I tumori gastrointestinali

Carmine Pinto

Clinical Cancer Centre Oncologia Medica

IRCCS-Arcispedale S.Maria Nuova Reggio Emilia

I tumori

gastrointestinali

Agenda

 “Mutation burden” and Immunogenicità

 Immunonoterapia nel carcinoma gastrico

 Immunonoterapia nel carcinoma colo-rettale

Slide 18

Mutation burden vs response to PD-1/PD-L1 blockade

Potential Immuno-Oncology Targets

EFFECTOR CELL

BCR-ABL DR5 TKIs

CXCR4 BET ADCs

PD-1 TIM-3 LAG-3

CTLA-4 TIGIT

CCR2/5 IL-8 GITR

OX40 CD137

ICOS CD27 IL-2

KIR SLAMF7

Radiation Chemotherapy Vaccines Viruses CD40

Inhibit/target tumor cell pathways 3

Block tumor

inhibition/checkpoints 4

Block inhibitory stromal effects 5

1

Optimize antigen presentation 6

Block or deplete immune regulators 7

Activate T effector cells

Enhance NK-cell activity 2

IDO CD73 CSF1R

Glutaminase CTLA-4-NF CTLA-4-Probody

CCR4 TGFß

ADCs, antibody drug conjugates; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCR4, chemokine CXC motif receptor 4; GITR, glucocorticoid-induced tumor necrosis factor receptor-related protein; IDO, indoleamine 2, 3- dioxygenase; KIR, killer cell immunoglobulin-like receptor; LAG3, lymphocyte-activation gene 3; NK, natural killer; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; SLAMF7, signaling lymphocytic activation molecule family member 7.Chen DS, Mellman I. Immunity.2013; 39:1-10.

We can modulate

immune response to

restore the ability of

effector cells to traffic

to the tumor to detect

and destroy cancer

cells ^1-6

Potential Immuno-Oncology Targets in GI Cancers ¹

*The image shows only a selection of the receptors/pathways involved.²

CD137, cluster of differentiation 137; CD27, cluster of differentiation 27; CTLA-4, cytotoxic T-lymphocyte antigen-4; LAG-3; lymphocyte activation gene-3; PD-1, programmed death receptor-1; TIM-3, T-cell immunoglobulin and mucin domain-3.

1. Clinicaltrials.gov. Accessed July 16, 2017. 2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.

PD-1 CTLA-4

Inhibitory receptors*

Activating receptors*

TIM-3

LAG-3 CD27

OX40

CD137

Tumors may exploit immune checkpoint signals to evade immune detection ²

Predictive/prognostic biomarkers in GI cancers (Hot vs Cold tumors)

 Activity of checkpoint inhibitors in MSI-high metastatic colorectal cancer

 Similar activity in MSI-high non-colorectal GI cancers (gastric cancer)

 NGS provides information about tumor mutational burden

 Activity of checkpoint inhibitors and HBV status (gastric cancer)

 Immune signatures (Asian vs non-Asian populations in

gastric cancer; Immunoscore in colon cancer)

6/9 Gastro-Intestinal

cancers

Signaling mechanisms of PD-1 and PD-L1 inhibition of PD-1 signaling in H-MSI cancers

Lemery et al, NEJM 2017

Meta-analysis on PD-L1 prognostic and predictive value in GI cancers

Results for Overall Survival

Dai et al, OncoTargets Ther, 2017

Agenda

 “Mutation burden” and Immunogenicità

 Immunonoterapia nel carcinoma gastrico

 Immunonoterapia nel carcinoma colo-rettale

Classificazione su base molecolare

31%

Sottotipi di carcinoma gastrico

Sottotipo Incidenza (%)

Caratteristiche patologiche e cliniche

Casratteristiche molecolari

EBV 9 Maschi 81%

Fondo/corpo

Estensiva DNA metilazione

PIK3CA m 80%

PD- L1-2 iperespressione EBV-CIMP

CDKN2A silenziamento Segnali di citochine

alterate

MSI 22 Età mediana 72 aa

Moderata DNA metilazione

Ipermutazioni CIMP-gastrico MLH1 silenziamento Variazione di pathways

mitotiche Instabilità

cromosomiale

50 Giunzione esofago-gastrica Sottoistotipo intestinale

TP53

RTK-RAS attivazione Genoma

stabile

20 Sottoistotipo diffuso

Età più precoce mediana 59 aa

CDH1 e RHOA mutazioni CLDN18-ARHGAP fusione

Adesione cellulare

Prognosis associated with subtypes

Sohnet al, Clin Cancer Res 2017

Br J Surg, 2017

Forest plot for the effect of microsatellite instability (MSI) status on overall survival

Br J Surg, 2017

PD-L1 Status and Outcome in Gastric Cancer

PD-L1, programmed death ligand 1.

1. Zhang L et al. Int J Clin Exp Pathol. 2015;8(9):11084-11091. 2. Zhang M, et al. Sci Rep. 2016;6:1-92.

0.0

C u mu lati v e Su rv iv al

0.2 0.4 0.6 1.0 0.8

48 72 96 168

0

Time After Surgery (months)

PD-L1 Positive (n=67)

PD-L1 Negative (n=65)

24 120 144

PD-L1 Expression Negative Positive

Negative-censored Positive-censored

• PD-L1 is associated with poor prognosis in gastric cancer patients ¹

• Overexpression of PD-L1 in about 25%–65% of gastric cancer patients suggests that immune checkpoint

inhibition may be an effective therapy ²

Elevated PD-L1 and PD-L2 Expression in EBV+ Gastric Cancer

Slide 23

Immuno-Oncology Studies

*Clinical trial includes patients with gastroesophageal junction cancer.

1L, first-line; 2L, second line; 3L, third line; 5FU, 5-florouracil; adj, adjuvant; BSC, best supportive care; cape, capecitabine; CapeOX, capecitabine + oxaliplatin; chemo, chemotherapy; FOLFOX, oxaliplatin + leucovorin + fluorouracil; FP, fluoropyrimidine; GEJ, gastroesophageal junction; I-O, immuno-oncology; PBO, placebo; PD-L1, programmed death ligand 1; S-1, tegafur-gimeracil-oteracil potassium; SOX, tegafur/gimeracil /oteracil potassium + oxaliplatin; XELOX, oxaliplatin + capecitabine.

1. Clinicaltrials.gov. Accessed June 29, 2017. 2. Ohashi S et al. Gastroenterology. 2015;149(7):1700-1715. 3. Lote H et al. Cancer Treat Rev. 2015;41(10):893-903.

Combination Therapy Monotherapy

JAVELIN Solid Tumor*: Ph 1 Avelumab

NCT02340975*: Ph 1/2 Tremelimumab ± durvalumab Checkmate 032*: Ph 1/2

Nivolumab ± ipilimumab KEYNOTE-061*: Ph 3

Pembrolizumab vs paclitaxel

2 L+

NCT02864381*: Ph 2 Nivolumab ± andecaliximab

ECHO-203: Ph 1/2 Durvalumab ± epacadostat KEYNOTE-059*: Ph 2

Pembrolizumab

1 L+

JAVELIN Gastric 100*: Ph 3 1L Mnt: Avelumab vs oxaliplatin + FP

KEYNOTE-062*: Ph 3 (PD-L1+) Pembrolizumab ± (cisplatin + 5-FU/cape)

vs PBO + (cisplatin + 5-FU/cape)

PLATFORM*: Ph2

1L Mnt: Durvalumab/capecitabine NCT02443324*: Ph 1 Pembrolizumab + ramucirumab

ATTRACTION-04* (ONO-4538-37): Ph 2/3 Nivolumab + SOX/CapeOX vs PBO +

SOX/CapeOX

ATTRACTION-05* (ONO-4538-38): Ph 3 Nivolumab + S-1/CapeOx vs PBO +

S-1/CapeOx

N e o - /A dj

ATTRACTION-02* (ONO-4538-12): Ph 3 Nivolumab vs PBO

JAVELIN Gastric 300*: Ph 3 Avelumab + BSC vs BSC ± chemo

3 L+

KEYNOTE-585*: Ph 3

Pembrolizumab + (cisplatin + 5-FU/cape) vs PBO + (cisplatin + 5-FU/cape)

KEYNOTE-059*: Ph 2

Pembrolizumab ± (cisplatin + 5-FU/cape)

LEGEND

I-O/non–I-O combination clinical trials I-O/I-O combination clinical trials Monotherapy clinical trials

I-O/I-O & I-O/non-I-O combinations trial

Checkmate 649*: Ph 3

Nivolumab + ipilimumab/XELOX/FOLFOX vs XELOX/FOLFOX

KEYNOTE-059*: Ph 2

Pembrolizumab

KEYNOTE-059: Pembrolizumab

Phase 2 Multicohort Study of Pembrolizumab for G/GEJ Adenocarcinoma

 Primary Endpoints: ORR by RECIST v1.1, safety and tolerability

 Secondary Endpoint: DOR by central review, PFS, OS

 Exploratory Biomarker Endpoints: Efficacy by microsatellite instability and gene expression profile

*Capecitabine was used in place of 5-FU only in Japan.

5-FU, 5-fluorouracil; CT, chemotherapy; DOR, duration of response; G, gastric; GEJ, gastro-esophageal junction; ORR, objective response; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; q3w, every 2 weeks;

RECIST, Response Evaluation Criteria In Solid Tumours.

1. Fuchs C, et al. ASCO 2017. Abstract 4003. 2. Bang et al. ASCO 2017. Abstract 4012. 3. Catenacci DV et al. World GI 2017. Abstract LBA-009.

Pembrolizumab 200 mg q3w Cohort 1

• ≥2 prior lines of CT

For 24 months or

until progression,

intolerable toxicity, or other reason Cohort 2

• No prior therapy

Cohort 3

• No prior therapy

• PD-L1 positive

Pembrolizumab 200 mg q3w

Pembrolizumab 200 mg q3w + Cisplatin 80 mg/m

q3w +

5-FU 800 mg/m

q3w or Capecitabine 1000 mg/m

q3w*

Follow-up for survival by

telephone until death, withdrawal, or

study end n=25

n=259

n=31

Objective Response

 Median (range) follow-up in cohort 1 (all patients): 5.6 months (0.5–24.7)

 Median (range) follow-up in cohort 1 (3L and 4L+ patients): 5.8 months (0.5–21.6)

*Only confirmed responses were included.

†CR + PR + SD≥2 months

CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate;

PD, progressive disease; PR, partial response; SD, stable disease.

1. Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28. 2. Adapted from Fuchs C et al. Oral presentation at ASCO 2017. Abstract 4003.

All Patients ¹ (N=259)

Third Line ² (n=134)

Fourth Line+

(n=125) Respons

e* % 95% Cl % 95% Cl % 95% Cl

ORR (CR +

PR) 12 8–17 16.4 10.62–

23.8 6.4 2.8–12.2

CR 3 1-6 3.0 0.8–7.5 1.6 0.2–5.7

PR 9 6–13 13.4 8.2–20.4 4.8 1.8–10.2

SD 16 12–21 NR NR

PD 56 49–62 NR NR

DCR ^† 27 22–33 31.3 23.6–39.9 22.4 15.4–30.7

KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy

PFS and Overall Survival in All Patients

CI, confidence interval; mos, months; no, number; OS, overall survival; PFS, progression free survival.

Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28.

Data cutoff: April 21, 2017.

KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy

P rogr e s s ion -Fre e S urv iv a l, (% )

Time (months)

0 10 20 30 40 50 60 70 80 90 100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Median (95% CI) 6-month rate 2.0 (2.0-2.1) mos 14.6%

No. at Risk

259 137 55 37 28 25 8 6 4 2 1 0 0 0

Ov e ra ll S urv iv a l, (% )

Time (months)

0 10 20 30 40 50 60 70 80 90 100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Median (95% CI) 6-month rate 5.5 (4.2-6.5) mos 45.7%

259 203 147 115 95 78 54 36 27 14 8 2 1 0

No. at Risk

Objective Response by Biomarker Expression

*Only confirmed responses were included. ^†CR + PR + SD≥2 months. ^‡Positivity based on PD-L1 expression on tumour cells, lymphocytes and macrophages.

CI, confidence interval; CPS, combined positive score;CR, complete response; DCR, disease control rate; GEP, gene expression profile; MSI, microsatellite instable; MSI-H, microsatellite instable high; NR, not reported; ORR, objective response rate; PD-L1, programmed death-ligand 1; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease.

1. Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28. 2. Adapted from Fuchs C et al. Oral presentation at ASCO 2017. Abstract 4003.

• 57% of patients were PD-L1 positive as determined by CPS ^‡

• Responses observed regardless of PD-L1 status, although numerically higher in PD-L1+ patients

• 57.1% ORR in MSI-H patients (n=7) versus 9.0% in non-MSI-H (n=167)

• T-cell–inflamed GEP score significantly associated (P=0.014) with improved response to pembrolizumab

18 -G e ne T -c e ll –inf la med G E P S c ore

0.5

Nonresponder Responder 0.0

-0.5

Response

PD-L1 Expression ¹ MSI Status ² PD-L1

Positive (n=148)

PD-L1 Negative

(n=109)

MSI-High (n=7)

Non–MSI-High (n=167)

% 95% CI % 95% CI % 95% CI % 95% CI

ORR 16 11-23 6 3-13 57.1 18.4-90.1 9.0 5.1-14.4

CR 3 1-8 3 1-8 14.3 0.4-57.9 2.4 0.7-6.0

PR 13 8-19 3.7 1-9 42.9 9.9-81.6 6.6 3.3-11.5

SD 18 12-25 15 9-23 NR NR

PD 53 44-61 60 50-69 NR NR

DCR ^† 34 26-42 19 12-28 71.4 29.0-96.3 22.2 16.1-29.2 KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy

18-Gene T-cell–inflamed GEP Score ²

Treatment-Related Adverse Events

 Median (range) duration of exposure was 2.1 (0.0-23.7) months

KEYNOTE-059 Cohort 1: 3L+ Pembrolizumab Monotherapy

aAbnormal hepatic function, bile duct stenosis, encephalitis, increased blood bilirubin level, hyperglycemia, acute kidney injury, and pneumonitis.

AE, adverse event.

Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28. Data cutoff: April 21, 2017.

Event, n (%) N = 259

Any 159 (61)

Grades 3-5

Anemia, grade 3 Fatigue, grade 3 Dehydration, grade 3

46 (18) 7 (3) 6 (2) 3 (1)

Serious 29 (11)

Led to Discontinuation ^a 7 (3) Led to Death

Acute kidney injury Pleural effusion

2 (1)

1 (1)

1 (1)

Efficacy Endpoints

Response ^b

All Patients N=25

PD-L1 Positive ^a n=16

PD-L1 Negative n=8

% (95% CI ^b ) % (95% CI ^b ) % (95% CI ^b )

ORR 60 (39-79) 69 (41-89) 38 (9-76)

DCR

80 (59-93) 75 (48-93) 75 (35-97)

CR 4 (0-20) 0 (0-22) 13 (0-53)

PR 56 (35-76) 69 (41-89) 25 (3-65)

SD 32 (15-54) 19 (4-46) 50 (16-84)

PD 4 (0-20) 6 (0-30) 0 (0-37)

KEYNOTE-059 Cohort 2: 1L Pembrolizumab + Cisplatin + 5-FU/Capecitabine

aPD-L1 positive was defined as combined positive score (CPS) ≥1 (previously reported as and equivalent to CPS ≥1%), where CPS = number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells x 100.^bOnly confirmed responses were included.^cCR + PR + SD ≥6 months.

AE, adverse event; CI, confidence interval; CR, complete response; DCR, disease control rate; mo, month; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression- free survival; PR, partial response; SD, stable disease.

Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28.

12% (n=3) of patients discontinued because of chemotherapy-related AEs (stomatitis, hypoacusis, and increased creatinine level) Progre s s io n -Fre e Surv iv a l, %

Time (months)

0 10 20 30 40 50 60 70 80 90 100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

No. at Risk

25 24 21 17 8 8 5 4 3 3 3 3 0 0

O v e ral l Surv iv a l, %

Time (months)

0 10 20 30 40 50 60 70 80 90 100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

25 24 22 19 18 17 13 12 12 10 8 7 1 0

Median (95%

CI)

6-mo rate 6.6 (5.9-10.6)

mo 68.0% Median (95%

CI) 6-mo rate

13.8 (8.6-NR)

mo 76.0%

Progression-Free Survival

(total population) Overall Survival

(total population)

Data cutoff: April 21, 2017.

• Median (range) follow-up in cohort 2:

13.8 (1.8-24.1) mos

Outcomes in 1L PD-L1+ Patient Population

• Safety was consistent with previous reports, with no new signals identified Overall Survival Confirmed Response ^a

N=31

% 95% CI

ORR (CR + PR) 26 12-45

CR 7 1-21

PR 19 8-38

SD 29 14-48

PD 39 22-58

DCR

36 19-55

Median (Range)

DOR, months 9.6 (2.1-17.8+)

Median (95%

CI)

PFS, months 3.3 (2.0-6.0)

PFS, 6-month rate 34.9%

• Median follow-up:17.5 months (range: 1.7-20.7)

Median (95% CI)

6-mo rate 20.7 mo

(9.2–20.7) 72.9%

KEYNOTE-059 Cohort 3: 1L Pembrolizumab in PD-L1+ Patients

a Only confirmed responses were included. ^bCR + PR + SD ≥6 months.

1L, first line; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not estimable; NR, not reported;

ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to tumour response.

Adapted from Wainberg ZA, et al Oral presentation at ESMO 2017. Abstract LBA28.

Data cutoff: April 21, 2017.

100

90 80 70 60 50 40 30 20 10 0

Ov e ra ll S urv iv a l, %

0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months

No. at risk

31 29 23 21 21 19 18 17 14 9 3 0 0 0

Study Design

Phase 3 randomized, multicenter, double-blinded trial of nivolumab in patients with unresectable advanced gastric or gastroesophageal junction cancer refractory to or intolerant of standard therapy

 Patients were permitted to continue treatment beyond initial RECIST v1.1–defined disease progression, as assessed by the investigator, if receiving clinical benefit and tolerating study drug

 Retrospective determination of tumor PD-L1 expression, defined as staining in ≥1% (or ≥5%) of tumor cells, was performed in a central laboratory using immunohistochemistry (28-8 pharmDx assay) for patients with available tumor samples

AEs, adverse events; BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status;

IV, intravenous; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; Q2W, every two weeks; R, randomization;

TTR, time to treatment response.

Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.

ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients

2:1

Nivolumab 3 mg/kg IV Q2W

Placebo Key eligibility criteria:

•Unresectable advanced or recurrent gastric or

gastroesophageal junction cancer

•Refractory to/intolerant of

≥2 standard therapy regimens

•ECOG PS of 0 or 1

Primary endpoint:

• OS

Secondary endpoints:

• Efficacy (PFS, BOR, ORR, TTR, DOR, DCR)

• Safety

Exploratory endpoint:

• PD-L1 tumor expression ^a Stratification:

•Country (Japan vs South Korea vs Taiwan)

•ECOG PS (0 vs 1)

•Number of organs with metastases (<2 vs ≥2)

R an do mi zati on

Baseline Characteristics

79.1%

ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients

Nivolumab 330 275 192 143 123 97 84 54 34 22 12 7 6 1 0

Placebo 163 121 82 54 37 24 18 8 6 5 4 3 3 2 0

Months

Median OS, months (95% CI)

Nivolumab 5.3 (4.6–6.4) Placebo 4.1 (3.4–4.9)

Hazard ratio, 0.62 (95% CI: 0.50–0.76) P < 0.0001

No. at Risk

12-month OS rate 27%

12%

24-month OS rate

*Time from first dose to data cut-off for surviving patients.

CI, confidence interval; OS, overall survival.

Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.

Overall Survival

ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients

O v er all S u rv iv al (% )

2

0 4 6 8 10 12 14 16 18 20 22 24 26 28

0 10 20 30 40 50 60 70 80 90 100

• Compared to placebo, treatment with nivolumab resulted in a 38% reduction in risk of death

12%

5%

Placebo

Nivolumab

Median follow-up*: 15.7 months (range, 12.1–27.2)

PD-(L)1 Inhibition Demonstrated Long-Term OS Benefits Across Tumor Types

2L, second line; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; KN, KEYNOTE; Nivo, nivolumab; NSCLC, non-small cell lung cancer; OS, overall survival; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; R/M, recurrent or metastatic; SCCHN, squamous cell carcinoma of the head and neck.

1. Adapted from Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813. 2. Adapted from Borghaei H et al. Poster presentation at ASCO 2016. 9025. 3. Adapted from Ferris RL et al. Oral presentation at ASCO 2016. 6009. 4. Adapted from Rittmeyer A et al. Lancet. 2017;389:255-26. 5. Adapted from Herbst RS et al. Oral presentation at WCLC 2016. 6769.

Checkmate 057: Non-squamous NSCLC

Time (months)

OS (% )

Docetaxel Nivolumab Checkmate 025: Nivo Monotherapy in 2L+ RCC

27 18

15 9

6 12 21

3

0 24 30

0 3 6 9 12 15 18 21 24 27 30 33

OS (% )

Time (months)

Everolimus Nivolumab 100

80 60

0 40 20

100 80 60 40

0 20

Checkmate 141: Nivolumab in R/M SCCHN After Platinum Therapy

Time (months)

OS (% )

Nivolumab 100

Investigators Choice Checkmate 017: Squamous NSCLC

OS (% )

0 3 6 9 12 15 18

33 27

24 21 18 15 12 9 6 3

0 30

Docetaxel Nivolumab

Time (months) 100

80 60 40

0 20

0 20 40 60 80

OAK: 2L+ NSCLC (ITT population)

100

OS ( % )

Time (months)

Docetaxel

Atezolizumab

KN-010: ≥1% PD-L1 2L+ NSCLC

OS (% )

0 20 40 60 80 100

0 3 6 9 12 15 18 21 24 27 0 5 10 15 20 25 30 35

Pembro 2 Docetaxel Pembro 10

Time (months) 0

20 40 60 80

HR=0.73 (98.5% CI: 0.57–0.93)

HR=0.62 (95% CI: 0.47–0.80)

HR=0.75 (95% CI: 0.63–0.91)

HR=0.70 (95% CI: 0.51–0.96)

Pembro 2: HR=0.72 (95% CI: 0.60–0.86) HR=0.73 (95% CI: 0.62–0.87)

Pembro 10: HR=0.60 (95% CI: 0.49–0.72)

0 10 20 30 40 50 60 70 80 90 100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

0 10 20 30 40 50 60 70 80 90 100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 ONO- 4538 Placeb o

PD-L1 <1% PD-L1 ≥1%

Median OS, months (95% CI)

Nivolumab (n=114)

6.1 (4.8–8.6)

Placebo (n=52)

4.2 (3.0–6.9)

Hazard ratio: 0.71 (95% CI: 0.50–1.01)

Median OS, months (95% CI)

Nivolumab (n=16)

5.2 (2.8–9.4)

Placebo (n=10)

3.8 (0.8–5.0)

O v er all S u rv iv al (% )

Nivolumab 11 4

10

0 75 56 49 42 37 24 15 11 7 3 2 1 0

Placebo 52 40 27 22 16 14 11 6 5 4 3 2 2 2 0

Nivolumab 16 15 10 7 5 4 4 2 2 0 0 0 0 0 0

Placebo 10 8 4 2 1 1 1 0 0 0 0 0 0 0 0

Months Months

No. at Risk

*n=192 PD-L1 evaluable patients.

CI, confidence interval; OS, overall survival; PD-L1, programmed death ligand 1.

Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.

Overall Survival by PD-L1 Expression Level

ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients

Survival advantage was observed for nivolumab versus placebo regardless of PD-L1 expression

Hazard ratio: 0.58 (95% CI: 0.24–1.38)

O v er all S u rv iv al (% )

No. at Risk

• 26/192 patients were determined to be PD-L1 positive as detected by DAKO 28-8 of tumor cells only

Nivolumab 3 mg/kg (n = 268)

Placebo (n = 131)

ORR, n (%) 95% CI P value

31 (12) 8–16 P<0.0001

0–2.8 0

Best Overall Response, n (%)

CR 0 0

PR 31 (12) 0

SD 77 (29) 33 (25)

PD 124 (46) 79 (60)

NE 36 (13) 19 (15)

DCR, n (%) 95% CI P value

108 (40) 34.4–46.4

P=0.0036

33 (25) 18.0–33.5

Median TTR*, mos (range) 1.6 (1.4–7.0) —

Median DOR*, mos (95% CI) 9.8 (6.4–20.5) —

Efficacy

*n=31 patients.

2L, second line; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; mos, months; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumours; SD, stable disease; TTR, time to tumour response.

Adapted from Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.

ATTRACTION-02 (ONO-4538-12): 2L+ Nivolumab Monotherapy

Patients, n (%)

Nivolumab 3 mg/kg n = 330

Placebo n = 161 Any

Grade

Grade 3–

4

Any Grade

Grade 3–

4

Any treatment-related AE 142 (43) 36 (11) 43 (27) 7 (4) Serious treatment-related AEs 35 (11) 23 (7) 8 (5) 4 (2) Treatment-related AEs leading to

discontinuation 9 (3) 4 (1) 4 (2) 3 (2)

Treatment-related AEs leading to

dose delay 29 (9) 16 (5) 2 (1) 1 (<1)

Treatment-related deaths 5 (2) 2 (1)

Treatment-related AEs (>2%) Pruritus

Diarrhea Rash Fatigue

Decreased appetite Nausea

Malaise

AST increased Hypothyroidism Pyrexia

ALT increased

30 (9) 23 (7) 21 (6) 18 (5) 16 (5) 15 (5) 13 (4) 11 (3) 11 (3) 9 (3) 8 (2)

0 2 (<1)

0 2 (<1)

4 (1) 0 0 2 (<1)

0 1 (<1) 1 (<1)

9 (6) 3 (2) 5 (3) 9 (6) 7 (4) 4 (2) 6 (4) 3 (2) 1 (<1)

3 (2) 1 (<1)

0 0 0 2 (1) 1 (<1)

0 0 0 0 0 0

AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Adapted from Boku N et al. Oral presentation at ESMO 2017. Abstract 617O.

Safety Summary

ATTRACTION-02 (ONO-4538-12): Nivolumab in Asian Patients

Study Design

*Nivolumab + ipilimumab combination treatment administered for 4 cycles followed by nivolumab 3 mg/kg IV Q2W. ^† Time from first dose to data cut-off; follow-up was shorter for patients who died prior to data cut-off.

1L, first line; EG, esophagogastric (included gastric/esophageal/gastroesophageal junction cancer), ORR, objective response r ate; OS, overall survival; PD L1, programmed death-ligand 1; PFS, progression-free survival; Q2W, once every two weeks;

Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumours.

Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.

Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W*

(NIVO 3 + IPI 1) n=52 Nivolumab 1 mg/kg +

Ipilimumab 3 mg/kg IV Q3W*

(NIVO 1 + IPI 3) n=49 Nivolumab 3 mg/kg IV Q2W

(NIVO 3) n=59

Western patients with advanced/metastatic EG cancer with progression on ≥1 prior chemotherapy

N = 160

Median (range)

follow-up, mo

: 28 (17 to 35) 24 (21 to 33) 22 (19 to 25)

Primary endpoint: Secondary endpoints: Exploratory endpoint:

• ORR per RECIST v1.1 • OS

• PFS

• Time to response

• Duration of response

• Safety

• PD-L1 tumor expression (Dako 28-8 pharmDx assay)

• ORR and OS by MSI status

Checkmate 032: 2L+ Nivolumab ± Ipilimumab in Western Patients

Objective Response

NIVO 3 n = 59

NIVO 1 + IPI 3 n = 49

NIVO 3 + IPI 1 n = 52

ORR, n (%)* 7 (12) 12 (24) 4 (8)

[95% CI] [5, 23] [13, 39] [2, 19]

BOR, n (%)*

Complete response 1 (2) 1 (2) 0

Partial response 6 (10) 11 (22) 4 (8)

Stable disease 12 (20) 8 (16) 15 (29)

Progressive disease 34 (58) 23 (47) 24 (46)

Not evaluable 6 (10) 6 (12) 9 (17)

DCR, n (%) ^† 19 (32) 20 (41) 19 (37)

Median TTR (range),

months 1.6 (1.2 to 4.0) 2.7 (1.2 to 14.5) 2.6 (1.3 to 2.8) Median DOR (95% CI),

months 7.1 (3.0, 13.2) 7.9 (2.8, NE) NR (2.5, NE)

* Investigator review. ^† Patients with a BOR of complete response, partial response, or stable disease.

2L, second line; BOR, best objective response; CI, confidence interval; DCR, disease control rate; DOR, duration of response; IV, intravenous; NE, not estimable; NIVO 3, nivolumab

3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO3 + IPI, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; NR, not reached; Q2W, once every two weeks; Q3W, once every 3 weeks; TTR, time to treatment response.

Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.

Checkmate 032: 2L+ Nivolumab ± Ipilimumab

mPFS (95%

CI), months

6-month PFS rate,

%

12-month PFS rate,

%

NIVO 3 1.4 (1.2–1.5) 17 8

NIVO 1 + IPI 3 1.4 (1.2–3.8) 24 17

NIVO 3 + IPI 1 1.6 (1.4–2.6) 12 10

Progression-Free Survival and Overall Survival

*Investigator review.

1L, first line; CI, confidence interval; mOS, median OS; mPFS, median PFS; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO 3 + IPI 1, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; OS, overall survival; PFS, progression-free survival; Q2W, once every two weeks; Q3W, once every 3 weeks.

Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.

Progression-Free Survival Overall Survival

mOS (95%

CI), months

12- month

OS rate, %

18- month

OS rate, %

NIVO 3 6.2 (3.4–12.4) 39 25

NIVO 1 + IPI 3

6.9 (3.7–11.5) 35 28

NIVO 3 + IPI 1

4.8 (3.0–8.4) 24 13

Checkmate 032: 2L+ Nivolumab ± Ipilimumab

No. at Risk:

59 13 10 6 5 3 1 1 1 1 0

P robabi li ty of P FS *

Time (months) 0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

3 6 9 12 15 18 21 24 27 30

49 16 10 7 6 5 5 4 1 0 0

52 13 5 4 4 3 2 2 0 0 0

NIVO 3

NIVO 3 + IPI 1 NIVO 1 + IPI 3

59 40 26 21 20 15 11 5 5 4 1 0

Time (months)

P robabi li ty of S urv iv a l

0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

3 6 9 12 15 18 21 24 27 30 33

49 35 24 19 14 14 11 8 3 0 0 0

52 33 20 18 11 8 4 3 0 0 0 0

No. at Risk:

NIVO 3

NIVO 3 + IPI 1

NIVO 1 + IPI 3

Efficacy by PD-L1 Status ¹ and MSI-H Status ²

NIVO 3 n=59

NIVO 1 + IPI 3 n=49

NIVO 3 + IPI 1 n=52

PD-L1 expression ≥1%

n=16

<1%

n=26

≥1%

n=10

<1%

n=32

≥1%

n=13

<1%

n=30 OS rate (95% CI), %

12 mos 34 (12–57) 45 (25–62) 50 (18–75) 32 (16–48) 23 (6–47) 25 (11–42)

ORR, % 19 12 40 22 23 0

MSI-H expression MSI-H n = 7

Non-MSI-H n = 18

MSI-H n = 2

Non-MSI-H n = 21

MSI-H n = 2

Non-MSI-H n = 22 OS rate (95% CI), %

12 mos 57 (17–84) 33 (14–54) 50 (1–91) 36 (16–56) 50 (1–91) 23 (8–43) 18 mos 29 (4–61) 17 (4–36) 50 (1–91) 30 (12–50) 50 (1–91) 6 (0–23)

ORR, n (%)* 2 (29) 2 (11) 1 (50) 4 (19) 1 (50) 1 (5)

DCR, n (%) ^† 5 (71) 5 (28) 1 (50) 9 (43) 1 (50) 8 (36) mDOR (95% CI),

mos 10 (7–13) NR (3–NE) NR (NE–NE) 5 (3–NE) NR (NE–NE) 3 (NE–NE)

*Investigator Review. ^† Patients with a BOR of complete response, partial response, or stable disease.

2L, second line; CI, confidence interval; DCR, disease control rate; DOR, duration of response; mos, months; mDOR, median duration of response; MSI-H, microsatellite instability high; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 3 + IPI 1, 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO3 + IPI Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1.

1. Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014. 2. Ott P et al. Poster presentation at ESMO 2017. Abstract 674P.

• Responses were observed irrespective of PD-L1

• Clinical activity and durable responses were observed in both MSI-H and non-MSI-H patients

Checkmate 032: 2L+ Nivolumab ± Ipilimumab

Patients, n (%)

NIVO 3 n=59

NIVO 1 + IPI 3 n=49

NIVO 3 + IPI 1 n=52

Any

Grade Grade 3–4 Any

Grade Grade 3–4 Any

Grade Grade 3–4

Any TRAE 41 (69) 10 (17) 41 (84) 23 (47) 39 (75) 14 (27)

Serious TRAEs 6 (10) 3 (5) 21 (43) 17 (35) 13 (25) 9 (17)

TRAEs leading to treatment

discontinuation

2 (3) 2 (3) 10 (20) 10 (20) 7 (13) 5 (10)

TRAEs in ≥15% of

patients in any treatment arm

ALT increased 5 (8) 2 (3) 8 (16) 7 (14) 5 (10) 2 (4)

AST increased 7 (12) 3 (5) 8 (16) 5 (10) 2 (4) 1 (2)

Decreased appetite 9 (15) 0 5 (10) 0 3 (6) 0

Diarrhea 9 (15) 1 (2) 15 (31) 7 (14) 5 (10) 1 (2)

Fatigue 20 (34) 1 (2) 14 (29) 3 (6) 10 (19) 0

Pruritus 10 (17) 0 9 (18) 1 (2) 12 (23) 0

Rash 5 (8) 0 10 (20) 0 8 (15) 0

Treatment-Related Adverse Events

 One Grade 5 TRAE was reported (tumor lysis syndrome in a patient treated with NIVO 3 + IPI 1)

2L, second line; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO 3 + IPI 1, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; Q2W, once every two weeks; Q3W, once every 3 weeks. TRAE, treatment-related adverse event.

Janjigian Y et al. Oral presentation at ASCO 2017. Abstract 4014.

Checkmate 032: 2L+ Nivolumab ± Ipilimumab

Study Design ^1,2

Randomized, multicenter, phase 2/3 trial of nivolumab + chemotherapy as first- line treatment in patients with unresectable advanced or recurrent GC or GEJC

Key Inclusion Criteria

• Treatment-naïve patients

• Unresectable advanced or recurrent HER2-negative GC/GEJC

• ECOG PS 0–1

• Neoadjuvant or adjuvant chemotherapy completed

≥180 days prior to recurrence

• Primary Outcome Measures:

– PFS (Part 2) – OS (Part 2)

• Secondary Outcome Measures:

– ORR, PFS, DOR, DCR, TTR, BOR, lesion size (Part 2) – Safety (Parts 1 and 2)

• Start Date: March 2016

• Estimated Study Completion Date: NA

• Estimated Primary Completion Date: August 2020

• Status: Recruiting

• Study Sites: Japan, Korea, Taiwan

• Study Director: Ono Pharmaceutical/Bristol-Myers Squibb

Nivolumab 360 mg IV Q3W + SOX*

*IV oxaliplatin 130 mg/m² on day 1 followed by 20 days off and oral SOX or oral capecitabine twice daily for 14 days followed by 7 days. SOX dose was mg/m²/dose (body surface area <1.25 m², 40 mg/dose; ≥1.25 and <1.5 m², 50 mg/dose; ≥1.5 m², 60 mg/dose. Capecitabine dose was 1,000 mg/m²/dose (body surface area <1.36 m², 1,200 mg/dose; 1.36 and <1.66 m², 1,500 mg/dose; 1.66 and <1.96 m², 1,800 mg/dose; 1.96 m², 2,100 mg/dose). Treatment continued until progressive disease per RECIST v1.1, unacceptable toxicity, or withdrawal of consent. ^†Investigator will choose SOX or CapeOX therapy, taking into account the condition of each patient.

1L, first line; BOR, best overall response; CapeOX, capecitabine, oxaliplatin; chemo, chemotherapy; CR, complete response; DCR, disease control rate; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HER2, human epidermal growth factor receptor 2; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PS, performance status; R, randomized;

RECIST, Response Evaluation Criteria In Solid Tumours; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TTR, time to response.

1. Clinicaltrials.gov. NCT02746796. Accessed June 27, 2017. 2. Adapted from Kang YK. Poster presentation at ESMO 2017. Abstract 671P.

Part 1 (n=40) Part 2 (n=~650)

R

Placebo + SOX/CapeOX

Nivolumab + SOX/CapeOX

Nivolumab 360 mg IV Q3W + CapeOX*

ATTRACTION-04 (ONO-4538-37): 1L Nivolumab + SOX/CapeOX

R 1:1

• Continuation to Part 2 criteria:

– Confirmed tolerability and safety – At least 2/15 subjects had

CR or PR by RECIST v1.1

Efficacy

ATTRACTION-04 (ONO-4538-37) Part 1: 1L Nivolumab + SOX/CapeOX

aDefined as disappearance of all non-lymph node target lesions. Any pathological target lymph nodes must have had a reduction in the short axis to <10 mm. ^bDefined as the percentage of patients in whom the BOR is CR, PR, or SD. ^COne patient had a protocol deviation of nivolumab treatment for another study and was excluded from efficacy analyses.

1L, first line; BOR, best overall response; CapeOX, capecitabine, oxaliplatin; CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not evaluable; Nivo, nivolumab; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TTR, time to treatment response.

Adapted from Kang YK. Poster presentation at ESMO 2017. Abstract 671P.

Time Since Treatment Initiation (months) Cha ng e From Bas e li ne in th e Sum o f the Lo ng e s t Ta rge t Le s io n Dia m e te rs, (% )

Tumor Reduction

Nivo + CapeOx

Time Since Treatment Initiation (months)

-30% Tumor Reduction 20% Tumor Increase 20% Tumor Increase

-30% Tumor Increase

0 1 2 3 4 5 6 7 8 9 10

-100 -75 -25 0 25 50

-50

0 1 2 3 4 5 6 7 8 9 10

-100 -75 -25 0 25 50

-50

Discontinued On-treatment

Nivo + SOX

Cha ng e From Bas e li ne in th e Sum o f the Lo ng e s t Ta rge t Le s io n Dia m e te rs, (% )

Discontinued On-treatment

Nivolumab + SOX n=21

Nivolumab + CapeOX n=17 ^c

ORR, % (95% CI) 67 (43–85) 71 (44–90)

BOR, n (%)

CR

1 (5) 0

PR 13 (62) 12 (71)

SD 4 (19) 2 (12)

PD 2 (10) 2 (12)

Not evaluable 1 (5) 1 (6)

DCR,

n (%) 18 (86) 14 (82)

Median TTR, months (range) 2.1 (1.2–4.3) 1.4 (1.2–4.3)

Median DOR, months (95% CI) NR (4.3–NE) 5.8 (2.8–NE)

Safety

ATTRACTION-04 (ONO-4538-37) Part 1: 1L Nivolumab + SOX/CapeOX

*One patient had grade 2 increased aspartate aminotransferase attributed to nivolumab and grade 2 intracranial hemorrhage att ributed to SOX and one patient had grade 3 increased alanine aminotransferase attributed to nivolumab.

1L, first line; CapeOX, capecitabine, oxaliplatin; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TRAE, treatment-related adverse event.

Adapted from Kang YK. Poster presentation at ESMO 2017. Abstract 671P.

Patients, n (%)

Nivolumab + SOX n=21

Nivolumab + CapeOX n=18

Any grade Grade 3–4 Any grade Grade 3–4 Any treatment-related AE 21 (100) 11 (52) 18 (100) 12 (67) Treatment-related AEs leading to

discontinuation 2 (10) ^a 1 (5) 0 0

Treatment-related AEs leading to

dose delay 10 (48) 5 (24) 8 (44) 4 (22)

Treatment-related deaths 0 0

Treatment-related AEs (≥25%)

Diarrhea 13 (62) 1 (5) 8 (44) 1 (6)

Peripheral sensory neuropathy 12 (57) 1 (5) 12 (67) 2 (11)

Decreased appetite 11 (52) 0 10 (56) 2 (11)

Nausea 10 (48) 0 9 (50) 2 (11)

Decreased neutrophil count 10 (48) 3 (14) 10 (56) 1 (6)

Decreased platelet count 9 (43) 0 4 (22) 1 (6)

Fatigue 7 (3) 0 6 (33) 1 (6)

Peripheral neuropathy 6 (29) 1 (5) 2 (11) 0

Constipation 5 (24) 0 5 (28) 0

Vomiting 5 (24) 0 6 (33) 0

Peripheral edema 5 (24) 0 1 (6) 0

Palmar-plantar erythrodysesthesia

syndrome 0 0 8 (44) 0

Slide 30

JAVELIN Basket Trial: Avelumab

Chung et al, Abstract 4009, ASCO 2016

Slide 32

JAVELIN Basket Trial: Avelumab

Chung et al, Abstract 4009, ASCO 2016

NCT02443324: Phase 1 Multi-Cohort Study of Ramucirumab Plus Pembrolizumab

Phase 1a: DLT Assessment

(n=6 to 12)

Primary: Safety and tolerability

Secondary: PK

Schedule 1:

Ram 8mg/kg, Day 1 and 8 Pembro 200 mg fixed, Day 1 Both IV every 3 weeks

Schedule 2:

Ram 10 mg/kg, Day 1 Pembro 200 mg fixed, Day 1 Both IV every 3 weeks

Phase 1b: Cohort Expansion (n=155)

Primary: Safety and tolerability Secondary: PK and efficacy Exploratory: Biomarkers and IG

Cohort A: Gastric/GEJ (2L+) Cohort A2: Gastric/GEJ (1L)

Cohort B: Gastric/GEJ (2L+)

In te rim A na ly s is

All treated patients

≥2nd-Line Cohorts A/B,

n=41

1st-Line Cohort A2,

n=28 Median follow-up

duration, mo (95% CI)

10.3

(9.7–15.5) 4.6 (2.3–5.8) BOR, n (%)

CR – –

PR 3 (7) 4 (14)

SD 18 (44) 14 (50)

PD 13 (32) 5 (18)

Not Evaluable 7 (17) 5 (18)

ORR 7% ^b 14% ^c

DCR ^d 51% 64%

Median DOR, mo (95% CI)

6.7 (4.4–6.7) NR Median TTR, mo

(95% CI)

1.4 (1.4–4.1) 2.0 (1.3–3.6) Duration of SD, mo

(95% CI)

5.0 (4.0–8.5) 5.6 (3.2–5.8)

Efficacy Outcomes in Evaluable Patients

aPatients may continue treatment for up to 35 cycles, until confirmed progressive disease or discontinuation for any other reason. ^bObjective response rate in the response evaluable population (n=34) was 9%. ^cObjective response rate in the response evaluable population (n=23) was 17%. ^dPatients with best response of CR, PR, or SD.

1L, first line; 2L, second line; BOR, best overall response; CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; GC, gastric cancer; GEJ, gastroesophageal junction; GEJC, GEJ cancer; IG, immunogenicity; NR, not reached; ORR, objective response rate; PD, progressive disease; PK, pharmacokinetics; PR, partial response; Pembro, pembrolizumab; Ram, ramucirumab; SD, stable disease; TTR, time to response.

Adapted from Chau I et al. Poster presentation at ASCO 2017. Abstract 4046, showing only the GC/GEJC cohorts.

• The safety profile of ramucirumab combined with pembrolizumab is consistent with

monotherapy treatment for each drug, with no additive toxicities

NCT02572687: A Multi-Cohort Phase 1 Study of Ramucirumab Plus Durvalumab

G/GEJ N=26 BOR, n (%)

CR -

PR 4 (15%)

SD 8 (31%)

PD 11 (42%)

NE ^b 3 (12%)

ORR, n (%) 4 (15%) ^c

DCR

(CR+PR+SD), n (%) 12 (46%) ^d Median DOR,

mos (95% CI) 5.6 (-,-)

Median TTR, mos (95% CI) 1.5 (1.3, 5.6)

aPatients are treated until confirmed progressive disease, or any other decision to discontinue. ^bPatients have not had their first scan on treatment. ^cObjective response rate in the response evaluable population (n=23) was 17%. ^dDisease control rate in the response evaluable population (n=23) was 52%.

BOR, best overall response; CI, confidence interval; CR, complete response; DCR, disease control rate; DLT, dose limiting toxicities; DOR, duration of response; G, gastric;

GEJ, gastroesophageal junction; IG, immunogenicity; mos, months; NE, not evaluable; ORR, objective response rate; PK, pharmacokinetics; PR, partial response; Q2W, every 2 weeks; SD, stable disease; TTR, time to response.

Adapted from Golan T et al. Poster presentation at 19^th World Congress on Gastrointestinal Cancer. Abstract PD-010 to show only GC/GEJC cohorts.

Phase 1a Phase 1b

Cohort Expansion

(n=~60 patients) Primary: Safety

Secondary: PK, IG, preliminary efficacy Exploratory: Biomarker

DL T Rev iew

G/GEJ

(28-day treatment cycle) Ramucirumab 8 mg/kg Q2W

Durvalumab 750 mg Q2W

Summary of Responses

• Combination of durvalumab and ramucirumab in patients with advanced G/GEJ

adenocarcinoma did not reveal any unexpected safety signals

• No SOC ⁵ FP/Pt ± RT

• Ramucirumab ± paclitaxel ^3,4

• Irinotecan, docetaxel or paclitaxel ¹ 2L

• Pt + FP doublet- or triplet- based regimen

• Trastuzumab + cisplatin + capecitabine/5-FU

(Neo)Adjuvant ¹

HER2 positive HER2 negative 1L ¹

• 6–8 cycles or until disease progression

Maintenance

Potential for checkpoint inhibitor Ab therapy

± other I-O agents

± antiangiogenics

± cytotoxics

± other targeted therapy

If prolonged progression- free interval after 1L, can

rechallenge with Pt/FP ²

May discontinue due to toxicity or

infection

1L, first line; 2L, second line; 3L, third line; 5-FU, 5-fluorouracil; Ab, antibody; FP, fluoropyrimidine; HER2, human epidermal growth factor 2; I-O, immuno-oncology; Pt, platinum;

RT; radiation therapy; SOC, standard of care.

1. Waddell T et al. Ann Oncol. 2013;24(suppl 6):vi57-vi63. 2. Hershman DL et al. J Clin Oncol. 2014;32(18):1941-1967. 3. Fuchs CS et al. Lancet. 2014;383(9911):31-39. 4. Wilke H et al. Lancet Oncol. 2014;15(11):1224-1235. 5.

Smyth EC et al. Ann Oncol. 2016;27(suppl 5):v38-v49.7.

Future Directions in Gastric Cancer

3L+

Agenda

 “Mutation burden” and Immunogenicità

 Immunonoterapia nel carcinoma gastrico

 Immunonoterapia nel carcinoma colo-rettale

Slide 3

Molecular classification of colon cancer

Guinney et al, Nature Medicine 2015

Slide 4

Mutational load differences

Histology of MSI Cancers

Histology of MSI cancers

Slide 6

dMMR in colorectal cancer

15% of colorectal carcinomas across

all stages

Slide 9

Galon et al, ASCO 2016

Immunoscore as prognostic marker in stage

I/II/III colon cancer

Slide 7

Immunoscore as prognostic marker in stage I/II/III colon cancer

Galon et al, ASCO 2016

Slide 8

Immunoscore as prognostic marker in stage I/II/III colon cancer

Galon et al, ASCO 2016

Slide 18

Immunoscore as prognostic marker in stage I/II/III colon cancer

Galon et al, ASCO 2016

The immunoscore study

Immunoscore as prognostic marker in stage

I/II/III colon cancer

Study implications

Immunoscore as prognostic marker in stage

I/II/III colon cancer

Single agent anti-PD1 in mCRC

MSI-H in mCRC ≈ 4%

dMMR Status: Prevalence

dMMR/MSI-H Status and Outcomes in mCRC

dMMR, n (%)

pMMR, n

(%) Total, N

CAIRO* 18 (5.6%) 304 (94.4%) 322 CAIRO2* 29 (5.6%) 487 (94.4%) 516

COIN ^† 65 (4.4%) 1396

(95.6%) 1461 FOCUS ^‡ 41 (5.4%) 723 (94.6%) 764 Pooled data

set 153 (5.0%) 2910

(95.0%) 3063

*dMMR testing assessed by IHC, with PCR in the absence of MMR protein expression. ^†dMMR testing assessed by PCR. ^‡dMMR testing assessed by IHC.

CRC, colorectal cancer; dMMR, mismatch repair deficient; HR, hazard ratio; MSI-H, microsatellite instability high; OS, overall survival; pMMR, mismatch repair proficient.

1. Venderbosch S et al. Clin Canc Res. 2014;20:5322-5530. 2. Tabernero J (Venook AP).

Presented at ASCO 2017.

CALGB/SWOG 80405

Median OS (95% CI)

MSI-H MSS 1.00

0.75

0.50

0.25

0 12 24 36 48 60 72

Time From Randomization (months) Propo rtion W ith ou t Ev e nt

0.00

n=31 n=444

21.0 months (11.8–41.8) 33.3 months (30.1–35.7) Unadjusted model HR: 1.39, P=0.13

Overall Survival: Pooled Data Set

_{Median OS}

dMMR BRAF mutation (n=53): 11.7 months dMMR BRAF wild-type (n=100): 15.0 months pMMR BRAF mutation (n=197): 11.3 months pMMR BRAF wild-type (n=2713): 17.3 months BRAF

and pMMR

BRAF

pMMR 1.0

0.8

0.6

0.4

0.2

0 10 20 30 40 50 60

OS (months)

Surv iv a l Proba bi li ty

P<0.001

0.0

BRAF

and dMMR

BRAF

dMMR

Checkpoint Inhibition Represents a Logical Therapeutic Target in dMMR/MSI-H mCRC

 dMMR/MSI-H tumors are highly immunogenic, which may make these tumors susceptible to

immune checkpoint inhibitors ¹

 dMMR/MSI-H mCRC tumors exhibit high mutational load, increased

presence of tumor-specific neoantigens, and increased immune infiltration ^1,2

 Several immune checkpoint

proteins,including PD-1, PD-L1 and CTLA-4, may be highly expressed ²

CTLA-4, cytotoxic T-lymphocyte antigen 4; dMMR, mismatch repair deficient; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high;

PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; TIL, tumor-infiltrating lymphocyte.

1. Llosa NJ et al. Cancer Discov. 2015;5(1):43-51. 2. Le DT et al. N Engl J Med. 2015;372(26).2509-2520.

Selected Planned/Ongoing Immuno-Oncology Trials for dMMR/MSI-H mCRC ¹

Combination Therapy Monotherapy

Checkmate 142: Ph 2 1L, nivolumab + ipilimumab

KEYNOTE-177: Ph 3 1L, pembrolizumab vs chemo ±

bevacizumab/cetuximab

COMMIT (NCT02997228): Ph 3 1L, FOLFOX + bevacizumab ±

atezolizumab

* Chemotherapy (standard treatment; FOLFOX or FOLFIRI) ± targeted therapy(panitumumab, cetuximab, bevacizumab, or afibercept)

1L, first line; 2L, second line; chemo, chemotherapy; dMMR, mismatch repair deficient; FOLFOX, fluorouracil + leucovorin + oxaliplatin; mFOLFOX, leucovorin calcium + fluorouracil + oxaliplatin; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high.

1. Clinicaltrials.gov. Accessed June 27, 2017. 2. Paul B et al. Immunotherapy. 2016;8(6):693-704.

• Treatment of dMMR/MSI-H mCRC with immuno-oncology compounds has shown promising results ² Checkmate 142: Ph 2 2L+, nivolumab + BMS-986016

(anti-LAG3)

Corvus (NCT02655822): Ph 1 2L-6L, atezolizumab ± CPI-444

ECHO-202/KEYNOTE-037: Ph 1/2 2L+, pembrolizumab + epacadostat

LEGEND

Clinical trial is not yet opened Clinical trial is ongoing

Checkmate 142: Ph 2 2L+, nivolumab + ipilimumab

1L 2L+

SAMCO (NCT03186326): Ph 2 2L+, avelumab vs chemo ± targeted

therapy*

Checkmate 142: Ph 2 2L+, nivolumab monotherapy

KEYNOTE-164: Ph 2 2L, pembrolizumab

NCT02227667: Ph 2

3L+, durvalumab