The 25th Anti-Cancer Drug Development Forum

Forefront practical application of cancer genome
Venue; The Cancer Research Institute Hospital of Japanese Foundation for cancer Research in Tokyo

Tumor-agnostic clinical development - ideal and reality

Academia Task for Tumor-Agnostic ClinicalDevelopment and the Post-Launch
Takayuki YOSHINO, MD, PhD
Director, Department of Gastroenterology and Gastrointestinal Oncology,
National Cancer Center Hospital East, Japan

June 30th, 2018 In May 2017, the U.S. FDA granted accelerated approval for pembrolizumab, an anti-PD-1
monoclonal antibody for treatment of adult and pediatric patients with unresectable ormetastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
solid tumors. The FDA approval represents the first disease agnostic anti- cancer therapy
based on tumor biomarker.

 MSD Merck Japan & FALCO has submitted the application for approval for adult patientswith unresectable or metastatic, MSI-H solid tumors at March 2018.
 Japanese PMDA is also anticipated to grant the same regulatory for pembrolizumab, towhich the PMDA has applied ‘Conditional Early Approval System for Pharmaceuticals (oneof Priority Review System)’ at June, 2018.

Agenda•TODAY:
Accomplishment of SCRUM-Japan for MSI-High tumors before the launch•

TOMORROW:
Guideline in place•

THE DAY AFTER TOMORROW:

TMB-high
RWD
International Collaboration

The Nationwide Cancer Genome Screening Consortium in Lung and GI Cancers: SCRUM-Japan(n= 9,590 : Feb/2015 - May/2018)
More than 260 participating
institutions

Pan-cancer panel(OCP/OCAv3) analysis

No. of enrollment

Molecular-profile based IND regist trials
Umbrella type 26 studies

No. ofenrollment

Lung Cancer
Clinico-Genomic DatabaseNon-sq NSCLCSq NSCLC

GI Cancer

Collaboration with 17 pharma

Non-Sq NSCLC

CRC

Esophageal
Gastric
Small intestine
CRC
HCC
Biliary
Pancreas
NET
GIST
Others

Total

4,309
3,673
636

5,281
370
1,142
93
2,329
66
417
652
73
79
60

9,590

Phase I / basket type 16 studies

Accomplishment on GI-SCREEN
Feb Feb
2014 2015

As of June, 2018

Apr
2015

SCRUM-Japan
GI-SCREEN
GI-SCREEN 2013-01-CRC
2013-01CRC
Version
1.2→2.0

2017

2016

Ongoing

853 Cases

2018

GI-SCREEN MSI CRC

1,711 Cases

GI-SCREEN CRC

3,182 Cases（2,329 Cases after SCRUM-Japan Project）

SCRUM-Japan
GI-SCREEN
2015-01-non CRC

GI-SCREEN Non-CRC
Ongoing

OngoingFinish

GI-screen 2013-01-CRC：Sub-study 1
Cancer genome alteration, MSI, PD-L1, PD-L2 and clinical data (incl. outcome)

2,952 Cases

Immune Profiling

Plasma OncoBEAM RAS CRC Kit

Finish Tissue RASKET-B Kit
Finish Tissue MSI Promega Kit

44 CasesOngoing

GOZILA

56 CasesOngoing

Ukit

59 CasesGI-SCREEN CRC-MSI

Prevalence of microsatellite instability-high (MSI-H) or mismatch repairdeficient (dMMR) CRC: Cross-trial comparison
Trial NameN

Prevalence of MSI-H/dMMR

Overlapping
BRAF V600E
mutation

Pooled dataset 1

3,063

5.0%

34.6%

AIO Colorectal Study Group 2

104

4%

Not reported

Australia and United States 3

NA

Not reported

30%

Review Article 4NA

3 - 5%

Not reported

GI-SCREEN-JAPAN 5

853

1.9%

40%

NCCE 6

277

1.9%

40%

GI-SCREEN CRC - MSI *unpublished
Universal Screening
in Stage II and III +unpublished
Note: GI-SCREEN-JAPAN is the Nationwide Cancer Genome Screening Project for Gastrointestinal Cancer in Japan: NA, not applicable:*Ongoing Prospective Observational Study as of 31st Mar, 2018: +Our institutional Data as of 31st Mar, 2018
1 Venderbosch S, et al. Clin Cancer Res 2014, 2 Muller CI, et al. Int J Colorectal Dis 2008, 3 Goldstein J, et al. Ann Oncol. 2014, 4 Cohen R, et al. Curr Ocol Rep 2016, 5 Kajiwara T, Yoshino T. ASCO 2016, 6
Kawazoe A, Yoshino T. ASCO-GI 2016

Quasi-monomorphic variation range: QMVR
Okamoto W, …., Yoshino T. ESMO 2017

BAT26
tumor DNA

MSI

normal DNA

QMVR:
the mean allele size ±3bp

• The mean allele size of mononucleotide markers was generated from the normal
DNA.
• QMVR was defined as the mean allele size ±3bp.
• Because of few variant alleles observed in Caucasians as well as in Asians, QMVR
might be applicable as references.
Tissue MSI Promega Kit

Tissue MSI Promega Kit

BackgroundOkamoto W, …., Yoshino T. ESMO 2017

• According to the pilot study performed by FALCO Biosystems, the QMVR
in 149 healthy Japanese individuals were almost the same as those of the
Caucasian group. (1)
NR21

BAT26

BAT25

NR24

MONO27

Pilot study (1)98.4-104.4

111.4-117.4

121.0-127.0

129.5-135.5

149.9-155.9

Patil DT, et al. (2)98-104112-118

121-127

129-135

149-155• Three large Japanese cohorts suggested that the frequencies of variant
alleles for 5 mononucleotide markers were rare.(1)
NR21

BAT26

BAT25

NR24

MONO27

MSI analysis of GI-SCREEN
2013-01-CRC

4/602(0.66％)

0/602
(0%)

3/602
(0.50%)

0/602
(0%)

0/602
(0%)

Saitama Cancer Center

3/774(0.39%)

2/3320(0.06%)

12/3320(0.36%)

2/774(0.26%)

Not evaluated

FALCO Biosystems

2/252(0.79%)

0/252
(0%)

1/252
(0.40%)

0/252
(0%)

0/252
(0%)

(1) Bando H, et al. ASCO GI. 2017(2) Patil DT, et al. Diagn Mol Pathol. 2012

Schema of the clinical evaluation study
Standard method

Testing method(GI-SCREEN CRC-MSI study)(This study)

Tumor tissue

Tumor tissue

Normal tissue
DNA extraction

DNA extraction

PCR

PCR (The New MSI kit)

(NR-21, BAT-26, BAT-25, NR-24, MONO-27)(NR-21, BAT-26, BAT-25, NR-24, MONO-27)

The Promega MSI testing was performed using genomic DNA extracted
from both tumor and paired normal tissue.

The new MSI kits were manufactured under the Quality Management System(QMS) for in vitro diagnostics (IVDs).

Capillary electrophoresis

Capillary electrophoresis

Tumor tissue

MSI

MSI

QMVR

Tumor tissue

MSI

MSI
MSI

Normal tissue

Decision
The presence of MSI was determined by the appearance of new alleles in the tumor
sample that were not present in the normal sample

Decision
The presence of MSI was determined by appearance of the tumor allele peakoutside the Quasi-Monomorphic Variation Range (QMVR)Results: Primary and Secondary endpoints
Okamoto W, …., Yoshino T. ESMO 2017

Standard method

Testing method

Negative (MSS/MSI-L)

Positive (MSI-H)

Negative (MSS/MSIL)

424

0

Positive(MSI-H)0

11
N = 435

Primary endpoint• Sensitivity : 11 / (0+11) =100%• Specificity : 424 / (424+0) =100%
Secondary endpoints• Concordance rate
• Positive predictive value• Negative predictive value: (424+11) / (424+0+0+11) =100%: 11 / (0+11) =100%: 424 / (424+0) =100%
Tissue MSI Promega Kit

Can we adapt the findings from the CRC study to Non-CRC?
-Our ExperienceMSI-High CRC
BAT26

NR21

BAT25

Tumor Tissue

MONO27

NR27

We will soon start the confirmatory study toinvestigate the concordance between MMR-IHC
and MSI-PCR in Non-CRC, utilizing the SCRUMJapan Platform before the launch ofpembrolizumab.

Can we adapt the findings from the CRC study to Non-CRC?
-Our Experience- We also identified this difference in Ovarian and Breast Cancers.

Accomplishment on GI-SCREEN
Feb Feb
2014 2015

As of June, 2018

Apr
2015

SCRUM-Japan
GI-SCREEN
GI-SCREEN 2013-01-CRC
2013-01CRC
Version
1.2→2.0

2017

2016

Ongoing

853 Cases

2018

GI-SCREEN MSI CRC and Non-CRC

1,711 Cases

MMR-IHC tests are included for Non-CRC

GI-SCREEN CRC

3,182 Cases（2,329 Cases after SCRUM-Japan Project）

SCRUM-Japan
GI-SCREEN
2015-01-non CRC

GI-SCREEN Non-CRC
Ongoing

OngoingFinish

GI-screen 2013-01-CRC：Sub-study 1
Cancer genome alteration, MSI, PD-L1, PD-L2 and clinical data (incl. outcome)

2,952 Cases

Immune Profiling

Plasma OncoBEAM RAS CRC Kit

Finish Tissue RASKET-B Kit
Finish Tissue MSI Promega Kit

44 CasesOngoing

GOZILA

56 CasesOngoing

Ukit

59 CasesClinical Questions
•
•
•
•
•

Should all cancer patients be tested for MSI / MMR?
When is the optimal timing for tests?
Which tests are recommended?
What is the appropriate biospecimen for tests?
Which treatment is best for MSI-H / MMR-D patients, particularly for metastatic
solid tumors?
• Which line of therapy should immunotherapy be used in MSI-H / MMR-D solid
tumors ?
etc.

25,487 Total Views (17,167 Page views and 8,320 PDF Downloads)
Since November 2017 as of 29th June 201816

Summary of Asian Recommendations including consideration of leftversus right-sided primary tumour location
Yoshino T, et al. Annals of Oncology 2018
Molecular pathology and biomarkers
Recommendation 6 with revision: Tumour mismatch repair（MMR）testing
6a. Immunohistochemistry（IHC）tests for MMR proteins or PCR tests for microsatellite
instability（MSI） in the metastatic disease setting can assist clinicians in genetic counselling［Ⅱ, B］.
6b. Tumour MMR testing has strong predictive value for the use of immune check-point inhibitors in
the treatment of patients with mCRC［Ⅱ, B］.

The frequency of DNA MMR deficiency in stage IV CRC is about 4–8% in Western countries [9], and about 1.9–
3.7% in Japan [61, 62]. Since Asian experts view IHC and PCR as complementary techniques for evaluating
tumour MMR deficiency, all the Asian experts agreed [A=100%] with the recommendations for tumour MMR
testing accompanied by the modifications to recommendations 6a and b indicated in bold text above. They
also all agreed that tumour MMR testing has strong predictive value for the use of immune check-point
inhibitors in the treatment of mCRC patients [63, 64].

Next Step: GL for MSI-High Solid Tumor
9. Van Cutsem E, Yoshino T, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27: 1386-1422.
61. Fujiyoshi K, Yamamoto G, Takenoya T et al. Anticancer Res 2017; 37: 239-247.
62. Kajiwara T, Shitara K, Denda T, …. Yoshino T. The Nationwide Cancer Genome Screening Project for Gastrointestinal Cancer in Japan (GI-SCREEN): MSI-Status and cancerrelated genome alterations in advanced colorecta cancer (CRC)- GI-SCREEN 2013-01-CRC substudy. J Clin Oncol 2016; 34 (15 suppl): abstr 3573.
63. Le DT, et al. N Engl J Med 2015; 372: 2509-2520. 64. Overman MJ, et al. Lancet Oncol 2017; 18: 1182-1191.

What we learned from the US FDA Approval
Goal is to identify patients most likely to benefit from treatment

Challenges in drug development for a tumor-agnostic indication• Study design for providing evidence of clinical efficacy (vs traditionalrandomized controlled studies)• Identification of study population

Liquid Biopsy
Liquid biopsies
CTCs(circulatingtumor cells)

Cancer cells released
from primary tumor
mass into the bloodstreamctNA(circulatingtumor nucleic
acids)

ctDNA (circulatingtumor DNA), miRNAs,
mRNA, and lnRNA

Exosomes

Small membrane derived
vesicles contain various
molecules such as signal
proteins, micro RNA,mRNA, lipids, and exoDNA

Samples: blood, serum/plasma, urine, CSF, saliva

19

Diaz LA, et al. J Clin Oncol. 2014.

Advantages of ctDNA Analysis
Minimal InvasivenessRapid turnaround time
Low cost of sampling procedureCapturing intratumoral heterogeneity

20

Nakamura Y and Yoshino T. Oncologist 2018.

GI-SCREEN GOZILA Projectv2.10:panel
ctDNA
A Guardant360
Comprehensive
LiquidBiopsyAll guideline and emerging biomarkers in one test

Point Mutations and Sp lice Site-Disrup ting Alterations – 73 Genes
AKT1

ALK

APC

AR

ARAF

ARID1A

ATM

BRAF

BRCA1

BRCA2

CCND1

CCND2

CCNE1

CDH1

CDK4

CDK6

CDKN2ACTNNB1

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

PDGFRAPIK3CA

PTEN

PTN11

RAF1

RB1

RET

RHEB

RHOA

RIT1

ROS1

SMAD4

SMO

STK11

TERT**

TP53

TSC1

VHL

Ind els – 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

ERBB2

FGFR1

Amp lifications – 18 Genes
AR

BRAF

CCND1

CCND2

CCNE1

CDK4

CDK6

EGFR

FGFR2

KIT

KRAS

MET

MYC

PDGFRAPIK3CA

RAF1

FGFR3

RET

ROS1

NTRK1

Fusions – 6 Genes
ALK

26

FGFR2

Simultaneous Press Release from Japan and USA

22

GI-SCREEN GOZILA Project

Nakamura Y, Yoshino T. Oncologist. 2018

Umbrella & Basket Clinical Trials (IIS Only to be listed)•Each arm to have a junior/senior investigator leadership team
based on NGS-Based Liquid Screening•Flexible design: arms open and close with best available science
GOZILA Project
Guardant Originates in Zipangu Liquidbiopsy Arrival
Nationwide Genome
Screening Project
SCRUM-Japan GI-SCREEN
24 sites

CRC cohort, N = 1,000 Before anti-EGFR, N = 500
 Refractory to anti-EGFR, N = 500

ctDNA analysis

HER2 Positive

Trastuzumab+ Pertuzumab(TRIUMPH)

BRAF V600E MT

Eribulin(BRAVERY)

BRAF
Non-V600E MT

Binimetinib+
Encorafenib +Cetuximab(BIG BANG)

MET Amplification

Drug A + Drug B

CRC Only

Non-CRC cohort, N = 1,000
 Gastric cancer, N = 300
 Esophageal cancer, N = 150
 Hepatocellular carcinoma, N = 100
 Biliary tract cancer, N = 150
 Pancreatic cancer, N = 100
 Neuroendocrine tumor/carcinoma, N = 50
 GIST, N = 100
 Others, N = 50

Non-GI Cancer cohort, N = 100

Pan Cancer

FPI, 1Q 2019
FPI, 3Q, 2018

ctDNA analysis

bTMB-High Cancer

Nivolumab(TMB-H basket)

Any X alteration

X-targeted Tx
FPI, 1Q, 2019

Any Y alteration

Y-targeted Tx
FPI, 4Q, 2019

Global Collaboration for ctDNA Analysis
to elucidate the Clinical Utility

TMBs Across Various Advanced GI Malignancies in GI-SCREEN &Collaboration with Certain Companies

The OCP panel can assess TMB with a high correlation with WES.
TMB varied widely across various advanced GI malignancies.
TMB analysis may be used as an agnostic histologic indicator to
identify patients with GI malignancies who can benefit from
immunotherapy
Nakamura Y, Yoshino T. ASCO 2018

N

X-Axis =Number of nonsynonymous mt/Mb (OCP)
Y-Axis =Number of nonsynonymous mt/Mb (WES)Median TMB, mt/Mb

Frequency of(Range)

TMB > 20 mt/Mb, %

CRC

751

15.3 (0.0 - 103.6)

23.6

Non-MSI-H

199

15.3 (0.0 - 34.5)

17.1

MSI-H

4

23.0 (19.2 - 26.8)

75.0

GC

509

7.7 (0.0 - 69.0)

13.3

EC

143

11.5 (0.0 - 49.9)

17.5

PC

136

15.3 (3.8 - 69.0)

27.9

BTC

92

15.3 (0.0 - 57.5)

26.1

SIC

30

15.3 (3.8 - 38.4)

30.0

GIST

29

7.7 (0.0 - 26.8)

6.9

HCC

27

11.5 (0.0 - 34.5)

7.4

NET/NEC27

11.5 (0.0 - 76.7)

14.8

AC

12

11.5 (3.8 - 46.0)

25.0

ACC

3

19.2 (7.7 - 23.0)

33.3

Nakamura Y, Yoshino T. ASCO 2018

TMB-H Basket| Nivolumab for TMB-H GI Cancers
From September, 2018

 Advanced GI cancers refractory or intolerant to standard
chemotherapy
 Colorectal cancer
 Gastric cancer
 Esophageal cancer Others (Biliary tract cancer, Pancreatic cancer, Hepatocellular
carcinoma, Small intestine cancer, Appendiceal cancer, Anal
canal cancer, Neuroendocrine tumor/carcinoma, GIST

Nivolumab
3 mg/kg DIV, Q2W
until PD

 Tumor mutation burden-high identified by Guardant360
Sample size: 70 (40 at 1st sate, 30 at 2nd stage)
Study design: Bayesian two-stage adaptive design
Primary endpoint: Objective response rate (ORR) by RECIST v1.1
Secondary endpoints: Progression-free survival (PFS) by RECIST v1.1 and irRECIST, Duration of response (DoR) by RECIST v1.1
and irRECIST, Disease control rate (DCR) by RECIST v1.1 and irRECIST, Overall survival (OS), Incidences of adverse events
UMIN000033182

26

Prospective registry study for control data at CTD evaluation :SCRUM-Japan Registry (since 07/2017)
 Data collection for efficacy①Following data collection in each line
Tx

ORR：Objective Response RateDoR：Duration of ResponseDCR：Disease Control RatePFS：Progression Free Survival
TTF：Time to Treatment Failure②

OS：Overall Survival

Subjects for SCRUM registryHER2

TRIUMPH Study Design
Eligibility criteria A
 Metastatic CRC
 Age ≥ 20 years
 ECOG PS 0-1
 RAS wild-type in tissue HER2 positive confirmed bytissue analysis
and/or
HER2 amplified and RAS wildtype confirmed by ctDNA
analysis Refractory or intolerable tostandard therapy, including
anti-EGFR mAb

Nakamura Y, Yoshino T. Oncologist. 2018

Eligibility criteria B

Meeteligibility
criteria A

 No prior treatment
with HER-targeted
therapy Measurable lesion
based on RECIST Adequate organfunction Normal left
ventricular ejection
fraction, etc.

Meeteligibility
criteria B

Not meeteligibility
criteria B

Trastuzumab
8 mg/kg followed by 6 mg/kg+
Pertuzumab
840 mg followed by 420 mg
Q3W until PD

Natural history follow-up

 Design: Unblinded, single-arm, multi-center phase II study
 Primary endpoint*: Objective response rate (ORR) by investigator’s assessment
 Secondary endpoints*: PFS, DoR, TTF, DCR, OS, Incidence of adverse events, Efficacy of the previous antiEGFR treatment
 Sample size: 18 patients (25 patients, if enrolled at good rate)* Endpoints will be evaluated in each analysis set with HER2 positive in tissue or ctDNAOngoing investigator-initiated IND registration study for orphan-fractionated cancer
associated with registry data collection: TRIUMPH study / SCRUM-Japan Registry
Nationwide Cancer
Genome Screening

HER2 amplified CRC

SCRUM-Japan
GI-SCREEN
20 participating
centers（HER2 ≥ 4 copies）
13 non-participating ecnters
HER2 amplified CRC
screened in SCRUMJapan

study
treatment

Central labo
eligible

TRIUMPH study
7 participating centers
HER2 amplified CRC
screened in SCRUMJapan

HER2

Trastuzumab+P
ertuzmab

HER2 positive

HER2 IHC

ineligible

HER2 ISHout of study for
any reason

Natural history data（internal control）

SCRUM-Japan
Registry
Registry

Natural history data（external control）（HER2 ≥ 4 copies）
International Harmonization of Diagnostic Criteria for HER2-Amplified Metastatic Colorectal Cancer, collaborated with
SWOG-USA, HERACLES-Italy, and Korea

Prospective collaboration for HER-2 +ve for mCRC

HER-2

TRIUMPH Study






HER2-positive mCRC
Age ≥ 20 years
ECOG PS 0-1
RAS wild-type
Refractory or intolerable tostandard therapy, including antiEGFR mab

KOREAN Study






HER2-positive mCRC
Age ≥ 20 years
ECOG PS 0-1
RAS wild-type
Refractory or intolerable tostandard therapy, including antiEGFR mab

Trastuzumab
Meeteligibility

8 mg/kg followed by 6 mg/kg＋

Pertuzumab
840 mg followed by 420 mg
Q3W until PD

Natural history follow-up
Not meeteligibility Prospective combination for regulatory approval

Natural history follow-up

Trastuzumab＋
Pertuzumab＋
AtezolizumabGlobal Collaboration for HER2 Positive mCRC

Fujii S, Yoshino T, et al, ASCO 2018

Ongoing project

Ongoing projectUtilization of Real World Data| Comparison of Endpoints in
Each Sub-study with Data in SCRUM Japan Registry
SCRUM Japan
Registry
Trastuzumab+ Pertuzumab(TRIUMPH)

HER2 positive
mCRC

BRAF V600E MT
cohortEribulin(BRAVERY)

BRAF V600E MT
mCRC

BRAF non-V600E MT
cohortEncorafenib+ Binimetinib+ Cetuximab(BIG BANG)

BRAF non-V600E
mCRC

MET amplification
cohortDrug A+ Drug B(MET-BEIGE)

Gene X alteration
cohortX-targeted Tx

HER2 amplification
cohortNationwide Genome
Screening Project
SCRUM-Japan GI-SCREEN

MET-amplified
mCRC
Gene X alteredGI cancer

32

Collection of
RWD

Conclusion•

TODAY:
Elucidate the prevalence & characteristics of MSI-High Pan-Cancer before the launch•

TOMORROW:New Guideline Projection with US Investigators (Dr. Axel Grothey as one of co-chairs)•

THE DAY AFTER TOMORROW:
Further identification of study population for a tumor-agnostic indication
Utilization of RWD for approvalInternational Collaboration to get approval from regulators, incl. FDA, EMA and PMDA
Our mission is to provide an engaging smile on patients’ face, prioritized for cancer patients.

Achievement of SCRUM-Japan:
The Nationwide Cancer Genome Screening Project
https://ncc-kashiwa.smktg.jp/public/seminar/view/53
Contact email address;
scrum-seika2018@east.ncc.go.jp

Thank you for your kind attention!!

tyoshino@east.ncc.go.jp

Let’s go where no one has gone before!