June 22nd, 2018

Highlights of Posters

on Colorectal Cancer (CRC)

Takayuki YOSHINO, M.D.Director, Department of Gastroenterology and Gastrointesinal Oncology,

Naional Cancer Center Hospital East (NCCE), Japan

ESMO 20th World Congress on Gastrointesinal Cancer, Barcelona

Highlights No-lights as well!

Disclosure of Conlict of Interests　

Research Funding: Chugai, MSD, Sanoi, Sumitomo Dainippon, GlaxoSmithKlin

e and Boehringer Ingelheim

Lecture Fee:Sanoi, Chugai, Eli Lilly, and Merck Serono

Colorectal Cancer (CRC) Track

• Selected Abstract (Oral): 23

• Poster Discussion (PD): 15

• Poster (P): 136

Presentaions on ESMO-GI 2018

I would like to

Highlight ONLY

PD & P!

Posters are presented today, and

there are only few hours let for preparing

for my presentaion slide deck!!!

However, NO enough ime for preparaion…

Oh My God!

# Brief Title Author

PD-006 DNA CNV for CRLM M Marques

PD-007 Network analysis S Choi

PD-008 Molecular character of immune M Giordano

PD-009 Acquired resistance for EGFR blockade T Yamada

PD-010 REVERCE QoL T Yoshino

PD-011 SAPHIRE M Takahashi

PD-012 ETS and tr-Symtoms: 3 Pani studies J Taieb

PD-013 Usefulness of ICG J Park

PD-014 Brain meta: Danish populaion-bd A Boysen

PD-015 1L in mCRC with mucinous V Catalano

PD-016 Safety of SEMS(Stents) for GiP V P-Barcia

PD-017 Extrahepaic PD in CRLM E Ongaro

PD-018 Let vs. Right: Belgium populaion-bd K Janssens

PD-019 RENCA Macrobead therapy A Nazarian

PD-020 XELAVIRI RAS status and Age D Modest

Poster Discussions

“Highlights”

Posters

Selecion from 15 Poster Discussions

# Brief Title Author

PD-006 DNA CNV for CRLM M Marques

PD-007 Network analysis S Choi

PD-008 Molecular character of immune M Giordano

PD-009 Acquired resistance for EGFR blockade T Yamada

PD-010 REVERCE QoL T Yoshino

PD-011 SAPHIRE M Takahashi

PD-012 ETS and tr-Symtoms: 3 Pani studies J Taieb

PD-013 Usefulness of ICG J Park

PD-014 Brain meta: Danish populaion-bd A Boysen

PD-015 1L in mCRC with mucinous V Catalano

PD-016 Safety of SEMS(Stents) for GiP V P-Barcia

PD-017 Extrahepaic PD in CRLM E Ongaro

PD-018 Let vs. Right: Belgium populaion-bd K Janssens

PD-019 RENCA Macrobead therapy A Nazarian

PD-020 XELAVIRI RAS status and Age D Modest

Poster Discussions

“Highlights”

Posters

Focusing on

4 chemo abstracts

Selecion from 15 Poster Discussions

QOL evaluaion by EQ-5D

PD

or

unaccep

t able

toxiciie

s

1:1

• Metastaic CRC

• Treatment failure with

FP, oxaliplain, and

irinotecan

• Ani-EGFR naive

• KRAS exon 2 WT

• Pts. with minor RAS

mutaions are excluded

since March 2015

Treatment 1 (Tx1) Treatment 2 (Tx2)

R-C arm

C-R arm

Regorafenib

160 mgCetuximab

(+ irinotecan)

Cetuximab

(+ irinotecan)

Regorafenib

160 mg

Primary endpoint: OS

Secondary endpoint: TTF, PFS, ORR, DCR, toxiciies, and QOL by EQ-5D (pre, at week 4, and 8 in Tx1 and 2)

0.00

0.25

0.50

0.75

1.00

Pro

po

rio

n

0 6 12 18 24 30 36 42Time (months)

HR* = 0.61 (95%CI: 0.39-0.96)

Straiied log rank p = 0.029*adjusted by intent to use irinotecan

Median follow-up: 29.0 months

Event/N

% Median (months)

R-C 37/51 73% 17.4 (10.5-20.7)

C-R 44/50 88% 11.6 (8.4-12.9)

QoL score by EQ5D

Before

Tx1

Tx1

4 weeks

Tx1

8 weeks

Before

Tx2

Tx2

4 weeks

Tx2

8 weeks

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Me

an

EQ

-5D

ind

ex

C-RR-C

Error bars represent 95% CI

Regorafenib

Cetuximab Cetuximab

Regorafenib

#PD-010 REVERCE QoLOS

-0.20 -0.15 -0.10 -0.05 0.00 0.05 0.10Esimate

Anorexia

Faigue

HFSR

Rash

Adverse event

G1 vs G0

G2 vs G0

G1 vs G0

G2 vs G0

G1 vs G0

G2 vs G0

G1 vs G0

G2 vs G0

Grade

0.001 (-0.052, 0.055)

-0.061 (-0.121, -0.002)

-0.030 (-0.067, 0.006)

-0.106 (-0.173, -0.039)

-0.004 (-0.040, 0.032)

-0.025 (-0.071, 0.022)

0.008 (-0.031, 0.047)

0.011 (-0.043, 0.065)

Esimate (95% CI)

0.958

0.043

0.106

0.002

0.832

0.300

0.686

0.695

P

Faigue had the largest negaive impact on QoL in

paients among the four adverse events.

N=180

PD

or

unaccep

t able

toxiciie

s

3 wks on, 1 wk of

3 wks on, 1 wk of

T Yoshino et al. ESMO-GI 2018 #PD-010.

QoL score was comparable in two arms with lower

score during regorafenib.

Group A(N=56)

Group B(N=57)

RR, %(95% Cl)

80.4(68.0-88.8)

87.7(76.4-94.2)

Group A (N=56)

Group B (N=57)

PFS rate (80% Cl), % H0: PFS rate ≤30%

46.4 (38.1-54.9) P=0.0037

47.4 (39.1-55.8) P=0.0021

Median PFSGroup A 9.1 (8.6-11.1)Group B 9.3 (6.0-13.0)

This study met primary endpoint with a PFS rate at 9 months

signiicantly above 30% threshold.

Group A(N=56)

Group B(N=54)

0

20

40

60

80

100

*PN related AEs; Peripheral motor and sensory neuropathy

(%)

35.7%

35.7%57.4%

9.3%

66.7%71.4%

Staisical analysis• Primary endpoint: PFS rate at 9 months ater

randomizaion• Secondary endpoints: PFS, OS, RR, TTF and safety• Sub-group: ETS, DpR, Primary tumor locaion

Straiicaion factor• Study site, age, number of metastasized organs, • response per RECIST v1.1 (CR, PR, or SD at randomizaion)

Key Eligibility Criteria• Aged ≥20 years, RAS wild type• Measurable lesion(s) • No previous chemotherapy• ECOG PS 0 or 1• No signs of PD within 14 days

ater the 6th cycle of treatment.

Disconinuaion of

protocol treatmentEnrollment* Randomizaion

1st-line mFOLFOX6 +

panitumumab

6 cycles

△

1

△

2

△

3

△

4

△

5

△

6

△

7

△△ △△ △

0 6 12 18 24Time from randomizaion (months) : 1 month=28 days

mFOLFOX6 + panitumumab (Group A; n=56)

5-FU/LV + panitumumab (Group B; n=57)

(%)100

80

60

40

20

0

HR=0.93, 95% Cl: 0.60-1.43

0 6 18 30 36Time from randomizaion (months) : 1 month=28 days

12 24

*Median OS was not reached in both group.

HR=1.41, 95% Cl: 0.69-2.88

mFOLFOX6 + panitumumab (Group A; n=56)

5-FU/LV + panitumumab (Group B; n=57)

(%)100

80

60

40

20

0

G1

≥G2

#PD-011 SAPHIRE (rP2): maintenance with FU + panitumumab

5-FU/LV plus panitumumab maintenance is beter

in terms of incidence of peripheral neuropathy.M Takahashi et al. ESMO-GI 2018 #PD-011.

Group A

Group B

Coninue mFOLFOX6 + panitumumab

Switch to 5-FU/LV + panitumumab

Primary endpoint: PFS rate at 9months

RR

PFS OS

PN-related Aes*

• Maintenance with panitumumab alone is likely inferior than 5-FU/LV plus

panitumumab in terms of PFS.

• 5-FU/LV plus panitumumab may be a preferred opion.

Lessons from SAPHIRE and VALENTINO (O-016) studies

F Pietrantonio et al. ASCO 2018 #3505, ESMO-GI 2018#O-016

#PD-012 ETS and Tumor-Related Symptoms: 3 Pani Studies

Events Median months (95% CI) HR P valueETS ≥30% 205 5.0 (3.9, 7.0) 0.80 (0.66–0.97) 0.021ETS <30% 213 3.4 (2.8, 4.6)

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Ka

pla

n-M

eie

r e

sim

ate

Time to irst symptom event on study (months)

Impact of ETS on Time to New Symptomaic Event

Favours ETS ≥30% Favours ETS <30%HR

(95% CI)

ECOG PS decline

New opiate use

First weight-loss event

New anaemia-type event

New asthenia-type event

Composite endpoint

10.50 1.5 2.0

Adjusted

HR (95% CI) p value

0.87 (0.69–1.08)

0.71 (0.55–0.92)

0.64 (0.48–0.85)

0.60 (0.41–0.88)

0.77 (0.60–1.00)

0.80 (0.66–0.97)

0.204

0.009

0.002

0.008

0.049

0.021

Impact of ETS on Composite Endpoint,

New Symptomaic Events and Time to ECOG Decline

Events Median months (95% CI) HR (95% CI) p value

DpR 73–100% 104 4.9 (4.1, 8.0) 0.49 (0.33, 0.73) 0.0004

DpR 53–72% 104 6.0 (3.7, 7.5) 0.49 (0.33, 0.73) 0.0004

DpR 31–52% 100 4.5 (3.0, 6.6) 0.55 (0.37, 0.82) 0.0037

DpR 0–30% 96 2.0 (1.4, 3.2) 0.83 (0.56, 1.25) 0.3745

DpR <0% 32 1.5 (0.9, 2.9)

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9 10 11 12

Time to irst symptom event of study (months)

Ka

pla

n-M

eie

r e

sim

ate

Impact of DpR on Time to New Symptomaic Event

3 Panitumumab Studies:

PRIME + PEAK + 314

• The onset of new tumour-related symptoms was delayed in paients

with RAS WT mCRC who achieved ETS ≥30% versus ETS <30%.

• Greater DpR was associated with a longer delay unil the onset of new

tumour-related symptoms.

• Retrospecive and the symptomaic endpoints were not pre-deined;

prospecive trials are needed.

J Taieb et al. ESMO-GI 2018 #PD-012.

#PD-020 RAS status and Age : XELAVIRI (P3, AIO-KRK0110)

mCRC

untreated,

ECOG 0-1

unresectable

lesions

mCRC

untreated,

ECOG 0-1

unresectable

lesions

R

1:1

Stratification

Leucocytes,

alkaline

phosphatase, prior

adjuvant therapy

FP* + Irinotecan + BevacizumabFP* + Irinotecan + Bevacizumab

FP* +

Irinotecan +

Bevacizumab

FP* +

Irinotecan +

Bevacizumab

PDA

B

=TFS (Time to failure of strategy)

FP*

+

Bevacizumab

FP*

+

Bevacizumab

N=434

<Presented as ESMO-GI 2017 #O-026/ESMO 2017#486O>

Group HR (90% CI)

FAS 0.86 (0.73-1.02) NI not shown

RAS/BRAF WT 0.61 (0.46-0.82) superiority of FP+IRI+BEV

RAS MT 1.09 (0.81-1.46) NI of FP+BEV

BRAF MT 1.62 (0.76-3.47) NI not shown

Cox model interaction-test for study arm *RAS status: p=0.03

Iniial FP+IRI+BEV

beter

Iniial FP+BEV

beter

non-inferiority

Time to failure of strategy- molecular groups

All pts arm A All pts arm B0

2

4

6

8

10

1.8 1.4

4.7

1.1

2.9

8.7

<65 yrs 65<75 yrs

75+ yrs

60-day mortality according to age

*5-FU/LV(q2w), Capecitabine(q3w)

D Modest et al. ESMO-GI 2018 #PD-020.

GroupOS, months

RAS/BRAF WT (Arm A) 25.2

RAS/BRAF WT (Arm B) 32.2

RAS MT (Arm A) 21.3

RAS MT (Arm B) 23.2

BRAF MT (Arm A) 12.4

BRAF MT (Arm B) 7.8

ArmOS (95% CI),

months

FP + BEV 21.9 (20.2-25.0)

FP+ IRI+ BEV 23.5 (20.9-27.9)HR=0.84 (95% CI 0.66-1.06)

p (log rank)=0.14

D Modest et al. ESMO-GI 2017 #O-026, ESMO 2017#486O.

0.8 1.0 3.00.3

OS• Iniial FP+BEV in pts it for intensive combinaion regimens cannot be

recommended in pts with RAS WT mCRC.

• Intensive 1st-line chemotherapy was not associated with a substanial

improvement of outcome in pts with RAS MT mCRC.

• Overall, age subgroups did not inluence TFS nor OS to a great extent

(moderate prognosic impact).

• However, risk of early mortality (@60 days) appeared to rise with age.

Congratulaions for your PD presentaions!

Poster Discussions

“Highlights”

Posters

Selecion from 136 Posters

Poster Discussions Posters

“Highlights”

Posters

“No-Light”

Posters!?

Selecion from 136 Posters

Highlights of

“No-Light” posters

Poster Discussions Posters

“Highlights”

Posters

Selecion from 136 Posters

#P-228　

VOLTAGE#P-253　

APOLLON#P-295　　　　　　　　　　　　

　　　　　DS-8201a

Radical Surgery

Without progression

Without

distant

metastasis

Within

14

days

More

than

14 days

Nivolumab monotherapy

Imaging/Endoscopy

Resectabl

e

Protocol

treatment

Nivolumab 2 cycles

Nivolumab 3 cycles

Postoperaive adjuvant

chemotherapy

(e.g., FOLFOX and XELOX)

Preoperaive chemoradiotherapy

(capecitabine + 50.4Gy)

Informed consent

Enrollment

Imaging/Endoscopy

Imaging/Endoscopy

Imaging/Endoscopy

Diagnosic imaging

No.2

post CRT, before nivolumab • Biopsy, blood and stool

collecion

No.3

ater 3cycles of nivolumab• Biopsy, blood and stool

collecion

No.1:

before CRT• Biopsy, blood and stool

collecion

No. 4

ater 5cycles of nivolumab• Biopsy, blood and stool

collecion• Surgical sample collecion

Serial sample collecions at

4 imes

+By a local pathological assessment, *Only single cells were observed. Local pathologist diagnosed as near pCR

(AJCC grade 1)

Case report: 44 year-old male (ID No. 7)From 4/Sep/2017 to 13/Oct/2017, CRT was performed (RT 50.4Gy/28Fr, Capecitabine 3000mg/day).

From 24/Oct/2017 to 22/Dec/2017, 5 doses of nivolumab were administered.

On 16/Jan/2018, radical surgical resecion was performed.

Before CRT

Ater CRT, before Nivo

Ater 3 cycles of Nivo

Ater 5 cycles of Nivo • Large intesine: No residual carcinoma, consistent

with pCR status post-chemoradiotherapy• lymph node: Negaive for metastaic

tumor （ 0/31 （

• AJCC tumor regression: grade 0 by local

pathologists.

#P-228 VOLTAGE: Nivo for LARCResectable primary rectal cancer

(cT3–4 Nany M0, Inferior margin < 12 cm from the anal verge)

or

Resectable recurrent rectal cancer conined to the pelvis

IDAge/Sex

PS

Primary/Recurrent

Clinical diagnosis

MMR status

AJCC TRG

pCR+

Adverse events

Nivolumab period Perioperative period

Phase Ib part

149/F

0 PrimaryT3N0M0 Stage II

pMMR

Grade 0

Yes• Pruritus: Gr1 • No AE

259/F

0 PrimaryT3N0M0 Stage II

pMMR

Grade 0

Yes• No AE • Nausea: Gr1

353/F

0 PrimaryT3N0M0StageII

pMMR

Grade 1*

No*• No AE • Gastritis: Gr2

• Pain: Gr1• Extrapyramidal disorder : Gr1

Phase II part

448/F

0 PrimaryT3N1M0Stage III

pMMR

Grade 3

No• Pruritus: Gr1 • Back pain: Gr1

548/F

0 PrimaryT3N0M0Stage II

pMMR

Grade 2

No

• Hyperthyroidism: Gr1

• Sore throat: Gr1

• Hypothyroidism: Gr1• AST elevation: Gr2• ALT elevation: Gr3

659/M

0 PrimaryT3N0M0Stage II

pMMR

Grade 0

Yes• Pruritus: Gr1 • No AE

744/M

0 PrimaryT3N0M0Stage II

pMMR

Grade 0

Yes

• Allergic rhinitis: Gr1

• Dry skin: Gr1• Pelvic infection: Gr3, Gastrointestinal

anastomotic leak: Gr3 →SAE• Upper respiratory infection: Gr3• Stoma site erosion: Gr2

H Bando et al. ESMO-GI 2018 #P-228.

Dosage and Schedules

Pmab

TAS-102

Day

Course 2

1 8 15 22 29

Course 1

6 mg/kg

35 mg/m² BID

Endpoints

Primary

• PFS rate at 6 months

Secondary

• Safety: Adverse events.

• Eicacy: OS, PFS, RR, DoR, DCR, TTF

Maximum % Change in

Target Lesion Size in overall

Events Median PFS 95% CI

46 5.8 months 4.46-6.50

Best Overall Response Rate

　 All, n (%) L, n (%) R, n (%)

CR 0 (0.0) 0 (0.0) 0 (0.0)

PR 20 (37.0) 18(38.3) 2(28.6)

SD 24 (44.4) 22(46.8) 3(28.6)

PD 11 (18.5) 7(14.9) 3(42.9)

RR 20 (37.0) 18(38.3) 2(28.6)

DCR 44 (81.5) 40 (85.1) 4 (57.1)

At risk

L: Let-sided tumors (N=47),

R: Right-sided tumors (N=7)

100

80

60

40

20

0

PFS

rat

e (

%)

0 3 6 9 12

54 41 26 7 0

% r

ed

uci

on

175

125

100

75

50

150

302010

0-10-20-30

-50

-75

-100

PD

SD

PR

PFS in over all

(N=54)

Maximum % Change in

Target Lesion Size by TL

(Let, N=47; Right, N=7)

PFS by primary tumor locaion

(Let, N=47; Right, N=7)

#P-253 APOLLON (P1/2): TAS-102 + Panitumumab

K Yamazaki et al. ESMO-GI 2018 #P-253.

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

12

3

45

6

7

Propriety drug-linker and payload

Conjugaion chemistryThe linker is connected to the cysteine

residue of the anibody Payload (Dxd)

Exatecan derivaive

Cysteine residue

Drug-Linker

Cys

Study Design

HER2-status

centrally

conirmed

HER2-posiive mCRC

(IHC 3+ or IHC 2+/ISH+)

DS-8201a 6.4 mg/kg q3wk

n=50

Cohort A

HER2-expressing mCRC

(IHC 2+/ISH-)

DS-8201a 6.4 mg/kg q3wk

n =20

Cohort B

HER2-expressing mCRC

(IHC 1+)

DS-8201. 6.4 mg/kg q3wk

n=20

Cohort C

Cohorts B and C will open for enrollment depending on the

risk/beneit assessment in cohort A

Eicacy Outcomes with DS-8201a in HER2-expressing Solid

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

ConfirmedORRa

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/mutated

38.7% (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

Doi T, et al. Lancet Oncol. 2017, Iwata H, et al ASCO 2018

Other Cancers

N = 37

Payload with a diferent MoA High potency of payload Payload with short systemic half-life Bystander efect Tumor-selecive cleavable linker Stable linker-payload High drug-to-anibody raio

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

#P-295 DS-8201a for mCRC Trial in progress

tyoshino@east.ncc.go.jp

tyoshino@east.ncc.go.jp

Thank you for your kind atenion!!!