Immunotherapy in GI cancers - congres-sofog.com · Checkpoint blockers Efficacy signal in MSI-H...

Immunotherapy in GI cancers

Julien TAIEB

Sorbonne Paris Cité

Hopital Européen Georges Pompidou

Inserm U970

J Taieb ESDO Leuven 2017

How to progress in GI cancer treatmentBetter define subgroups

With different prognostic and different treatments

Combine different targeted agents in accordance with the molecular profile

of the patients tumor

Find predictive markers for precision medecine

Induce an efficient immune response from the host

against the tumor


Immunité innée et adaptativeInnée :

- Rapide

- Non spécifique

Adaptative :

- Plus lente

- Spécifique

Immunité anti-tumorale

Terme, Taieb et al. Immunooncology 2014

Immature DC

mature DC

TUMOR

CD8+ TLymphocyte

CD4+T Lymphocyte

Lyse

antigens

Peptide / MHC IPeptide / MHC II

Major immunotherapeutic approaches

Checkpoint blockade

Anti-cancervaccines

Adoptive transfer


1. Parkhurst MR, et al. Mol Ther 2011;19:620–626.

Anti-CEA T cell transfer

CEA decrease

(maximum decline74–99% vs baseline)

Radiological response Inflammatory colitis


Immune check points

Mellman I et al., Science, 2011


Immune check points

Mellman I et al., Science, 2011

ActivateThe activators

InhibitThe inhibitors


.

Immune check points

Pardoll DM et al., Nat Rev Cancer, 2012

T cellregulation

T cell function


http://fr.wikipedia.org/wiki/Lymphocytes_T

In 2017, Efficacy in phase III

Anti-CTLA4

(Ipilimumab, tremelumumab)

• Melanoma• M+ (L1, L2)

• Adjuvant (st III)

Anti-PD(L)1

(Nivolumab, Pembro, Atezolizumab, avelumab, darvalumab…)

• Melanoma M+ (L1, L2) Nivo +Ipili +++

• Melanoma M+ and Lung M+ (L1 & L2)

• Lung M+ (L2) Nivo/Atezolizumab

• Kidney M+ (L2) Nivolumab

• Squamous Cell Cancer of the Head and Neck (L2). Nivolumab

• Bladder (phase 2: Atezolizumab)

PD1/PD-L1

Blockade

reported ORR

SCLC

15%

Mel

30-40%

RCC

15-20%

Bladder

25%

HNSCC

15-25%Gastric

20%

HCC

20%

Hodgkin

65-85%

MSI High

CRC

60%

TNBC

20%NSCLC

15-20%

Ovarian

15%

Colon cancer

-100

0

100

-100

0

100

-100

0

100

-100

0

100Melanoma1

-100

0

100NSCLC2

-100

0

100Gastric6

-100

0

100

-100

0

100H&N3 TNBC5

-100

0

100cHL7

-100

0

100NHL PMBCL8

Urothelial4

Ch

ang

e F

rom

Bas

elin

e in

Tu

mo

r S

ize,

%

-100

0

100

Mesothelioma9

-100

0

100

Anal14

-100

0

100

-100

0

100

SCLC11

-100

0

100NPC13

-100

0

100Biliary Tract15

-100

0

100Colorectal16

Esophageal12

-100

0

100

Ovarian10

-100

0

100ER+/HER2– BC17 Cervical18 Thyroid19 Salivary20

-100

0

100

Checkpoint blockers Efficacy signal

in MSI-H colorectal cancer

Le DT, et al. N Engl J Med. 2015;372(26):2509-2520

Radiographic responses*

*RECIST-based radiographic response**Adjusted for elapsed time since the initial diagnosis

Treatment with pembrolizumab (anti-PD-1 antibody)(n=11 mismatch repair-deficient CRC, n=21 mismatch-repair proficient CRC, n=9 mismatch-repair deficient non-CRC)

OS in CRC

Adjusted OS HR for mismatch-repair deficient vs proficient CRC: 0.18, P = .05

Immune-related ORR in mismatch-repair deficient vs proficient CRC: 40% vs 0%


Response to Pembrolizumab for MSI-H/dMMR

• 11 patients achieved a CR and were taken off therapy after 2 years of treatment.

• No evidence of cancer PD has been observed in those patients with a median time off therapy of 8.3 months.

Le DT, Science 2017

Best responseMSI-H CRC

N = 61a

MSI-H

Non-CRC

N = 77b

n % (95% CI) n % (95% CI)

ORR (95% CI), % 17 28% (17-41) 29 38% (27-49)

Complete response 0 0 2 3% (0-9)

Partial response 17 28% (17-41) 27 35% (25-47)

Stable disease 14 23% (13-36) 16 21% (12-32)

Progressive disease 28 46% (33-59) 24 31% (21-43)

DCR (CR+PR+SD) 31 51% (38-64) 45 58% (47-70)

Median duration of response (range), monthsc Not reached (2.9+ to 12.5+) Not reached (2.4+ to 9.2+)

Median time to response (range), months 4.0 (2-10) 2.1 (1-4)

Pembrolizumab for MSI-H/dMMR CRC and Non-CRC

Diaz LA, ASCO 2017, J Clin Oncol 35l(suppl 15), 3618J Taieb ESDO Leuven 2017

Keynote 16

Le DT et al., ASCO 2016, CSS 103

• ASCO update

• Tolerability :• Rash prurit 25% Diarrhea/Colitis 11%• Arthralgia 15% Thyroïditis/Hypothyroïdia 11%, • Fatigue 9%• grade 3-4 toxicities : 14%

including pancreatitis 4% and diarrhea /colitis / thrombocytopenia / leucopenia /anemiain 2% each

• Efficacy :• MSI : RR 28% with 11%CR ; DCR 51%

MSS : RR 0% ; DCR 16%

KEYNOTE 164 is ongoing in MSI-H (phase II, 120 pretreated pts)


May 23, 2017

FDA GRANTS ACCELERATED APPROVAL TO PEMBROLIZUMAB

FOR FIRST TISSUE/SITE-AGNOSTIC INDICATION

• 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 with MSI-H or dMMR colorectal cancer that has progressed following treatment with a

fluoropyrimidine, oxaliplatin, and irinotecan

Non MSI GI cancer will be treatable by anti-PD1 in the future => MSI testing has to be performed in daily practice


Phase 2 CheckMate 142 Study Design: MSI-H Cohort

19

Nivo 3 mg/kg (Q2W)

mStage 1

MSI-H

• Second-line colon MSI-H

• ≥ 1 prior treatment for metastatic disease

• ≥ 1 target lesion

• ECOG PS of 0-1

≥ 7/19 Nivo 3 mg/kg (Q2W)

mStage 2Responsesa

Responsesa

≥ 7/19

• Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses)

• Then Nivo 3 mg/kg (Q2W)

cStage 2b

3–6/19

• Nivo 3 mg/kg +

Ipi 1 mg/kg

(Q3W x 4 doses)

• Then Nivo 3 mg/kg(Q2W)

cStage 1

Responsesa

aIn patients with centrally confirmed MSI-H statusbCurrently enrolling

cStage 1 = combination therapy stage 1; cStage 2 = combination therapy stage 2; Ipi = ipilimumab; mStage 1 = monotherapy stage 1; mStage 2 = monotherapy stage 2; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks


Patient Demographics and Disease

Characteristics

Overman M, Lancet Oncol 2017

Overall Response and Disease ControlCheckMate 142 Nivolumab alone


Median time to response is 2,8 (1,4-3,2)

Only 3 patients with ORR experiencing progression

Median duration of response are not yet reached and are responder are alive at the time of analysis

Changes in Tumor Burden CheckMate 142 Nivolumab alone


• Median TTR: 2.8 (1.1–14.0) months

• Median DOR: not reached

• 85% (39/46) of responses ongoing

Tt discontinuations

38 pts( 51%) :

27 (36%) for PD

6 (8%) Toxicity

5 (7%) other

Progression-Free Survival

Median PFS, mo 14,3 months

PFS rate, % (95% CI)

12 months 50 % (38, 61)


Overall Survival

Median OS, mo (95%

CI)

NR (18, NE)

OS rate, % (95% CI)

12 months 73% (62, 82)

23 death/74 patients

36 investigator assessed PD

Median Follow up 12 months

CheckMate 142 Nivolumab alone

Investigator-assessed ORR and disease control (n=74)

CheckMate 142 Nivolumab alone


dMMR/MSI-H per Local Assessment (N = 74)a

Patients, n (%) Grade 1 or 2 Grade 3 or 4

Any Event 36 (49%) 15 (21%)

TRAE reported in ≥ 10% of patientsFatigueDiarrheaPruritus HypothyroidismLipase increasedRashColitisAdrenal insufficiencyIncrease ASAT/ALAT

16 (22.%)15 (20%)10 (14%)7 (10%)3 (4%)

8 (11%)00

5 (7%)

1 (1%)1 (1%)

00

6 (8%)0

1 (1%)1(%)

1 (1%)

.

Safety SummaryCheckMate 142 Nivolumab alone


ConclusionsCheckMate 142: nivolumab alone

• Nivolumab monotherapy provided durable responses and disease control in patients with dMMR/MSI-H CRC

• Responses and disease control were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or a clinical history of Lynch syndrome

• Patient-reported outcome analyses showed clinically meaningful improvements in functioning, symptoms, and QOL

– Patients who continued treatment for ≥ 19 weeks attained a level of health that would be considered as equal to or exceeding the general health of many populations

• Nivolumab was well tolerated with no new safety signals observed

• These results suggest that nivolumab could be considered a new standard of care for patients with dMMR/MSI-H CRC and warrants further investigation in patients with other dMMR/MSI-H tumors


FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer

On July 31, 2017, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and

irinotecan. The approval was based on data from Study CA209142 (CHECKMATE 142; NCT 02060188)

Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of

patients (pts) with deficient DNA mismatch repair (dMMR)/high

microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC):

CheckMate 142 Study

André T et al; ASCO 2017; abst 3531

Study Design: CheckMate 142 Study

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

Current analysis included all patients (n=84) who received their first dose ≥ 6 months prior to the data cut-off

Median (range) time from first dose to data cut-off: 8.6 (6.3 – 19.4) months

Patients

NIVO 3 mg/kg +

IPI 1 mg/kg Q3W

(4 doses and then NIVO 3 mg/kg Q2W)

NIVO 3 mg/kg +

IPI 1 mg/kg Q3W

(4 doses and then NIVO 3 mg/kg Q2W)

If ≥ 7/19 confirmed

responders,

continue enrollmentNIVO 3 mg/kg Q2W NIVO 3 mg/kg Q2W

If ≥ 7/19 confirmed

responders, continue

enrollment

• Histologically

confirmed

metastatic/

recurrent CRC

• dMMR/MSI-H per

local laboratory

• ≥ 1 prior line of

therapy

Stage 2Stage 1

MONOTHERAPY

ARM

COMBINATIONARM

n = 74 pts

n = 84 pts

André T et al; ASCO 2017, Abst 3531

dMMR/MSI-H

(n = 84)

Age

Median (range), years

< 65 years, n (%)

57 (21-81)

61 (73)

ECOG performance status, n (%)

0

1

31 (37)

53 (63)

Mutation status, n (%)

BRAF/KRAS wild type

BRAF mutated

KRAS mutated

22 (26)

21 (25)

30 (36)

Prior lines of therapy, n (%)

0

1

2

3

≥ 4

1 (1)

17 (20)

31 (37)

23 (27)

12(14)

Prior radiotherapy, n (%) 17 (20)

Patient Demographics and Disease Characteristics

CheckMate 142 Study: nivolumab + ipilimumab


NIVO + IPI

(n = 84)

Investigator-

Assessed

ORR, n (%)

[95% CI]

46 (55)

[43.5, 65.7]

Best overall response, n (%)

CR

PR

SD

PD

ND/reported

2 (2)

44 (52)

26 (31)

9 (11)

3 (4)

Disease control for ≥ 12 weeks, n (%)a 66 (79)

Overall Response and Disease Control:


NIVO Monotherapy1

(n = 74)

Investigator-Assessed

23 (31)

[20.8, 42.9]

0

23 (31)

29 (39)

18 (24)

4 (5)

51 (69)

aPatients with CR, PR, or SD for ≥ 12 weeks André T et al; ASCO 2017, Abst 3531


Best Change in Target Lesion Size

NIVO + IPI (n = 84) NIVO Monotherapy1 (n = 74)

100

75

50

25

0

-25

-50

-75

-100

100

Best

Red

ucti

on

Fro

m B

aselin

ein

Targ

et

Lesio

n (

%) 75

50

25

0

-25

-50

-75

-100

Best

Red

ucti

on

Fro

m B

aselin

ein

Targ

et

Lesio

n (

%)

80% of patients had reduction in tumor burden from baseline 62% of patients had reduction in tumor burden from baseline

Confirmed CR or PR per investigator % Change truncated at 100 André T et al; ASCO 2017, Abst 3531


34

100

80

60

40

20

0

100

80

60

40

20

B

Be

st

red

uc

tio

n f

rom

ba

se

lin

e

in t

arg

et

les

ion

(%

)

KRAS/BRAF wild type KRAS mutationBRAF mutation Unknown

Results

Figure 2. Association of best reduction in target lesion size (B) BRAF and KRAS mutation status in patients with dMMR/MSI-H mCRC treated with NIVO + IPI

35

C

100

80

60

40

20

0

100

80

60

40

20

Be

st

red

uc

tio

n f

rom

ba

se

lin

e

in t

arg

et

les

ion

(%

)

Lynch syndrome (Yes) UnknownLynch syndrome (No)

Figure 2. Association of best reduction in target lesion size with(C) Lynch syndrome in patients with dMMR/MSI-H mCRC treated with NIVO + IPI

Results

Changes in Tumor Burden


• Median TTR: 2.8 (1.1–14.0) months• Median DOR: not reached• 85% (39/46) of responses ongoing

Ch

ange

in t

arge

t le

sio

n fr

om

bas

elin

e, (%

)

Time since start of treatment (week)

0 7872666054484236302418126 84 90

100

75

50

25

-25

-50

-75

-100

0

1st occurrence of new lesion

CR or PR

On treatment



No. at Risk

1.0

0.9

0.8

0.5

0.4

0.3

0.2

0.0

Pro

ba

bilit

y o

f P

rog

res

sio

n-F

ree

Su

rviv

al

0.6

0.1

0 3 6 9

Time (months)

12 15 18 21

65 35 17 13 8 1 084

Progression-Free SurvivalCheckMate 142 Study: nivolumab + ipilimumab

Median PFS, mo (95% CI) NR (11.5, NE)

PFS rate, % (95% CI)

6 months 77 (66.5, 85.1)

9 months 77 (66.5, 85.1)

NE = not estimable; NR = not reached André T et al; ASCO 2017, Abst 3531

Median OS, mo (95% CI) NR (NE, NE)

OS rate, % (95% CI)

6 months 89 (80.2, 94.2)

9 months 88 (78.1, 93.1)

Overall SurvivalCheckMate 142 Study: nivolumab + ipilimumab

NE = not estimable; NR = not reached

Pro

ba

bilit

y o

f S

urv

iva

l

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

Time (months)

No. at Risk


Checkmate 142 Treatment-Related Adverse Events in ≥ 15% of Patients With MSI-H

Event, n (%)

Nivolumab3 mg/kg(n = 70)

Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg

(n = 30)

Any grade Grade 3–4 Any grade Grade 3–4

Any event 41 (58.6)a 10 (14.3) 25 (83.3) 8 (26.7)

Fatigue 13 (18.6) 1 (1.4) 6 (20.0) 0

Diarrhea 10 (14.3) 1 (1.4) 13 (43.3) 0

Pruritus 8 (11.4) 0 5 (16.7) 1 (3.3)

Nausea 5 (7.1) 0 6 (20.0) 0

Pyrexia 3 (4.3) 0 7 (23.3) 0

Any event leading to discontinuation

4 (5.7) 2 (2.9) 4 (13.3) 4 (13.3)

39

aOne Grade 5 event of sudden death


NIVO + IPI(n = 84)

Patients, n (%) Any Grade Grade 3 or 4Any TRAE 57 (68) 24 (29)Serious TRAEs 15 (18) 14 (17)

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

TRAEs reported in ≥ 10% of patientsDiarrhea 20 (24) 1 (1)Fatigue 14 (17) 1 (1)Aspartate aminotransferase increase 14 (17) 8 (9)Pyrexia 13 (16) 0Pruritus 13 (16) 2 (2)Alanine aminotransferase increase 12 (14) 7 (8)Nausea 12 (14) 0Hyperthyroidism 11 (13) 0Hypothyroidism 11 (13) 0

Safety Check Mate 142 Study: nivolumab + ipilimumab

• No treatment-related deaths were reported


NIVO + IPI provided durable responses, sustained disease control,

and encouraging survival data in pretreated patients with dMMR/MSI-H mCRC

–ORR of 55%, with 79% of patients achieving disease control for ≥ 12 weeks

–85% of responses ongoing, and the median DOR was not yet reached

–88% of patients alive at 9 months, 77% without progression

NIVO + IPI demonstrated a manageable safety profile; 29% of patients had grade 3/4 TRAEs

This trial is ongoing and patients will continue to be followed for survival

41 patients in this study were treated in St Antoine hospital and translational research are planned (we have primary and metastatic tissue for

all)

A French study will began in Septempter 2017 (GERCOR group) with nivolumab and ipilumumab (55 patients) in the same population and we

will collect archival tissue for all patients

ConclusionsCheck Mate 142 Study: nivolumab + ipilimumab

dMMR/

MSI-H

COL-11

Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2017. © 2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not

be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often

as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Summary of Efficacy in Patients With MSSNivolumab ± Ipilimumab in Metastatic CRC

43


(n = 10)


(n = 10)

ORR, n (%) 1 (10) 0

Median PFS, mo (95% CI) 2.28 (0.62, 4.40) 1.31 (0.89, 1.71)

Median OS, mo (95% CI) 11.53 (0.62, NE) 3.73 (1.22, 5.62)

NE = not estimable

…vs NR OS and 14 PFS in MSI-H pts treated with nivolumab alone…vs median not reached in MSI-H pts treated with the combo

Phase Ib: Atezolizumab + cobimetinibin MSS pretreated mCRC

Bendell JVC. et al., ASCO 2016, OS 3502

• Tolerability :

• No DLT, Diarrhea : 70%, rash: 40%, Fatigue : 52%• Grade 3-4 toxicities : 34% incl. diarrhea : 9%

• Efficacy :

• Response 17% (4 OR, 5 SD) : 3 MSS/1 statut MSI ukn, 4 to 7 mo

-100-90-80-70-60-50-40-30-20-10

0102030405060708090

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23Ch

ange

in s

um

of

lon

gest

dia

met

ers

fro

mb

asel

ine,

%

Time on study (mo)

PDSDPR/CRDiscontinued atazolizumabNew lesion

Tumor Biopsy : no correlation with PDL1 at D0

Conclusion• Trials are ongoing in mCRC and in the adjuvant setting (soon)

• Colon cancer probably less easy than others

• MSI-H tumors : a good target

• Others may be: PolE, PolD, MSS with immune infiltrates…

• Combination with targeted agents: • + chemotherapy, sequence?• + radiotherapy? • + targeted agents: anti-angiogenics; MEK…?


Anti-CTLA-4 or anti-PD-1 or anti-PD-L1

Perioperative First-line Second-lineThird-line +

refractory to standard

Ipilimumab (BMS): anti-CTLA-4

Nivolumab (ONO/BMS):anti-PD-1

Pembrolizumab (MSD):anti-PD-1

KEYNOTE-177 Ph IIIPembro vs CT

MSI-H

Durvalumab (AZ): anti-PD-L1

Atezolizumab (Roche): anti-PD-L1

Phase III Adjuvant NCIFOLFOX 6 m+/- atezo 1y

MSI-H

Ph IIIFOLFOX+BVs Atezo

Vs Atezo+FOLFOX+BMSI-H

Phase IIIAtezo+ cobimetinib vs Atezo vs

regorafenibMSS

Avelumab (Merck/Pfizer)anti-PD-L1

SAMCOR Phase II

Avelumab vs CTMSI-H

After ASCO: even more trials for colorectal cancer

1. Study designs available at: www.clinicaltrials.gov (accessed September 2017). Agents have not yet received EMA approval for treatment of indication listed

http://www.clinicaltrials.gov/

Gastric cancer

Cu

mu

lati

ve s

urv

ival

0.0

0.2

0.4

0.6

1.0

0.8

PD-L1 Positive(n=67)

PD-L1 Negative(n=65)

48 72 96 1680 24 144120

1. Kim JW et al. Gastric Cancer 2016;19:42–2; 2. Böger C et al. Oncotarget 2016;7:24269–83; 3. Saito H et al. J Surg Oncol 2013;107:517–22; 4. Takano S et al. Surg Today 2016;46:1341–7; 5. Zhang L et al. Int J Clin Exp Pathol. 2015;8:11084–91.

Rationale for immuno-oncology in GC• Pathology of GC associated

with immune system evasion

• Immunosuppressive proteins expressed on immune cells in patients with GC patients, including key checkpoint inhibitors:1–4

• Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4)

• PD-1

Overall survival

PD-L1 in gastric carcinoma5

Study Design and Endpoints

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; PFS, progression-free survival; Q2W, every 2 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors; TTR, time to tumor response.

R2:1

Nivolumab3 mg/kg IV Q2W

Placebo

Key eligibility criteria:

• Age ≥ 20 years

• Unresectable advanced or recurrent gastric or gastroesophageal junction cancer

• Histologically confirmed adenocarcinoma

• Prior treatment with ≥ 2 regimens and refractory to/intolerant of standard therapy

• ECOG PS of 0 or 1

Primary endpoint:• OS

Secondary endpoints:• Efficacy (PFS, BOR, ORR, TTR,

DOR, DCR)• Safety

Exploratory endpoint:• Biomarkers

Stratification based on:

• Country (Japan vs Korea vs Taiwan)

• ECOG PS (0 vs 1)

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

• 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

49ASCO GI 2017Kang et al. ASCO GI 2017

Overall Survival

Time (months)

Pro

bab

ility

of

Surv

ival

(%)

22181614121086420

0

10

20

30

40

50

60

70

80

90

100

Hazard ratio, 0.63 (95% CI, 0.50–0.78)

P < 0.0001

0351019395795142275330

0133410163253121163

Nivolumab

Placebo

At risk:

20

193

82

Patients, nEvents,

nMedian OS

[95% CI], months12-Month OS Rate [95%

CI], %

Nivolumab 330 225 5.32 [4.63–6.41] 26.6 [21.1–32.4]

Placebo 163 141 4.14 [3.42–4.86] 10.9 [6.2–17.0]


Overall Survival by Subgroup

Subgroup Hazard Ratio [95% CI]

Histological type (Lauren classification)

Intestinal type

Diffuse type

Mixed

Unknown

0.59 [0.41–0.85]

0.82 [0.57–1.17]

0.37 [0.13–1.04]

0.56 [0.37–0.84]

Number of organs with metastasis

< 2

≥ 2

0.70 [0.46–1.08]

0.61 [0.48–0.78]

Peritoneal metastasis

No

Yes

0.63 [0.50–0.81]

0.74 [0.48–1.15]

Liver metastasis

No

Yes

0.63 [0.50–0.80]

0.67 [0.42–1.07]

Measurable lesion

No

Yes

0.70 [0.43–1.14]

0.63 [0.50–0.80]

Number of previous regimens

2

3

≥ 4

0.82 [0.50–1.35]

0.87 [0.61–1.22]

0.44 [0.31–0.61]

Subgroup Hazard Ratio [95% CI]

All 0.64 [0.52–0.80]

Country

Japan

Korea

Taiwan

0.63 [0.46–0.85]

0.70 [0.51–0.96]

0.46 [0.23–0.92]

Age, years

< 65

≥ 65

0.75 [0.57–0.98]

0.53 [0.38–0.74]

Sex

Male

Female

0.58 [0.45–0.75]

0.83 [0.56–1.23]

ECOG PS

0

1

0.59 [0.40–0.87]

0.67 [0.52–0.86]

Prior gastrectomy

No

Yes

0.69 [0.49–0.98]

0.60 [0.46–0.79]

Primary sites

Gastric (fundus, corpus, antrum, and pylorus)

Gastroesophageal junction

Unknown

0.69 [0.55–0.87]

0.44 [0.20–0.97]

0.52 [0.26–1.06]

0 1 2 3

Favors nivolumab Favors placebo

Hazard ratio [95% CI]

0 1 2 3

Favors nivolumab Favors placebo

Hazard ratio [95% CI]


Maximum Reduction in Tumor Burden From BaselineNivolumab Placebo

Max

imu

m R

edu

ctio

n F

rom

Bas

elin

e in

Tar

get

Lesi

on

s (%

)

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100a

a Patients with a change in tumor burden that exceeds 100%.

a

Patients with Tumor reduction: 37.3% Patients with Tumor reduction: 12.4%


31% ORR

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

Pro

bab

ilit

y o

f S

urv

ival

(%

)

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

Placebo

PD-L1 <1% PD-L1 ≥1%

Hazard ratio, 0.58 (95% CI,

0.24–1.38)

Median OS, months (95% CI)

Nivolumab (n=16) 5.2 (2.8–9.4)

Placebo (n=10) 3.8 (0.8–5.0)

Pro

bab

ilit

y o

f S

urv

iva

l (%

)

114 100 75 56 49 42 37 24 15 11 7 4 3 1 0

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

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

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

Nivolumab

Placebo

Months MonthsNo. at Risk

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)

No strong signal for PDL1 predictive value

Overall survival by PD-L1 expression <1% vs ≥1%

PD-L1 evaluable patients (N=192)

53

Methods

54

aIV oxaliplatin 130 mg/m2 on day 1 followed by 20 days off and oral S-1 or oral capecitabine twice daily for 14 days followed by 7 days off. S-1 initial dose was 40 mg/m2/dose. Capecitabine initial dose was 1,000 mg/m2/dose

ECOG PS = Eastern Cooperative Oncology Group performance status; IV = intravenous; Q3W = every 3 weeks; RECIST = Response Evaluation Criteria in Solid Tumors

Figure 1. ATTRACTION-04 study design (part 1)

Results

55

Table 2. Summary of treatment-related adverse events

56

Figure 3. Best reduction in tumor burden

Results

Authors’ Conclusions

57

• Part 1 of this two-part randomized study met its primary and secondary endpoints; nivolumab + chemotherapy regimens (SOX or CapeOX)

had manageable safety profiles and demonstrated clinically meaningful antitumor activity

– Discontinuations due to treatment-related AEs were low (≤10% of patients) and no treatment-related deaths were reported

– The incidence and type of treatment-related AEs were consistent with AEs known to be associated with chemotherapy regimens and

with nivolumab5–9

– Objective responses were observed in more than two-thirds of patients, occurred early, and were durable, with encouraging PFS

• No substantial differences in clinical activity and safety were observed between the nivolumab + SOX and nivolumab + CapeOX treatment

regimens

• These results suggest that nivolumab in combination with SOX or CapeOX chemotherapy in patients with unresectable advanced or

recurrent gastric or gastroesophageal junction cancer may be a first-line therapy option

– Part 2 of this study is currently recruiting patients

4014: Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study

*Administered for 4 cycles followed by nivolumab 3 mg/kg IV q2wJanjigian YY, et al. J Clin Oncol 2017;35(Suppl):Abstr 4014

Study objective

• To evaluate the long-term survival, efficacy, and safety of nivolumab alone and in combination with ipilimumab in the oesophagogastric cohort of the CheckMate 032 study

PD/death/

toxicity

Nivolumab 3 mg/kg IV q2w

(n=59)Key patient inclusion criteria

• Advanced/metastatic oesophagogastric cancer

• Progression on ≥1 prior chemotherapy

• Western population

(n=160)

PRIMARY ENDPOINT

• ORR (RECIST v1.1)SECONDARY ENDPOINTS

• OS, PFS, TTR, DoR, safety, PD-L1 tumour expression

PD/death/

toxicity

Nivolumab 1 mg/kg + ipilimumab 3 mg/kg

IV q3w*

(n=49)

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg

IV q3w*

(n=52)

PD/death/

toxicity

4014: Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal(E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study – Janjigian YY, et al

Janjigian YY, et al. J Clin Oncol 2017;35(Suppl):Abstr 4014

1.0

0.8

0.6

0.4

0.2

0

Pro

ba

bili

ty o

f su

rviv

al

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

Time, months

1.0

0.8

0.6

0.4

0.2

0Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l

0 3 6 9 12 15 18 21 24 27 30

Time, months

mPFS, months

(95%CI)

PFS rate, %

6-month 12-month

Nivolumab 3 mg/kg 1.4 (1.2, 1.5) 17 8

Nivolumab 1 mg/kg +

Ipilimumab 3 mg/kg1.4 (1.2, 3.8) 24 17

Nivolumab 3 mg/kg +

Ipilimumab 1 mg/kg1.6 (1.4, 2.6) 12 10

mOS, months

(95%CI)

OS rate, %

12-month 18-month

Nivolumab 3 mg/kg 6.2 (3.4, 12.4) 39 25

Nivolumab 1 mg/kg +

Ipilimumab 3 mg/kg6.9 (3.7, 11.5) 35 28

Nivolumab 3 mg/kg +

Ipilimumab 1 mg/kg4.8 (3.0, 8.4) 24 13

OS PFS

4014: Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal(E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study – Janjigian YY, et al

Janjigian YY, et al. J Clin Oncol 2017;35(Suppl):Abstr 4014

Key results (cont.)

Best reduction in target lesions

Nivolumab 3 mg/kg

PD-L1-evaluable patients, 38 of 53

Nivolumab 3 mg/kg +

Ipilimumab 1 mg/kg


Nivolumab 1 mg/kg +

Ipilimumab 3 mg/kg


100

75

50

25

0

-25

-50

Be

st re

du

ctio

n fro

m b

ase

line

in

ta

rge

t le

sio

ns, %

100

75

50

25

0

-25

-50

100

75

50

25

0

-25

-50

PD-L1 <1% PD-L1 ≥1% PD-L1 not evaluable/missing

† †

*

*

* *

*

*

*

†

**

** * *

* * *

†

*

*

*

KEYNOTE-059: Efficacy and Safety of Pembrolizumab Alone or in Combination With Chemotherapy in Patients With Advanced Gastric or Gastroesophageal Cancer

Study Design

Treat for up to 35 cycles(~2 years), or until

progression or intolerable toxicity

Follow-up for survival bytelephone until death,

withdrawal, or study end

Cohort 3No prior therapy

PD-L1 positive


PD-L1 positive or negative

Cohort 1≥2 prior lines of chemotherapy PD-L1

positive or negative

Pembrolizumab 200 mg Q3W +Cisplatin 80mg/m2 Q3W +5-FU 800 mg/m2 Q3W or

Capecitabine 1000 mg/m2 BID Q3Wa

Pembrolizumab200 mg Q3W


Response assessment per RECIST v1.1: First scan 9 weeks after cycle 1, then every 6 weeks for year 1 and every 9 weeks thereafterPrimary end points: Safety (all cohorts); ORR by central review per RECIST v1.1 (cohort 1: all patients and patients with PD-L1-positive expression); ORR by central review per RECIST v1.1 (cohort 3)PD-L1 positive: combined positive score (CPS) ≥1 (previously reported as and equivalent to CPS ≥1%), where CPS=number of PD-L1-positive cellsb (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells x 100

aCapecitabine was administered only in JapanbPD-L1 IHC 22C3 pharmaDx (Agilent Technologies, Carpinteria, CA,USA)Wainberg et al., Abstract LBA28, ESMO 2017

KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer.

Study Design

aCapecitabine was administered only in Japan






PD-L1 positive









Data cutoff: April 21, 2017

Wainberg et al., Abstract LBA28, ESMO 2017


Characteristic N=259

Median age (range), years 62 (24-89)

Male, n (%) 198 (76)

Race, n (%)WhiteAsianOther

200 (77)41 (16)

7 (3)

ECOG, n (%)01

107 (41)151 (58)

Number of prior therapies, n (%)23≥4

134 (52)75 (29)50 (19)

Characteristic N=259

Location of primary tumor, n (%)GEJGastric

134 (52)124 (48)

Prior gastrectomy, n (%)TotalPartialNo

49 (19)17 (7)

193 (75)

PD-L1 expression , n (%)PositiveNegativeUnknown

148 (57)109 (42)

2 (1)

HER2 status, n (%)PositiveNegativeIntermediate

63 (24)194 (75)

2 (1)

Baseline Characteristics




Response

Responseb

All PatientsN = 259

PD-L1 Positivea

N = 148PD-L1 Negative

N = 109

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

ORR 12 8-17 16 11-23 6 3-13

DCRc 27 22-33 34 26-42 19 12-28

DOR

CR 3 1-6 3 1-8 3 1-8

PR 9 6-13 13 8-19 4 1-9

SD 16 12-21 18 12-25 15 9-23

PD 56 49-62 53 44-61 60 50-69

aCPS ≥ 1bOnly confirmed responses were includedcCR + PR + SD≥2 months

• Median (range) follow-up: 5.6 (0.5-24.7) months• 134 patients received pembrolizumab as third-line therapy; ORR was 16%, and DCR was 31%• 125 patients received pembrolizuman as fourth plus-line therapy; ORR was 7%, and DCR was 23%




aOnly patients with measurable disease per RECIST v1.1 by central review at baseline who had ≥1 postbaseline assessment wereincluded (n=223); assessment was nonevaluable in 1 patientbLongitudinal change in the sum of the longest target lesion diameters from baseline in responders (n=31)+No progressive disease at last disease assessment

Best Percentage Change and Longitudinal Change in Target Lesion Size




PFS and OS in All Patients




PFS and OS by PD-L1 Expression




Treatment-Related Adverse Events

Event, n (%) N = 259

Any 159 (61)

Grades 3-5Anemia, grade 3Fatigue, grade 3Dehydration, grade 3

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

Serious 29 (11)

Led to discontinuationa 7 (3)

Led to deathAcute kidney injuryPleural effusion

2 (1)1 (1)1 (1)

• Median (range) duration of exposure was 2.1 (0.0-23,7) months

aAbnormal hepatic function, bile duct stenosis, encephalitis, increase blood bilirubin level, hyperglycemia, acutekidney injury, and pneumonitis




Immune-Mediated Adverse Eventsa and Infusion-Related Reactions

• There were no grade 4/5 immune-mediated or infusion reactions

aBased on a list of terms specified by the sponsor and included regardless of attribution to studytreatment or immune relatedness by the investigatorb2 (1%) patients experienced grade 3 rash; 1 (<1%) patient experienced grade 3 adverse events: uveitis, hepatitis, jaundice, encephalitis, and maculopapular rash

Event, n (%)N=259

All Grades in >2 Patients Grades 3b

Any 50 (19) 13 (5)

Hypothyroidism 24 (9) 1 (<1)

Hyperthyroidism 9 (4) 0

Colitis 4 (2) 3 (1)

Infusion-related reactions 4 (2) 0

Pneumonitis 4 (2) 2 (1)

Thyroiditis 3 (1) 1 (<1)



aCapecitabine was administered only in Japan

KEYNOTE-059 Cohort 2: Safety and efficacy of pembrolizumab plus5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer

Study Design






PD-L1 positive











Characteristic N=25

Median age (range), years, y 64 (21-82)

Male, n (%) 16 (24)

Race, n (%)WhiteAsian

8 (32)17 (68)

ECOG PS, n (%)01

15 (60)10 (40)

Characteristic N=25


5 (20)20 (80)


4 (16)1 (4)

20 (80)

PD-L1 expression , n (%)PositiveNegativeUnknown

16 (64)8 (32)1 (4)

HER2 negative, n (%) 25 (100)





Response

Responseb

All PatientsN = 25

PD-L1 Positivea

N = 16PD-L1 Negative

N = 8

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

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

DCRc 80 59-93 75 48-93 75 35-97

BOR

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

aCPS ≥1 bOnly confirmed responses were includedcCR + PR + SD≥6 months

Median (range) follow-up in cohort 2: 13.8 (1.8-24.1) months





aOnly patients with measurable disease per RECIST v1.1 by central review at baseline who had ≥1 postbaseline assessment wereincluded (n=25); assessment was nonevaluable for 1 patientbLongitudinal change in the sum of the longest target lesion diameters from baseline in patients with ≥1 postbaseline assessment(n=25)+No progressive disease at last disease assessment







PFS and OS


Event, n (%) N = 25

Any 25 (100)

Grades 3/4NeutropeniaStomatitisAnemiaDecreased platelet countDecreased appetiteFatigue

19 (76)6 (24)5 (20)2 (8)2 (8)2 (8)2 (8)

Led to discontinuation 3 (12)

Led to death 0

• Median (range) duration of exposure was 7.1 (0.8-23.8) months• 3 (12%) patients discontinued treatment because of chemotherapy-related

adverse events (stomatitis [grade 3], hypoacusis [grade 2], increasedcreatinine level [grade 1])

• No patients discontinued treatment because of pembrolizumab-relatedadverse events




Immune-Mediated Adverse Eventsa

• There were no grade 4/5 immune-mediated or infusion reactions

aBased on a list of terms specified by the sponsor and included regardless of attribution to study treatment orimmune relatedness by the investigator

Event, n (%)

N=25

All Grades in >2 Patients

Grades 3 in All Patients

Any 12 (48) 4 (16)

Hyperthyroidism 4 (16) 0

Palmar-plantar erythrodysesthesia

2 (8) 2 (8)

Nephrotic syndrome 1 (4) 1 (4)

Rash 1 (4) 1 (4)

Maculopapular rash 1 (4) 1 (4)




KEYNOTE-059 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patientswith PD-L1-positive advanced gastric/gastroesophageal cancer

Study Design






PD-L1 positive










Wainberg et al., Abstract LBA28, ESMO 2017 aCapecitabine was administered only in Japan

Characteristic N=31

Median age (range), years, y 62 (32-75)

Male, n (%) 19 (61)

Race, n (%)WhiteAsian

16 (52)15 (48)

ECOG PS, n (%)01

14 (45)17 (55)

No. of prior therapies, n (%) 0

Characteristic N=31


12 (39)19 (61)


9 (29)3 (10)

19 (61)

PD-L1 positive, n (%) 31 (100)

HER2 negative, n (%) 31 (100)





Responsea

N = 31

% 95% CI

ORR 26 12-45

DCRb 36 19-55

BOR

CR 7 1-21

PR 19 8-38

SD 29 14-48

PD 39 22-58

aOnly confirmed responses were includedbCR + PR + SD≥6 monthsData cutoff: April 21, 2017

Median (range) follow-up in cohort 3: 17.5 (1.7-20.7) months

Response




aOnly patients with measurable disease per RECIST v1.1 by central review at baseline who had ≥1 postbaseline assessment wereincluded (n=31); assessment were nonevaluable/not evailable in 3 patientsbLongitudinal change in the sum of the longest target lesion diameters from baseline in patients with CR or PR (n=30)+No progressive disease at last disease assessment





PFS and OS





• Median (range) duration of exposure was 2.8 (0.7-20.3) months• 1 patient each experienced grade 3 adverse events (neutropenia, diffuse

uveal melanocytic proliferation, colitis, bile duct obstruction, decreasedneutrophils, dehydration, hyponatremia, and rash

• 1 patient died because of a treatment-related adverse events during safetyfollow-up (pneumonitis)

adeath occurred during safety follow-up


Event, n (%) N = 31

Any 24 (77)

Grades 3-5 7 (23)

Led to discontinuation 0

Led to deathPneumonitisa

1 (3)1 (3)



Immune-Mediated Adverse Eventsa

aBased on a list of terms specified by the sponsor and included regardless of attribution to studytreatment or immune relatedness by the investigator

Event, n (%)

N=31

All Grades in >2 Patients

Grades 3 Grade 5

Any 10 (32) 2 (7) 1 (3)

Pneumonitis 4 (13) 0 1 (3)

Colitis 1 (3) 1 (3) 0

Rash 1 (3) 1 (3) 0




Updated KEYNOTE-059 results

• Pembrolizumab continues to demonstrate, in patients with advanced G/GEJ cancer,

• Promising antitumor activity and durable response as monotherapy in patients whose disease hasprogressed after ≥2 prior lines of therapy

• Encouraging antitumor activity in combination with chemotherapy in previously untreated patients

• Encouraging antitumor activity as monotherapy in previously untreated patients with PD-L1-positive tumors

• Responses were regardless of PD-L1 expression, but higher in patients with PD-L1-positive tumors in cohorts 1 and 2

• Safety was manageable and consistent with that previous reports: no new safety signals



Summary and Conclusion (I)

• Results support further development of pembrolizumab for advanced G/GEJ cancer

• KEYNOTE-061 (NCT02370498) is an ongoing, phase 3, randomized clinical study of pembrolizumab versus paclitaxel in patients

with advanced G/GEJ cancer whose disease progressed after first-line therapy with platinum and fluoropyrimidine

• KEYNOTE-062 (NCT02494583) is an ongoing, phase 3, randomized clinical study of pembrolizumab alone or in combination with

chemotherapy versus chemotherapy alone as first-line therapy for advanced PD-L1 positive G/GEJ cancer



Summary and Conclusion (II)

Anti-CTLA-4 or anti-PD-1 or anti-PD-L1

Perioperative First-line Second-lineThird-line +

refractory to standard

Ipilimumab (BMS): anti-CTLA-4

Phase III 649/648Nivo Ipi vs CTX

Nivolumab (ONO/BMS):anti-PD-1

Phase III Adjuvant 577 Nivo vs placeboESO after RCTX

Phase III 649/648Nivo Ipi vs CTX

ONO-473 Phase III

Nivo vs Taxanes

ONO-4538-07Phase II

Nivo

Pembrolizumab (MSD):anti-PD-1

KEYNOTE-062 Ph IIIPembro vs Pembro, Cis,

5-FU vs Cis, 5-FU

KEYNOTE-181 Phase IIIPembro vs standard of care

KEYNOTE-061 Phase IIIPembro vs paclitaxel

KEYNOTE-180Phase IIPembro

Durvalumab (AZ): anti-PD-L1

Phase IIAdjuvant

Phase IIDurvalumab vs placebo

Phase Ib/IIDurva vs Treme vs Durva+Treme

Phase Ib and IIDurva+Treme

Atezolizumab (Roche): anti-PD-L1

Phase IIPerioperative FOLFOX/ FLOT

+/- atezolizumab

Avelumab (Merck/Pfizer)anti-PD-L1

JAVELIN GASTRIC 100Phase III

Maintenance after FOLFOX

(Phase I) and Phase IIIAvelumab

JAVELIN GASTRIC 300

After ESMO: even more trials for oesophagogastriccancer

1. Study designs available at: www.clinicaltrials.gov (accessed September 2017). Agents have not yet received EMA approval for treatment of indication listed

http://www.clinicaltrials.gov/

• Disease assessment imaging (CT or MRI) every 6 weeks

• Interim analysis data cutoff date: August 8, 2016

– Median follow-up was 13.3 months in the dose-escalation phase and 10.5 months in the dose-expansion phase

Dose Escalation

0.1–10 mg/kg

N = 48

Dose Expansion

3 mg/kg

N = 214

Uninfected (n = 23)

HCV infected (n = 10)

HBV infected (n = 15)

Uninfected (n = 113)

HCV infected (n = 50)

HBV infected (n = 51)

Sorafenib Experienced (2L)(n = 37)

Sorafenib Naive (1L)(n = 11)

Sorafenib Experienced (2L)(n = 145)

Sorafenib Naive (1L)(n = 69)

Study Endpoints

Primary

• Safety and tolerability (escalation)

• Objective response ratea (expansion)

Secondary

• Objective response ratea (escalation)

• Disease control rate

• Time to response

• Duration of response

• Overall survival

Other

• Biomarker assessments

• Patient-reported outcomesb

a RECIST v1.1; b Baseline and every 6 weeks through week 25 using the EQ-5D utility index and visual analog scale (VAS).

All

Pa

tie

nts

(N

= 2

62

)

CheckMate 040 Study Design

88ASCO GI 2017

Safety: Dose-Expansion Phase

Patients, n (%)

Uninfected (n = 113)

HCV Infected(n = 50)

HBV Infected(n = 51)

All Dose Expansion(N = 214)

Any Grade

Grade 3/4

Any Grade

Grade 3/4

Any Grade

Grade 3/4

Any Grade

Grade 3/4

Any treatment-related AE (TRAE) 84 (74) 22 (19) 40 (80) 15 (30) 35 (69) 3 (6) 159 (74) 40 (19)

TRAEs (≥ 5%)

Fatigue 34 (30) 2 (2) 8 (16) 1 (2) 7 (14) 0 49 (23) 3 (1)

Pruritus 18 (16) 0 14 (28) 1 (2) 13 (25) 0 45 (21) 1 (<1)

Rash 16 (14) 2 (2) 9 (18) 0 8 (16) 0 33 (15) 2 (1)

Diarrhea 19 (17) 2 (2) 5 (10) 0 3 (6) 1 (2) 27 (13) 3 (1)

Nausea 10 (9) 0 6 (12) 0 1 (2) 0 17 (8) 0

Dry mouth 9 (8) 0 2 (4) 0 2 (4) 0 13 (6) 0

Decreased appetite 6 (5) 0 2 (4) 1 (2) 3 (6) 0 11 (5) 1 (<1)

Laboratory TRAEs (≥ 5%)

AST increase 9 (8) 4 (4) 6 (12) 5 (10) 1 (2) 0 16 (7) 9 (4)

ALT increase 7 (6) 2 (2) 7 (14) 3 (6) 3 (6) 0 17 (8) 5 (2)

89ASCO GI 2017

NR, not reached.

TTR, median (range), mo 1.9 (1.4–5.6)

DOR, median (range), mo 17.1 (7.2–32.5+)

TTR, median (range), mo 2.7 (1.2–9.6)

DOR, median (range), mo NR (1.4–9.8+)

Uninfected(n = 14)

HCV(n = 7)

HBV(n = 6)

Dose Escalation Dose Expansion

Time to Response and Duration of Response

Sorafenib Experienced (2L)

Uninfected(n = 3)

HCV(n = 2)

HBV(n = 1)

0.1 mg/kg

1 mg/kg

0.3 mg/kg

10 mg/kg

1 mg/kg

3 mg/kg

Investigator Assessment

CR

Censored with ongoing response

Last dose

PR

Last dose when off treatment

90ASCO GI 2017

Overall SurvivalSorafenib Experienced (2L)

OS Rate (95% CI), % Dose Escalation (n = 37) Dose Expansion (n = 145)

6 months 67 (49–80) 82 (74–87)

9 months 67 (49–80) 71 (63–78)a

12 months 58 (40–72) NC

18 months 46 (29–62) NCa Data cutoff August 8, 2016. NC, not available/not calculated.

0.2

Dose Expansion: Median OS (95% CI), mo = 13.2 (13.2–NR)

Dose Escalation: Median OS (95% CI), mo = 15.0 (5.0–20.2)

Pro

bab

ility

of

Surv

ival

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.1

0.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39

91ASCO GI 2017

Response by PD-L1 Expression

• Responses were observed irrespective of PD-L1 expression on tumor cells

Sorafenib Experienced (2L)

Dose Expansion

Ch

an

ge i

n T

arg

et

Le

sio

n

Siz

e F

rom

Ba

se

lin

e (

%)

Patients

100

50

0

-50

-100

PD-L1 < 1% PD-L1 ≥ 1%

ORR, n/N (%)

95% CI, %

4/26 (15.4),

4.4–34.9

2/9 (22.2),

2.8–60

PD-L1 < 1% PD-L1 ≥ 1%

ORR, n/N (%)

95% CI, %

17/99 (17.2)

10.3–26.1

8/25 (32.0),

14.9–53.5

≥ 1% NAPD-L1: < 1%

-100Patients

100

50

0

-50

≥ 1% NAPD-L1: < 1%

Investigator Assessment

Dose Escalation

92ASCO GI 2017

Other GI cancer

Attraction 01 trialNivolumab monotherapy for advanced pretreated oesophageal cancer

94

Best Overall Response/ORR Investigator Central Review

Response N % (95% CI) N % (95% CI)

Complete response (CR) 2 3.1 (0.9, 10.7) 3 4.7 (1.6, 12.9)

Partial response (PR) 12 18.8 (11.1, 30.0) 8 12.5 (6.5, 22.8)

Stable disease (SD) 20 31.3 (21.2, 43.4) 16 25.0 (16.0, 36.8)

Progressive disease (PD) 29 45.3 29 45.3

NE 1 1.6 8* 12.5

ORR (CR+PR) 14 21.9 (13.5, 33.4) 11 17.2 (9.9, 28.2)

*Including subjects who have no target lesion

64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers10

Summary of Clinical Activity (N=64): As of Nov. 17, 2016

95

Results

Figure 2. Progression-Free Survival and Overall Survival (N=64): As of Nov. 17, 2016

CI = confidence interval

Nivolumab in L2+ Anal cancerNCI9673: Primary Endpoint of Response Rate

Lancet Oncology 2017 Cathy Eng

RESULTATS• Taux de réponse :

• 9/37 = 24% (IC95=15-33) en réponse dont 2 réponses complètes, et 1 réponse partielle chez un patient VIH

• 7/9 des répondeurs (78%) ont maintenu cette réponse jusqu'à l'analyse des données (temps médian 5.8mois IC95=3.9-8.1, durée la plus longue à 10.4mois)

• Réponse radiologique de -70% (IC95=57-90)

• Taux de stabilisation : • 17/37 = 47% (IC95=60-63) en maladie stable,

soit au total 72% (IC95=53-84) de contrôle de la maladie à la 1ère évaluation

Bryan S. Balancing cost-effectiveness with other values: the NICE experience - Gesundheitswesen 2009; 71: S30-S33

Conclusion

J Taieb WCGIC Barcelona 2016

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