGFR (Erlotinib, Gefitinib,Afatinib)

Comparison with paired tissue biopsy test results of ENSURE study (clinical study ofErlotinib).

Oncobeam RAS CRC

KRAS, NRAS （Cetuximab,Panitumumab）

Comparison with paired tissue biopsy test results collected from medical
institutions in Japan

ArcherMET

Met exon14 (tepotinib)

Efficacy of ctDNA-positive patients of VISION study.
Comparison with paired tissue biopsy test results of VISION study.

F1CDxLEGFR (Erlotinib, Gefitinib,Afatinib, Osimertinib)

Concordance study with approved liquid-biopsy-CDx

ALK (Alectinib, Crizotinib,Ceritinib)

Efficacy of ctDNA-positive sub-population of B-FAST study (clinical study ofAlectinib)

ROS1 (Entrektinib)

Comparison with paired tissue biopsy test results of STARTRK-2 study.
Efficacy of ctDNA-positive sub-population of STARTRK-2 study.

NTRK (Entrektinib)

Comparison with paired tissue biopsy test results of STARTRK-2 study.
Efficacy of ctDNA-positive sub-population of STARTRK-2 study.

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Approach to CDx Approval for Liquid Biopsy⚫For new drugs, it is strongly encouraged to obtain data on efficacy in
ctDNA-positive populations.

⚫Consistency of paired liquid and tissue biopsy test results in thetarget population of a drug could be the basis for approval of liquidbiopsy as CDx.
⚫For drugs developed in the old days when liquid biopsy was a dream,clinical utility of liquid biopsy may be extrapolated to drugs with thesame mechanism of action, since the inclusive relation of ctDNApositive populations in tissue-biopsy positive populations could bethe same.
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The Next Trend : NGS-based MRD test assays⚫Detect MRD and stratify for high or low risk of recurrence.
⚫Provide adjuvant treatment to high risk patients.
Relapse-free survival

MRD detected
ctDNA negative

ctDNA positive

Postoperative
ctDNA MRDAnalysis

NoAdjuvant
treatment

Monitoringtime
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CtDNA Assays for CDx vs MRD (1)Target ofdetection

CDx for malignant tumor drugs
MRD
Driver gene that closely related
Genes not related drugs
to the MOA of relevant drug
Usually one gene (except forTMB, MSI, etc.)

Usually multiple genes(personalized in some cases)

Follow-on products can be
developed based on analyticalequivalence.

It is difficult to develop afollow-on product.

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CtDNA Assays for CDx vs MRD (2)CDx for malignant tumor drugs

Primary
Intended use

Identification of responders ofthe drug

No CDx product can beapproved unless the relevantdrug is approved.

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MRD
Provide the prognostic risk ofthe patient
Identification of patients for
adjuvant treatment

MRD product can be approved
based on the prognostic
performance.
11Treatment to MRD positive patients:
Vision of the Future
MRD Assay product 1
positive

Regimen A

Study X

MRD Assay product 2
positive

Regimen A

Study YMRD Assay product 3
positive

Regimen A

Study Z

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Treatment to MRD positive patients:
Alternative Vision of the Future
MRD Assay product 1
positive
MRD Assay product 2
positive
MRD Assay product 3
positive

Regimen AStudy X

The critical question is whether
Product 2 and Product 3 can beconsidered clinically equivalent toProduct 1.

High Risk of Recurrence
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Relapse-free survival

Treatment to MRD positive patients:
Is MRD test qualitative or semi-quantitative?
No clinical recurrence, but the
ctDNA level is highctDNA negative

ctDNA level is moderate

ctDNA positive
ctDNA level is close to the LOD

High risk

Qualitative
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Which populations are likely
to benefit from treatment?

Low risk

Semi-Quantitative?
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Conclusion and Perspectives⚫With the approval of the ctDNA-based CGP in Japan, we can expect
further utilization of liquid biopsy and accumulation of evidence forpatient identification using ctDNA. CtDNA-based CDx is also
expected to increase.
⚫Clinical implementation of MRD is also expected, and it will be
important to build consensus among stakeholders on how togeneralize MRD test results and evidence of drugs for ctDNApositive patients.
⚫Regardless of CDx or MRD, in order for a drug to be approved for
ctDNA-positive patients, the diagnostic product must be approved,
and this should be carefully considered during development.
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