i tumori gastrointestinalimedia.aiom.it/userfiles/files/doc/aiom-servizi/... · immunonoterapia nel...

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

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

cells1-6

Potential Immuno-Oncology Targets in

GI Cancers1

*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 detection2

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




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

Cu

mu

lati

ve

Su

rviv

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)

24 144 120

PD-L1 Expression

Negative

Positive

Negative-censored

Positive-censored

• PD-L1 is associated with poor prognosis in gastric cancer patients1

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

inhibition may be an effective therapy2

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

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

2L

+

NCT02864381*: Ph 2 Nivolumab ± andecaliximab

ECHO-203: Ph 1/2 Durvalumab ± epacadostat

KEYNOTE-059*: Ph 2 Pembrolizumab

1L

+ 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

Neo

-

/Ad

j

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/m2 q3w +

5-FU 800 mg/m2 q3w or

Capecitabine 1000 mg/m2 q3w*

Follow-up for

survival by

telephone

until death,

withdrawal, or

study end

n=252

n=2591

n=313

Objective Response

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

Median (range) follow-up in cohort 1 (3L and 4L+ patients): 5.8 months (0.5–21.6)2

*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 Patients1 (N=259)

Third Line2 (n=134)

Fourth Line+ (n=125)

Response*

% 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.


Pro

gre

ss

ion

-Fre

e S

urv

iva

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

Ove

rall

Su

rviv

al,

(%

)

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

en

e T

-cell–in

flam

ed

GE

P S

co

re

0.5

Nonresponder Responder

0.0

-0.5

Response

PD-L1 Expression1 MSI Status2

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


18-Gene T-cell–inflamed GEP Score2

Treatment-Related Adverse Events

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


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 Discontinuationa 7 (3)

Led to Death

Acute kidney injury

Pleural effusion

2 (1)

1 (1)

1 (1)

Efficacy Endpoints Responseb

All Patients N=25

PD-L1 Positivea n=16

PD-L1 Negative n=8

% (95% CIb) % (95% CIb) % (95% CIb)

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

DCRc 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)

Pro

gre

ss

ion

-Fre

e S

urv

iva

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

Ove

rall

Su

rviv

al,

%

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)


• 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 Responsea

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

DCRb 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.


100

90

80

70

60

50

40

30

20

10

0

Ove

rall

Su

rviv

al,

%

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

expressiona

Stratification:

•Country (Japan vs South Korea

vs Taiwan)

•ECOG PS (0 vs 1)

•Number of organs with metastases

(<2 vs ≥2)

Ra

nd

om

iza

tio

n

Baseline Characteristics

79.1%


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.


Overall Survival


Ov

era

ll S

urv

ival (%

)

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 NSCLC2

Time (months)

OS

(%

)

Docetaxel

Nivolumab

Checkmate 025: Nivo Monotherapy in 2L+ RCC1

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

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 Therapy3

Time (months)

OS

(%

)

Nivolumab

100

Investigators Choice

Checkmate 017: Squamous NSCLC2

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)4

100

OS

(%

)

Time (months)

Docetaxel

Atezolizumab

KN-010: ≥1% PD-L1 2L+ NSCLC5

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)

Ov

era

ll S

urv

ival (%

)

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.


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)

Ov

era

ll S

urv

ival (%

) 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 0–2.8

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


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 rate; 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.


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.


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


No. at Risk:

59 13 10 6 5 3 1 1 1 1 0

Pro

ba

bil

ity o

f 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)

Pro

ba

bil

ity o

f S

urv

ival

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 Status1 and MSI-H Status2

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


Patients, n (%)

NIVO 3 n=59

NIVO 1 + IPI 3 n=49

NIVO 3 + IPI 1 n=52

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.



Study Design1,2

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)

Ch

an

ge

Fro

m B

as

eli

ne

in

th

e S

um

of

the

Lo

ng

es

t T

arg

et

Le

sio

n D

iam

ete

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

Ch

an

ge

Fro

m B

as

eli

ne

in

th

e S

um

of

the

Lo

ng

es

t T

arg

et

Le

sio

n D

iam

ete

rs,

(%)

Discontinued

On-treatment

Nivolumab + SOX n=21

Nivolumab + CapeOX n=17c

ORR, % (95% CI) 67 (43–85) 71 (44–90)

BOR, n (%)

CRa 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,b 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 attributed 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

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)a

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+)

Inte

rim

An

aly

sis

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

DCRd 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%)

NEb 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 19th World Congress on Gastrointestinal Cancer. Abstract PD-010 to show only GC/GEJC cohorts.

Phase 1a Phase 1b

Cohort Expansiona

(n=~60 patients)

Primary: Safety

Secondary: PK, IG, preliminary efficacy

Exploratory: Biomarker DL

T R

ev

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 SOC5 FP/Pt ± RT

• Ramucirumab ± paclitaxel3,4

• Irinotecan, docetaxel or paclitaxel1

2L

• Pt + FP doublet- or triplet- based regimen

• Trastuzumab + cisplatin + capecitabine/5-FU

(Neo)Adjuvant1

HER2 positive

HER2 negative 1L1

• 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/FP2

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




Molecular classification of colon cancer

Guinney et al, Nature Medicine 2015

Mutational load differences

Histology of MSI Cancers

Histology of MSI cancers

dMMR in colorectal cancer

15% of colorectal

carcinomas across

all stages

Galon et al, ASCO 2016

Immunoscore as prognostic marker in stage

I/II/III colon cancer



Galon et al, ASCO 2016

The immunoscore study



Study implications



Single agent anti-PD1 in mCRC

MSI-H in mCRC ≈ 4%

dMMR Status: Prevalence1

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 804052

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)

Pro

po

rtio

n

Wit

ho

ut

Eve

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 Set1 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

BRAFwt and pMMR

BRAFmt

pMMR

1.0

0.8

0.6

0.4

0.2

0 10 20 30 40 50 60

OS (months)

Su

rviv

al

Pro

ba

bil

ity

P<0.001

0.0

BRAFwt and dMMR

BRAFmt

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 inhibitors1

dMMR/MSI-H mCRC tumors exhibit

high mutational load, increased

presence of tumor-specific

neoantigens, and increased

immune infiltration1,2

Several immune checkpoint

proteins,including PD-1, PD-L1 and

CTLA-4, may be highly expressed2

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 mCRC1

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 results2

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

Response

dMMR

CRC

n=28

pMMR CRC

n=25

ORR, n (%)

[95% CI]

16 (57%)

[39–73]

0 (0%)

[0–13]

DCR, n (%)

[95% CI]

25 (89%)

[73–96]

4 (16%)

[6–35]

CR, n (%) 3 (11%) 0 (0%)

PR, n (%) 13 (46%) 0 (0%)

SD,* n (%) 9 (32%) 4 (16%)

PD, n (%) 1 (4%) 11 (44%)

NE†, n (%) 2 (7%) 10 (40%)

PFS, mo NR 2.3

OS, mo NR 5.98

*At Week 12. †Patients were considered not evaluable if they did not undergo a 12 week scan.

CRC, colorectal cancer; CI, confidence interval; CR, complete response; DCR, disease control rate; dMMR, mismatch repair deficient; IRAE, immune-related adverse event; irORR, immune-related objective response rate; irPFS, immune-related progression-free survival; irRC, immune-related response criteria; mCRC, metastatic colorectal cancer; MSI, microsatellite instability; NE, not evaluable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; pMMR, mismatch repair proficient; PR, partial response; Q2W, every two weeks; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.

1. Le DT et al. Oral presentation at ASCO 2016. 103. 2. Le DT et al. N Engl J Med. 2015;372(26):2509-2520.

Summary of Clinical Activity1,2

Phase 2, open-label trial of pembrolizumab as

monotherapy in 3 different treatment-refractory patient

populations

n=28

dMMR CRC

pMMR CRC

n=25

n=30 dMMR non-CRC

Key Inclusion Criteria

Pembrolizumab 10 mg/kg Q2W

N=83

• Primary Outcome Measures: irPFS, irORR (using irRC)

• Secondary Outcome Measures: OS, irPFS/PFS (using irRC and RECIST 1.1), ORR,

IRAEs, MSI and treatment response, markers of MSI status

• dMMR and pMMR CRC groups had received a median of 3 and 4 prior treatment regimens, respectively

• No new safety signal reported


Study Design1,2

Phase 2 multicenter, multicohort trial of pembrolizumab as monotherapy in

patients with previously treated, locally advanced unresectable or metastatic

colorectal cancer

1EP, primary endpoint; 2EP, secondary endpoint; DCR, disease control rate; DOR, duration of response; EGFR, epidermal growth factor receptor; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; Q3W, every 3 weeks; Q9W, every 9 weeks; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors; PFS, progression-free survival; OS, overall survival; VEGF, anti-vascular endothelial growth factor.

1. Diaz LA et al. Poster presentation at ASCO 2017. Abstract 3071. 2. Clinicaltrials.gov. NCT02460198. Accessed August 28, 2017.


NCT02460198, N=120

PD or

intolerable

toxicities

Safety follow-up (≤90 days)

Survival follow-up (Q9W)

200 mg pembrolizumab IV on Day 1 Q3W for up to

35 cycles (approx 2 years)

Patients

• Locally advanced unresectable or

metastatic dMMR/MSI-H mCRC

• ≥2 prior therapies (must include

prior fluoropyrimidine, oxaliplatin,

and irinotecan)

• ECOG PS 0 or 1

• Measurable disease

• Adequate organ function

• Primary Outcome Measures: ORR per RECIST v1.1

• Secondary Outcome Measures: DOR, DCR, PFS, OS

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

100

90

80

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

Results

*2 patients were nonevaluable.

CI, confidence interval; CRC, colorectal cancer; CR, complete response; DCR, disease control rate; mos, months; IRC, independent central radiology review; mDOR, median duration of response; mos, months; mPFS, median progression-free survival; MSI-H, microsatellite instability high; mTTR, median time to response; NR, not reached; OS, overall survival; PR, partial response; SD, stable disease.

Adapted from Diaz LA et al. Poster presentation at ASCO 2017. Abstract 3071.

MSI-H CRC

N=61*

n % (95% CI)

ORR 17 28% (17–41)

Complete

response 0 0

Partial

response 17 28% (17–41)

Stable disease 14 23% (13–36)

Progressive

disease 28 46% (33–59)

DCR

(CR+PR+SD) 31 51% (38–64)

mTTR, mos

(range) 4 (2–10)

mDOR, mos

(range) NR (2.9+–12.5+)

mPFS, mos

(95% CI) 2.3 (2.1–8.1)

12 mos OS 72%


Best Percentage Change From Baseline in Target Lesion Size

(RECIST v1.1 by IRC)

Prior lines of

therapy, n (%)

1 6 (10%)

2 28 (46%)

3 13 (21%)

4 5 (8%)

≥5 6 (10%)

Safety1

CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability-high.

1. Diaz LA et al. Poster presentation at ASCO 2017. Abstract 3071. 2. Keytruda Prescribing information. Keytruda U.S. Product Information. Available at: https://www.accessdata.fda.gov/drugsatfda_ docs/label/2017/125514s014lbl.pdf. Accessed August 28, 2017.

• Pembrolizumab is approved in the US for the treatment of adult and pediatric patients with unresectable

or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have

no satisfactory alternative treatment options, or CRC that has progressed following treatment with

a fluoropyrimidine, oxaliplatin, and irinotecan2

Events MSI-H CRC

N=61, n (%)

Any grade 35 (57%)

Grade 3–4 9 (15%)

Led to death

(Grade 5) 0

Led to

discontinuation 1 (2%)

Events ≥10% Any grade Grade 3–4 Grade 5

Arthralgia 10 (16%) 0 0

Nausea 9 (15%) 0 0

Diarrhea 8 (13%) 0 0

Asthenia 7 (12%) 1 (2%) 0

Pruritus 7 (12%) 0 0

Fatigue 6 (10%) 2 (3%) 0


Study Design

Tumor imaging assessments were performed every 6 weeks for 24 weeks and thereafter every 12 weeks until disease progression or

discontinuation

Treatment beyond progression was permitted if the patient was determined by the investigator to be benefiting from and tolerating study

therapy, and consent was provided by the patient

Primary Outcome Measures: ORR per investigator assessment (RECIST v1.1)

Secondary Outcome Measures: ORR per blinded independent central review (BICR), PFS, OS, and safety

*Number of patients from interim analysis.

BICR, blinded independent committee review; CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors.

1. Andre T et al. Poster presentation at ASCO 2017. Abstract 3531. 2. Overman MJ et al. Oral presentation at ASCO GI 2017. Abstract GI17.

Checkmate 142: Nivolumab ± Ipilimumab Cohorts

Monotherapy

Arm (n=74)

Patients

Combination

Arm (n=84*)

If ≥ 7/19 confirmed

responders,

continue enrollment

If ≥ 7/19 confirmed

responders, continue

enrollment

Stage 1 Stage 2

Nivolumab 3 mg/kg Q2W

Nivolumab 3 mg/kg Q2W

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg

Q3W (4 doses, then

nivolumab 3 mg/kg Q2W)

• Histologically confirmed

metastatic/

recurrent CRC

• dMMR/MSI-H per local

laboratory

• ≥1 prior line of therapy

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg

Q3W (4 doses, then

nivolumab 3 mg/kg Q2W)

Disease Characteristics and Prior Therapy<br />Nivolumab ± Ipilimumab in Metastatic CRC

Checkmate 142: Nivolumab ± Ipilimumab Cohorts

Response Rates*

†Symbol “+” indicates a censored value. January 2017 data cutoff.

CI, confidence interval; CR, complete response; IQR, interquartile range; NE, not evaluable; NR, not reached; PR, partial response; SD, stable disease; TTR, time to respond.

Adapted from Overman MJ et al. Lancet Oncol. 2017. doi:10.1016/S1470-2045(17)30422-30429.

Patients

dMMR/MSI per

Local

Laboratory

(n=74)

Objective Response, n (%)

[95% CI]

23 (31.1%)

[20.8–42.9]

CR, n (%) 0

PR, n (%) 23 (31%)

SD, n (%) 28 (38%)

PD, n (%) 19 (26%)

Not determined, n (%) 4 (5%)

Disease Control for ≥12 weeks, n (%) [95% CI]

51 (69%)

(57–79)

Median Duration of Response, Months (range)

NR

(NE)

Median TTR, Months (IQR)

2.8

(1.4–3.2)

Checkmate 142: Nivolumab Monotherapy

100

75

50

25

0

-25

-50

-75

-100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 122 138

Ch

an

ge in

Su

m o

f T

arg

et

Lesio

ns

Fro

m B

aselin

e (

%)

Tumor Reduction

Confirmed partial response or complete response

First documented occurrence of new lesion

Patient off treatment

% change truncated to 100%

Weeks

CI, confidence interval; CRC, colorectal cancer; dMMR, mismatch repair deficient; mOS, median overall survival; mPFS, median progression-free survival; MSI-H, microsatellite instability high; NE, not estimable;

PFS, progression-free survival.

Overman MJ et al. Lancet Oncol. 2017. doi:10.1016/S1470-2045(17)30422-30429.

Investigator-Assessed PFS and OS


Progression-free Survival Nivolumab (n=74)

mPFS, months (95% CI) 14.3 (4.3–NE)

12-month rate, % (95% CI) 50% (38–61)

Pro

gre

ss

ion

-Fre

e S

urv

iva

l (%

)

0 3 6 9 12 15 18 21 24

74 (0) 48 (2) 41 (3) 32 (9) 17 (22) 12 (26) 12 (26) 11 (27) 0 (38)

100

90

80

70

60

50

40

30

20

10

0

Number at risk (numbered censored)

27 30

6 (32) 3 (35)

MSI-H/dMMR mCRC per Local Lab

Overall Survival Nivolumab

(n=74)

mOS, months (95% CI) NR (18.0–NE)

12-month rate, % (95% CI) 73% (62–82)

74 (0) 64 (3) 59 (3) 55 (3) 37(18) 21 (34) 19 (34) 17 (34) 0 (51) 1 (50) 11 (40) 6 (45)

Ove

rall

Su

rviv

al

(%)

0 3 6 9 12 15 18 21 33

Time Since Start of Treatment (months)

24

100

90

80

70

60

50

40

30

20

10

0

MSI-H/dMMR mCRC per Local Lab

Number at risk (number censored)

27 30

Time Since Start of Treatment (months)

Censored observations Censored observations

Safety

The most common grade 3/4 TRAEs were increased concentrations of lipase (6 [8%]) and amylase (2 [3%])

Five (7%) patients discontinued treatment due to drug-related adverse events, including increased ALT, colitis,

duodenal ulcer, acute kidney injury, and stomatitis (one each)

No deaths were reported due to study drug toxicity

*One Grade 5 event of sudden death was reported; this death was not attributed to study drug toxicity on autopsy.

AE, adverse event; ALT, alanine aminotransferase; TRAE, treatment-related adverse event.

Overman M et al. Lancet Oncol. 2017 Jul 19. pii: S1470-2045(17)30422-30429.

Patients, n (%)

All Patients

(N=74)

Grade 1-2 Grade 3 Grade 4

Any TRAE* 36 (49%) 13 (18%) 2 (3%)

TRAEs reported in ≥10%

of patients

Fatigue

Diarrhea

Pruritus

Rash

Nausea

Hypothyroidism

16 (22%)

15 (20%)

10 (14%)

8 (11%)

7 (10%)

7 (10%)

1 (1%)

1 (1%)

0

0

0

0

0

0

0

0

0

0

0


Patients with CR, PR, or SD for ≥12 weeks. CI, confidence interval; CR, complete response; dMMR, mismatch repair deficient; DOR, duration of response; MSI-H, microsatellite instability high; NE, not estimable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TTR, time to response.

Andre T et al. Poster presentation at ASCO 2017. Abstract 3531.

dMMR/MSI-H (n=84)

Investigator assessed ORR, n

(%)

[95% CI]

46 (55%)

[43.5–65.7]

Best overall response, n (%)

CR

PR

SD

PD

Not determined/reported

2 (2%)

44 (52%)

26 (31%)

9 (11%)

3 (4%)

Disease control for ≥12

weeks,* n (%)

[95% CI]

66 (79%)

[68.3–86.8]

Median TTR, months (range) 2.8 (1.1–14.0)

Median DOR, months,

[95% CI]

NR

[NE–NE]

Efficacy

Ch

an

ge in

Targ

et

Lesio

n F

rom

Baselin

e (

%)

Time Since Start of Treatment (weeks)

0 78 72 66 60 54 48 42 36 30 24 18 12 6 84 90

100

75

50

25

-25

-50

-75

-100

0

1st occurrence of new lesion

CR or PR

On treatment

Checkmate 142: Nivolumab + Ipilimumab Combination

Off treatment

Confirmed CR or PR per investigator.

CR, complete response; PR, partial response.


100

75

50

25

0

-25

-50

-75

-100

Bes

t R

ed

uc

tio

n f

rom

Bas

eli

ne in

Targ

et

Les

ion

(%

)

Best Reduction in Target Lesion Size


• 80% of patients had a reduction in tumor burden from baseline

CI, confidence interval; NE, no estimatable; OS, overall survival; PFS, progression-free survival.


Investigator-Assessed PFS and OS


Pro

ba

bilit

y o

f S

urv

iva

l

Time (months)

0 3 6 9 12 15 18 21

84 77 73 40 22 19 13 0

1.0

0.9

0.8

0.5

0.4

0.3

0.2

0.0

0.6

0.1

0.7

No. at

Risk

OS rate (95% CI), %

6-month 89 (80.2–94.2)

9-month 88 (78.1–93.1)

Median OS (95% CI), months

NR (NE–NE)

Overall Survival

No. at

Risk

Pro

ba

bilit

y o

f P

FS

1.0

0.9

0.8

0.5

0.4

0.3

0.2

0.0

0.6

0.1

0 3 6 9

Time (months)

12 15 18 21

65 35 17 13 8 1 0 84

0.7

Progression-free Survival

PFS rate (95% CI), %

6-month 77 (66.5–85.1)

9-month 77 (66.5–85.1)

Median PFS (95% CI), months

NR (11.5–NE)

Safety

AEs were manageable, with Grade 3/4 TRAEs reported in 29% of patients

No treatment-related deaths were reported in this study

*All events (ALT level increase, autoimmune hepatitis, colitis, dyspnea, necrotizing myositis, pneumonitis, immune sarcoidosis, transaminase increase, thrombocytopenia) occurred in one patient each with the exception of acute kidney injury, which was reported in 2 patients.

AE, adverse event; ALT, alanine aminotransferase; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; TRAE, treatment-related adverse events.


dMMR/MSI-H

(n=84)

Patients, n (%) Any Grade Grade 3 or 4

Any TRAE 57 (68%) 24 (29%)

Serious TRAEs 15 (18%) 14 (17%)

Discontinuation due to TRAEs* 11 (13%) 8 (9%)

TRAEs reported in ≥10% of

patients

Diarrhea

Fatigue

Aspartate aminotransferase

increase

Pyrexia

Pruritus

Alanine aminotransferase

increase

Nausea

Hyperthyroidism

Hypothyroidism

20 (24%)

14 (17%)

14 (17%)

13 (16%)

13 (16%)

12 (14%)

12 (14%)

11 (13%)

11 (13%)

1 (1%)

1 (1%)

8 (9%)

0

2 (2%)

7 (8%)

0

0

0


Cohort Disease State Regimens Endpoint(s)

Monotherapy 2L+ mCRC Nivolumab

Primary Endpoint:

ORR (investigator assessment)

Secondary Endpoint:

ORR (BICR)

Other Endpoints:

PFS, OS, biomarkers, safety,

and tolerability

Nivolumab + Ipilimumab 2L+ mCRC

Nivolumab + ipilimumab

3 1L mCRC Nivolumab + ipilimumab

5 2L+ mCRC Nivolumab + anti-LAG3

Overview of Ongoing dMMR/MSI-H Cohorts in

Checkmate 142

1L, first line; 2L, second line; BICR, blinded independent central review; dMMR, mismatch repair deficient; LAG, lymphocyte activation gene; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Clinicaltrials.gov. NCT02060188. Accessed June 21, 2017.

Checkmate 142: MSI-H Cohorts

Several Exploratory Immuno-Oncology Trials

for non-MSI-H mCRC Are Ongoing1

1L, first line; 2L, second line; CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; Ph, phase.

1. Clinicaltrials.gov. Accessed June 27, 2017. 2. Le DT, et al. N Engl J Med. 2015;372:2509-2520.

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

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

NCT02335918: Ph 1/2 2L+, nivolumab + varlilumab

NCT02512172: Pilot/Ph1 1L+, pembrolizumab + CC-486, or

romidepsin

• Patients with MSS CRC have not been shown to benefit from

single agent PD-1/PD-L1 inhibition2

Phase Ib Dose Escalation and Cohort Expansion Study (NCT01988896)

Phase 1b Dose Escalation and Cohort Expansion in

MSI-Unselected CRC1,2

NCT01988896: Atezolizumab

PD-L1 and MEK Inhibition: A Rational Combination




Baseline Characteristics




Baseline Characteristics (cont.)




Efficacy: Confirmed Objective Response




Efficacy: Change in Tumor Burden




Efficacy: Duration of Treatment and Response




Efficacy: Progression-Free Survival And Overall Survival




Safety: Treatment-related AEs




Baseline Patient Characteristics

Presented By Rachel Sanborn at 2017 ASCO Annual Meeting

Phase 1 Combination of anti-CD27 agonist antibody

varilumab with nivolumab in advanced solid tumors

CRC 42

Varlilumab & Nivolumab Combination Therapy is Well Tolerated




Tumor Response




Durable Response in MMR-proficient CRC Patient




Further Investigation in Late-Phase

CRC Clinical Trials

COTEZO (NCT02788279): Ph3 3L+, atezolizumab ± cobimetinib

(up to 5% dMMR/MSI-H)

1L, first line; 3L, third line; CRC, colorectal cancer; dMMR, mismatch repair deficient; MSI-H, microsatellite instability high; Ph, phase.

Clinicaltrials.gov. Accessed June 27, 2017.

MODUL (NCT02291289): Ph 2 1L Maintenance, atezolizumab +

bevacizumab

Conclusions - Results

Advanced esophagogastric cancer

PD-1/PD-L1 blockade is active

Anti-CTL4 + anti-PD-1 may be more active than anti-PD-1

but with more toxicity

Advanced colorectal cancer

PD-1/PD-L1 blockade is active in MSI-H patients

PD-1 inhibition is progressing as the standard of care for the

treatment of MSI-H mCRC

Emerging data with immuno-oncology combinations have

demonstrated potential for even greater clinical benefit

ORR of 55% for patients receiving nivolumab + ipilimumab

combination therapy

PD-1/PD-L1 + MEK-inhibition may be active in MSS patients

Conclusions – Future directions

Biomarker development

Peri-operative and adjuvant setting

Maintenance therapy in metastatic disease

Combinatorial approaches

Chemotherapy

Target therapies

Checkpoint antagonists/agonists

Immune modulators

Loco-regional treatment (ablation, chemoradiation) for

abscopal effect

i tumori gastrointestinalimedia.aiom.it/userfiles/files/doc/aiom-servizi/... · immunonoterapia nel...

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