私はこう考える - 医薬品医療機器総合機構treatments in adult and pediatric patients...

Dec 20th, 2019

私はこう考えるCDx規制の評価点・問題点と取扱い案

Takayuki YOSHINO, MD, PhDDirector, Department of Gastroenterology and Gastrointestinal Oncology,National Cancer Center Hospital East (NCCE), JapanCo-principal investigator, SCRUM-Japan

PMDAワークショップ「がんゲノム医療実装を見据えたコンパニオン診断薬等の規制のあり方」

アカデミアセッション

DISCLOSURE INFORMATION

Takayuki Yoshino

- Institutional financial interests

Novartis Pharma K.K.

MSD.K.K.

Sumitomo Dainippon Pharma Co., Ltd.

CHUGAI PHARMACEUTICAL CO., LTD.

Sanofi K.K.

DAIICHI SANKYO COMPANY, LIMITED

PAREXEL International Inc.

ONO PHARMACEUTICAL CO., LTD.

GlaxoSmithKline K.K.

Boehringer Ingelheim Japan, Inc.

- Personal financial interests,

CHUGAI

Takeda

Eli Lily

Merck Biopharma

- Non-financial interests,

None

- Other

None

Key Word グループ化CDx

分析性能が確認されていれば，今はCompletely agree

These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.

International Collaboration for HER2+ mCRCAmong Japan, US and Korea

Fuji S, ….., Yoshino T. JCO Precis Oncol. 2019 in press

The consensus diagnostic criteria for HER2+ mCRC

• IHC 3+

or

• IHC 2+ and FISH HER2/CEP17 ratio ≥ 2.0

Tumor content >10% for surgically resected specimens(separate quantity criteria were established for biopsy specimens)

We were able to verify the HER2 classification consistency between CNV by NGS and IHC/FISH by harmonizing diagnostic criteria for HER2+. This strategy can help establish diagnostic criteria for HER2+ cancer by allowing for different methodologies to be used for pts screening for trial eligibility.

1.5

1.25

1.00

0.75

0.50

0.25

Log

GC

N

3.00

2.50

2.00

1.50

1.00

0.50

0.00

Log

CN

V

P < 0.0001 r = 0.90P < 0.0001

HER2- HER2+ HER2- HER2+

3

2.5

2

1.5

1

0.5

00 0.5 1 1.5

Log

CN

V

Log GCN

2.50

2.00

1.50

1.00

0.50

0.00

Log

CN

V

P = 0.0003

HER2- HER2+

2.50

2.00

1.50

1.00

0.50

0.00

Log

GC

N

P = 0.0002

HER2- HER2+

r = 0.973

2.5

2

1.5

1

0.5

00 0.5 1 1.5

Log

CN

V (

OC

A)

Log GCN

Exploratory cohort (Japan), N=475 Validation cohort (Korea), N=16

The CNV in cross-validation of two NGS panels showed strong correlation (r: 0.98, P < 0.0001). The CNV in patients fulfilling the consensus criteria was more than 4.0 in all cases, providing the accuracy of the IHC/FISH criteria and cross-validation of NGS panels.

4

Tissue-based


NGS以外の検査（例えばIHC/ISH）も含めることを推奨したい


Future Directionは?


Tumor-agnostic SpacectDNA TestVSQ

FDA firstly approves cancer treatment for any solid tumor with a specific genetic feature

Yoshino T. ESMO-Asia 2019

Tumor-agnostic

Drug approval Status so far

• US

– Pembrolizumab for MSI-H tumours on May 23, 2017 (No CDx)

– Nivolumab+Ipilimumab for MSI-H mCRC on July 10, 2018 (No CDx)

• Japan

– Pembrolizumab for MSI-H tumours on December 21, 2018 (CDx; Tissue MSI Promega Kit)

• Taiwan

– Nivolumab+Ipilimumab for MSI-H mCRC on May 14, 2019 (No CDx)


Tumor-agnostic

Results: Primary and Secondary endpoints

N = 435

• Sensitivity : 11 / (0+11) =100%

• Specificity : 424 / (424+0) =100%

Standard method

Negative (MSS/MSI-L) Positive (MSI-H)

Testing method

Negative (MSS/MSI-L) 424 0

Positive (MSI-H) 0 11

• Concordance rate : (424+11) / (424+0+0+11) =100%

• Positive predictive value : 11 / (0+11) =100%

• Negative predictive value : 424 / (424+0) =100%

Primary endpoint

Secondary endpoints

Tissue MSI Promega Kit

Bando H, Yoshino T. Cancer Science 2018 Tissue-based

Tumor-agnostic

Scientific Plausibility; Are biology between MSI-H CRC and Non-CRC the same or different?

◆ MSI-H cancer, regardless of tumor histology, is associated with a high mutational burden (hypermutatedphenotype)

◆ High mutational burden leads to high neoantigen expression

◆ High neoantigen expression leads to autologous immune recognition of cancer cells

◆ By blocking PD-1 on tumor neoantigen-specific T cells, pembrolizumab can activate anti-tumor immune responses

◆ Hypothesis: PD-1 blockade can restore effective anti-tumor immunity in MSI-H cancer, regardless of cancer type

Jonathan C. Dudley et al. Clin Cancer Res 2016;22:813-820


Tumor-agnostic

13

MOSAIC Algorithm using WES data

MSI Assessment by Using NGS Data

Hause RJ, et al. Nat Med 2016. Bonneville R, et al. JCO Precis Oncol 2017. Middha S, et al. JCO Precis Oncol 2017.

MANTIS Algorithm using WES data

MSI sensor Algorithm using MSK-IMPACT data


FoundationOneⓇ CDx にも含まれる

Tumor-agnostic

Tissue-based

14

Data from Dec 2018 to Aug 2019

RWD after CDx Launch

Post-marketing commitment 1 MSI-H/ MMR-D in Asian Patients with Cancer

Results will be disclosed at an upcoming international meeting!


Tumor-agnostic

15

Published at 24th October, 2019

Post-marketing commitment 2JSCO-led Collaborative GLs across JPN Clinical Oncology Societies

Clinical Practice Guidelines for Tumor-Agnostic Treatments in Adult and Pediatric Patients with Advanced Solid Tumors toward Precision Medicine

Led by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO), cooperated by The Japanese Society of Pediatric Hematology/Oncology (JSPHO)

e Position Paper in JSCO at Mach, 2019

Provisional Clinical Opinion For The Diagnosis And Use Of Immunotherapy In Patients With Deficient DNA Mismatch Repair Tumors

MSI-H

MSI-H

NTRK


Tumor-agnostic

http://www.jsmo.or.jp/en/




JSCO/ESMO/ASCO/JSMO/TOS International consensus conference recommendations for tumour-agnostic treatments in patients with solid tumours

ObjectivesThe ultimate goal is to develop ‘the international expert opinion paper for tumor-agnostic treatments in patients with advanced solid tumors’.

Clinical questions (CQs) regarding MSI / MMR /NTRK tests and how this will influence the treatment and management for patients with MSI-H / dMMR / NTRK fusion–positive solid tumors.

26 October 2019 Preparation Meeting in JPN

27 October 2019 Experts Face-to-Face Meeting in JPN

November 2019 1st Presentation at ESMO Asia 2019

December 2019 1st draft manuscript

January 2020 Final approval from all the authors

1Q 2020 Publication in the Annals of Oncology

Post-marketing commitment 3Ongoing JSCO/ESMO-led International Collaboration

Chaired by Drs. Takayuki Yoshino and Jean-Yves DOUILLARD

Tumor-agnostic


⇒Publication of editorial materials in the Ann Oncol (ESMO), IJCO (JSCO), JCO (ASCO) and Journal of cancer research and practice (TOS) by each Society Presidents



JSCO ESMOTakayuki Yoshino (JSCO Project Leader)

Yuko Kitagawa (JSCO President)

Kazuhiro Yoshida (JSCO 2019 Annual Meeting Congress

President)

Yasuhiro Kodera (JSCO Guidelines Committee Chair)

Hiroya Taniguchi (JSCO Expert)

Yoichi Naito (JSCO Expert)

Saori Mishima (JSCO Expert)

Jean-Yves Douillard (ESMO CMO)

Josep Tabernero (ESMO President)

Andres Cervantes (ESMO Educational Chair)

George Pentheroudakis (ESMO Guidelines Committee Chair)

Fabien Calvo (ESMO Precision Medicine Working Group Member)

Klizia Marinoni (ESMO Scientific Coordinator)

ASCO JSMOHoward Burris (ASCO President)

Michael J. Overman (ASCO Guidelines Committee Member)

Ashish Saxena (ASCO Guidelines Committee Member)

Eishi Baba (JSMO Guidelines Committee Chair)

Masayuki Takeda (JSMO Expert)

TOS OthersLi -Tzong Chen (TOS President)

Kun-Huei Yeh (TOS Expert)

Keisuke Kurimoto (JSCO observer)

Manabu Futamura (JSCO Observer)

Nobuhisa Matsuhashi (JSCO Observer)

Takao Takahashi (JSCO Observer)

Anne Kinsella (Medical Writer)

Experts identified by each Asian Society


世界の潮流

MSI/MMR Part MSI / MMR should be tested prior to or during the standard treatment for advanced solid

tumour. [LoE: V, GoR: A] Validated NGS is recommended for testing either upfront or when IHC is equivocal or not

available. [LoE: III, GoR for testing: B]

NTRK Part NTRK fusion testing should be considered prior to or during the standard treatment for

advanced solid tumour. [LoE: V, GoR: B] NGS which detects NTRK fusion is recommended for testing NTRK fusion. [LoE: V, GoR: C]

結果；NGS検査を治療開始前または治療中に推奨している。

Tumor-agnostic



Challenges in drug development for a tumor-agnostic indication

• Study design for providing evidence of clinical efficacy (vs traditional randomized controlled studies)

• Identification of study population

What we learned from the Tumor-agnostic Approval Goal is to identify patients most likely to benefit from treatment

The increasing number of novel targets for ADC will likely cross many tumor histologies. ADCs targeting HER2 are in clinical trials against a variety of receptor expressing cancers, and the opportunity for tumor agnostic development seems very plausible. The era of focusing on the tumor’s molecular biology has arrived and will forever alter our approach to drug development.


Tumor-agnostic

DS-8201a Structure and Mechanism of Action (MoA)

12

3

45

6

7

Propriety drug-linker and payload

Conjugation chemistryThe linker is connected to the cysteine residue of the antibody

Payload (Dxd)Exatecan derivative

Cysteine residueDrug-Linker

Cys

Study Design

HER2-statuscentrally

confirmed

HER2-positive mCRC (IHC 3+ or IHC 2+/ISH+)

DS-8201a 6.4 mg/kg q3wkn=50

Cohort A

HER2-expressing mCRC(IHC 2+/ISH-)

DS-8201a 6.4 mg/kg q3wkn =20

Cohort B

HER2-expressing mCRC(IHC 1+)

DS-8201. 6.4 mg/kg q3wkn=20

Cohort C

Cohorts B and C will open for enrollment depending on therisk/benefit assessment in cohort AEfficacy Outcomes with DS-8201a in HER2-expressing

Solid Tumors in the Ongoing Phase 1 Trial (April, 2018 cutoff)5

Confirmed

ORRa

Confirmed DCRa

(95% CI)a

PFS Median

(95% CI), mo

HER2+ breast cancerb 54.5% (54/99) 93.9% (93/99) NR

HER2+ gastric cancerb 43.2% (19/44) 79.5% (35/44) 5.6 (3.0, 8.3)

Other HER2-

expressing/mutated38.7% (12/31) 83.9% (26/31) 12.1 (2.7, 14.1)

aSubjects who had ≥2 postbaseline scans, had progressive disease, or discontinued

treatment for progressive disease or any other reason prior to second postbaseline

scan.bIHC 3+ or IHC2+ and ISH+.

Primary Endpoint Secondary Efficacy Endpoints

• ORR (proportion who achieved

a best overall response of CR or

PR) assessed by the

independent radiologic facility

review based on RECIST

version 1.1 in Cohort A

• OS

• PFS

• DCR

• DoR

• ORR based on RECIST version

1.1 in Cohorts B and C

• ORR assessed by the

investigator based on RECIST

version 1.1

.

8

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

Ch

an

ge

fro

m b

as

eli

ne

(%

)

C o lo re c ta l

N S C L C

O th e r

Other Cancers

N = 37

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

W e e k s

Ch

an

ge

fro

m b

as

eli

ne

(%

)

C o lo re c ta l

N S C L C

O th e r

Payload with a different MoA High potency of payload Payload with short systemic half-life Bystander effect Tumor-selective cleavable linker Stable linker-payload High drug-to-antibody ratio

T Yoshino et al. ESMO-GI 2018 #P-295. and ESMO 2018

DS-8201a, a HER-2 targeting ADC, in pretreated HER2+ mCRC

International Phase 2 trial incl. EU, US and Asia.

PI. Yoshino T, SC. Grothey A and Siena S

HER2

Metastatic Disease


Potential Candidates – Tumor-agnostic Approach

ALK BRAF BRCAness FGFR HER2 HER3 homologous recombination deficiency (HRD) KRAS G12C RET ROS1 Tumor mutation burden (TMB)-high Platinum-sensitive

etc


Tumor-agnostic

22

A Comprehensive Liquid Biopsy

GI-SCREEN GOZILA Project

Guardant360 ctDNA panel v2.10:All guideline and emerging biomarkers in one test

26

AKT1 ALK APC AR ARAF ARID1A ATM BRAF BRCA1 BRCA2

CCND1 CCND2 CCNE1 CDH1 CDK4 CDK6 CDKN2A CTNNB1 DDR2 EGFR

ERBB2 ESR1 EZH2 FBXW7 FGFR1 FGFR2 FGFR3 GATA3 GNA11 GNAQ

GNAS HNF1A HRAS IDH1 IDH2 JAK2 JAK3 KIT KRAS MAP2K1

MAP2K2 MAPK1 MAPK3 MET MLH1 MPL MTOR MYC NF1 NFE2L2

NOTCH1 NPM1 NRAS NTRK1 NTRK3 PDGFRA PIK3CA PTEN PTN11 RAF1

RB1 RET RHEB RHOA RIT1 ROS1 SMAD4 SMO STK11 TERT**

TP53 TSC1 VHL

AR BRAF CCND1 CCND2 CCNE1 CDK4 CDK6 EGFR ERBB2 FGFR1

FGFR2 KIT KRAS MET MYC PDGFRA PIK3CA RAF1

ALK FGFR2 FGFR3 RET ROS1 NTRK1

Point Mutations and Sp lice Site-Disrupting Alterations – 73 Genes

Indels – 23 Genes

ATM APC ARID1A BRCA1 BRCA2 CDH1 CDKN2A EGFR ERBB2 GATA3

KIT MET` MLH1 MTOR NF1 PDGFRA PTEN RB1 SMAD4 STK11

TP53 TSC1 VHL

Amplifications – 18 Genes

Fusions – 6 Genes

Key Additional inclusionTumor Mutational Burden (bTMB)Microsatellite instability Status (MSI)

Metastatic Disease

Liquid-based

G360

GOZILA Enrollment (As of Oct, 2019)CRC/non-CRC/Non-GI Cancer N

CRC Colorectal cancer 851 851

Non-CRC

Pancreatic cancer 478

1349

Gastric cancer 338

Biliary tract cancer 238

Esophageal cancer 152

Hepatocellular cancer 42

Small intestine cancer 23

GIST cancer 13

Neuroendocrine tumor 46

Appendiceal cancer 10

Anal canal cancer 6

Other GI cancer 3

Non-GIBreast cancer 1

3Others 2

Total 2203

Median time intervals from blood collection to reporting: 8 days Yoshino T. ESMO 2019 Revised

Metastatic Disease

Liquid-based

G360

24

Cases with MET amp (primary tissue, before treatment)

CRC (N = 1354 pts)

CNV>7: 3 pts (0.2%)

The frequency of de novo alternations of MET is extremely low.

In cases with MET amp, MET amp was mutually exclusive with mutations in RAS, BRAF and with ERBB2 amplification.

MET Clonal Evolution by Anti-EGFR mAb

1. Bardelli A, et al. Cancer discovery 2013 2. Raghav K, et al. Oncotarget 2016

Mishima S,…., Yoshino T, Strickler J. ESMO 2019

Tissue-basedとLiquid-based testsのconcordance試験の限界を示唆

Tissue-basedvs.

Liquid-based

Metastatic Disease

GOZILA Project | IITs* based on tissue- and Liquid Bx-based screening

CRC cohort, N = 1,500No history of anti-EGFR, N = 500

Refractory to anti-EGFR, N = 500

Chemo-naïve, N = 500

HER2 amplification

BRAF V600E MT

BRAF non-V600E MT

MET amplification

RAS WT

Trastuzumab + Pertuzumab(TRIUMPH)

Eribulin (BRAVERY)

Encorafenib + Binimetinib+ Cetuximab (BIG BANG)

Cabozantinib + Panitumumab(METBEIGE)

Re-challenge with anti-EGFR mAb(PURSUIT)

GOZILA Study

Non-CRC cohort, N = 1,500 Gastric cancer, N = 550

Esophageal cancer, N = 400

Hepatocellular carcinoma, N = 100

Biliary tract cancer, N = 150

Pancreatic cancer, N = 100

Neuroendocrine tumor/carcinoma, N = 50

GIST, N = 100

Others, N = 50

ctDNA analysis

(Guardant360)

ctDNA analysis

(Guardant360)

bTMB-High Nivolumab (bTMB-H basket)

SCRUM-Japan GI-SCREEN

Nationwide GenomeScreening Project

25

Nakamura Y and Yoshino T. Oncologist 2018 Revised.

Non-GI Cancer cohort, N = 1,000

HER2 amplification DS-8201a (HERB)

Any FGFR alteration TAS-120 (TiFFFANY)

HER2 amplification DS-8201a (HERALD)

ROS1 fusion Brigatinib (Barossa)

Tumor-agnostic approach

Organ-Specific approach

Pan Cancer

G360

• Each arm to have a junior/senior investigator leadership team• Flexible design: arms open and close with best available science

*Investigator-initiated Trial Yoshino T. ESMO 2019

Metastatic Disease

Liquid-based

TRIUMPH; PROGRESSION-FREE SURVIVAL

WITH TRASTUZUMAB AND PERTUZUMAB

Tissue positive ctDNA positive

Median PFS,

months (95% CI)

All

ctDNA RAS/BRAF/PIK3CA/BRAF WT

ctDNA RAS/BRAF/PIK3CA/BRAF MT

4.0 (1.4-5.6)

5.6 (2.8-7.7)

1.4 (0.5-1.8)

Median PFS,

months (95% CI)

All

ctDNA RAS/BRAF/PIK3CA/BRAF WT

ctDNA RAS/BRAF/PIK3CA/BRAF MT

4.0 (1.3-5.6)

5.6 (1.3-6.2)

1.4 (1.2-1.8)

No. at Risk

Quadruple WT

Any MT

* Including one patient without a ctDNA result

No. at Risk

All*

11 10 7 02

0 0 005

17 11 7 02

All

Quadruple WT

Any MT

15 9 6 02

11 9 6 02

0 0 004

Nakamura Y, Yoshino T.: ESMO 2019 526PD

100%

80%

60%

40%

20%

0%

0 2 4 6 8

Time (months)

All (N = 17)

ctDNA RAS/BRAF/PIK3CA/

ERBB2 WT (N = 11)


ERBB2 MT (N = 5)

100%

80%

60%

40%

20%

0%

0 2 4 6 8

Time (months)

All (N = 15)


ERBB2 WT (N = 11)


ERBB2 MT (N = 4)

Tissue-basedvs.

Liquid-based

G360

Preliminary Results; Higher Enrollment Rate with Use of Guardant360

in GOZILA Trial over Tissue: equivalent objective response rates

27

Yoshino T, et al. ESMO 2019

GI

SCREEN

(Tissue)

GOZILLA

(Blood)5.4%

2.2%

As of April, 2019, % of screened

Trial enrollment rates Overall best response

126/5740

60/1103

n=52

n=38

PR

SD

PD

Yoshino T. ESMO 2019

19% of pts

with

drivers

41% of pts

with

drivers

Results will be disclosed at upcoming international annual meeting.

Single institutional Experience

Metastatic Disease

Liquid-based

28

Future Perspective of ctDNA-guided Cancer Genome Medicine in mCRC

1st line 2nd line Later line・・・・

Alteration + Alteration + Alteration + Alteration +

Matched Clinical trial or SOC



Matched Clinical trial or SOC or BSC only

Liquid-basedTissue- or liquid-based Liquid-based Liquid-based

Significant progress made towards implementation of ctDNA• Advances in technology

Clinical Applications• Useful tool for studying molecular mechanisms of resistance

Metastatic Disease

Liquid-based

SCRUM-Japan GENESIS Project

Study participation

facility

Study participation

facility

Study participation

facility

Study participation

facility

Study participation

facility

SCRUM-Japan GENESIS

Collaboration

hospital

Public interest

group

Government

agency

Research

institute

Pharmaceutica

l

companies

On premise environment

Cloud environment

AI oncology integrated

analysis data store

Basic info. Clinical info. Specimen

info.

Chemotherapy

history

Inspection

result info.Genetic info.

Medical

historyMedication

historyTreatment

info.Adverse event

Medical image

info.・・・

・・・

Extract necessary information for development Storage / backup of analysis results

30 SCRUM-Japan Genesis

Various AI algorithms will be created based on SCRUM-Japan

Yoshino T, et all. Oral presentation at Google Cloud Next ’19

https://www.youtube.com/watch?v=iO4x1aJw_Jc

VSQ


SCRUM-Japan Genesis31

SCRUM-Japan GENESIS Virtual Sequencing Project

FFPE section image and genome

analysis results, collected by

SCRUM-Japan

Virtual Sequencing algorithm

HE staining NGS sequencing Genetic alteration identificationdissection

Virtual Sequencing

Development of prompt & accurate genome alteration estimation method

using AI image processing

Learning by

Training data

Validation by

Verification

data

Verify the accuracy of the

algorithm using verification

data

Gene X

Gene Y

Gene Z

……

…



VSQ


SCRUM-Japan Genesis32

Preliminary result for gene X

Only a previous study+ showed an AUC from 0.640 to 0.856 to predict for 10 genes in patients with lung cancer.

+Coudray N, et al. Nature Med. 2018

AUC 0.94 in ROC*

*Gene X positive prediction for whole

slide images under prespecified

conditions.



VSQ



Tumor’s molecular biology subtypeに基づくグループ化が最適。 RegulatoryとAcademiaのタスクの明確化。国際連携促進とglobal common senseに基づく臨床開発の方向性。

次の展開としてCDxの概念そのものが不要となるであろう。

[email protected]

私はこう考える - 医薬品医療機器総合機構treatments in adult and pediatric patients...

Documents