Paradigm Shift in gastric/esophageal cancer treatment from chemo to

immunotherapy

Richard Kim M.D.

Section of Chief of Medical Oncology

Associate Professor

Department of Gastrointestinal Oncology

Moffitt Cancer Center

Tampa, Fl

Disclaimer

“This program is provided as a service to the medical profession and represents the opinions of the speakers. Due to individual countries' regulatory requirements, approved indications and uses of products may vary. Before prescribing any products, please consult the local prescribing information available from the manufacturer(s)”

• Honoraria: Bristol Myers Squibb , Bayer, Merck, Lilly and Eisai

• Speakers’ Bureau: Lilly

• Research Funding: Bristol Myers Squibb (Inst), Eisai (Inst), Bayer

(Inst). Janssen (Inst)

Disclosures

Learning Objectives

• Understand the current treatment landscape of advanced

esophagogastric/gastric tumors

• Understand the mechanism of action of immune checkpoint

inhibitors

• Define the activity of antibodies against PD-1 and PD-L1 in

esophagogastric/gastric cancer

• Describe potential biomarkers of response

Case One • A 65-year-old gentleman presents to his physician with

3-months of dysphagia and weight loss.

• He undergoes upper endoscopy that revealed a tumor at the cardia of the stomach.

• Biopsy was positive for moderately differentiated adenocarcinoma.

• Subsequent work-up with PET/CT scan revealed a gastric tumor with extensive liver metastases and retroperitoneal adenopathy.

• PS:1

Case One

The patient is referred to medical oncology. At this time, what biomarkers do you order?

A. HER-2

B. PDL-1

C. Microsatellite instability testing

D. A and C

E. All of the above

Case One Pathology reported an infiltrative moderately differentiated adenocarcinoma HER2/neu positive 3+. A 2D echocardiogram discloses normal ejection fraction 55%-60%. Which of the following is the best next step in the treatment of this patient?

A. Systemic chemotherapy with epirubicin, oxaliplatin and 5-fluorouracil

B. Systemic chemotherapy with platinum, 5-fluorouracil and trastuzumab

C. Systemic chemotherapy with epirubicin, oxaliplatin, capecitabine and panitumumab

D. Capecitabine and cetuximab

E. Systemic chemotherapy with docetaxel, cisplatin and 5-fluorouracil

Treatment of Metastatic Disease (1st Line)

OX EOX/ EOF

Cape ECX/ EOX

XP FLO FOLFIRI S-1/ Cis DCF ECF

#Pts 498 513 160 109 170 305 221 126

%RR 44% 45% 41% 34% 32% 54% 36% 45%

TTP, months

6.7 6.5 5.6 5.5 5.0 6.0 5.6 7.4

OS, months

10.9 10.4 10.5 10.7 9.0 13.0 9.2 8.9

Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol 19:450;2008, Koizumi Lancet Oncol 9:215; 2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997

Patients with HER2+

advanced gastric cancer (n = 810; 22% of successful screenings)

Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA

Primary endpoint: OS

*Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6.

(n = 584)

R

Patients with advanced

gastric cancer screened for HER2 status (N = 3803)

Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-

FU

5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 +

Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose)

(n = 294)

5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6

(n = 290)

Bang YJ, et al. Lancet. 2010;376:687-697.

Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer (ToGA): OS

Pts at Risk, n

Events

167 182

Mos

294

290

277

266

246

223

209

185

173

143

147

117

113

90

90

64

71

47

56

32

43

24

30

16

21

14

13

7

12

6

6

5

4

0

1

0

0

0

11.1 13.8

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Surv

ival

Pro

bab

ility

FC + T

FC

HR

0.74

95% CI

0.60-0.91

P Value

.0046

Median OS

13.8 11.1

Bang YJ, et al. Lancet. 2010;376:687-697.

Key Points First Line Treatment • Chemotherapy with platinum compound (cisplatin,

oxaliplatin) plus a fluoropyrimidine (fluorouracil [5-FU], capecitabine, or S-1) is the global standard

• Selective patients can benefit from triplet combinations but increased side effects must be considered. Overtoxic treatments like docetaxel-containing triplet regimens cannot be recommended in older patients.

• Oxaliplatin and Irinotecan can substitute for cisplatin without compromising the efficacy of chemotherapy

• Trastuzumab in combination with chemotherapy is the recommended treatment for patients with HER2+ tumors 3+ by IHC or FISH positive.

Case Two

A. Docetaxel single agent

B. Pembrolizumab

C. Nivolumab

D. B and C

E. Paclitaxel/ramucirumab

F. A and E

62-year-old gentleman has metastatic gastric cancer that is HER2

negative and has progressed on first-line therapy with FOLFOX.

The patient has a performance status of 0. PDL-1 CPS score >5.

What would you recommend at this time?

Summary of 2nd-line therapies Agent RR% mPFS/mTT

P mOS Study

Docetaxel/irinotecan vs. Placebo

5.3 3.8

Kang et al., JCO 2012

Docetaxel vs. Placebo

7% 12.2 wks 5.2 3.6

COUGAR-02

Paclitaxel vs. Irinotecan

20.9% 13.5%

3.6 mos 2.3 mos

9.5 8.4

WJOG4007

Ramucirumab vs. Placebo

3% 3%

2.1 mos 1.3 mos

5.2 3.8

REGARD

Ramucirumab/paclitaxel vs. Paclitaxel

28% 16%

5.5 mos 3.0 mos

9.6 7.4

RAINBOW

Case Two

A. Docetaxel single agent

B. Pembrolizumab

C. Nivolumab

D. B and C

62-year-old gentleman has metastatic gastric cancer that is HER2

negative and has progressed on first-line therapy with FOLFOX.

and second line therapy with paclitaxel/ramucirumab. The patient

has a good performance status. PDL-1 CPS score >5. What

would you recommend at this time?

Immunotherapy 101

Esophageal and Gastric Cancer Subtypes1,2

9%

1. Cancer Genome Atlas Network. Nature. 2014;513:202-209. 2. Cancer Genome Atlas Network. Nature. 2017;541:169-175.

22%

Modulating the T-Cell Response

Mellman I, et al. Nature.

2011;480(7378):480-489.

PD-1/PD-L1 Pathway Inhibitors

• Binding of PD-1 to its ligands

PD-L1 and PD-L2 inhibits

effector T-cell function1

• PD-L1 expression on tumor

cells and macrophages

suppresses immune

surveillance, permitting

neoplastic growth2

• High-affinity, monoclonal

antibodies prevent PD-1 from

binding to PD-L1 and PD-L2 1. Keir ME, et al. Annu Rev Immunol.

2008;26:677-704.

2. Pardoll DM. Nat Rev Cancer.

2012;12(4):252-264.

TUM

OR

MHC-pep TCR

T Cell

PD-

1 PD-

L1

Anti-CTLA-4 Abs in EG adenoCA Ab No.

of Pts

RR mPFS OS

Median %

Tremelimumab (15 mg/kg q90d)

18 6% (33+ mos)

2.8 4.8 12-mos 33%

Ipilimumab [maintenance]

57 NS 2.9 12.7 NS

BSC (mostly Fp chemo)

57 NS 4.9 12.1 NS

Ralph, Clin Cancer Res 2010;16:1662 Moehler, J Clin Oncol 2016;34:4011 [abstr]

• Overall, minimal activity for anti-CTLA-4 blockade

KEYNOTE-012: Gastric Cancer Cohort Phase Ib; other cohorts include triple-negative breast cancer,

head/neck cancer, urothelial tract cancer

Bang Y-J, et al. J Clin Oncol. 2015;33(Suppl): Abstract 4001. Muro K, et al. Lancet

Oncol. 2016;17(6):717-726. Pembrolizumab is not approved in Gastric Cancer Indication

Best Overall Response, RECIST v1.1

Best Overall Response, RECIST v1.1

Bang Y-J, et al. J Clin Oncol. 2015;33(Suppl):

Abstract 4001.

aPatients with measurable disease per RECIST v1.1 by central review at baseline. bAll responses were confirmed. cPatient with centrally evaluable disease at baseline who discontinued therapy due to clinical progression before the

first scan. dPatients with centrally evaluable disease at baseline for whom best overall response could not be

determined.

Analysis cut-off date March 23, 2015

• Decrease in target lesions in 53%; objective response 23%

• PFS rate: 24%; 6-month; OS rate: 69%

• mPFS: 1.9 (95% CI 1.8, 3.5) months; mOS: not reached

• Trend (not significant) towards improved OS, ORR and PFS with higher levels of PD-L1 expression

Pembrolizumab (KEYNOTE-012): Anti–PD-1 mAb1

Pembrolizumab for Patients With PD-L1–Positive Advanced

Gastric Cancer (KEYNOTE-012): A Multicenter, Open-Label, Phase 1b Trial

N = 39

1. Muro K et al. Lancet Oncol. 2016;17:717-726.

Pembrolizumab (KEYNOTE-012):

Change From Baseline in Tumor Size1,a

a Only patients with measurable disease per RECIST v 1.1 by central review at baseline and at least 1 post-baseline tumor

assessment were included (n = 32).

1. Bang Y et al. ASCO 2015. Abstract 4001.

Treatment-Related Adverse Events, Incidence >3%

Treatment-Related Adverse Events, Incidence >3%

1. Bang Y-J, et al. J Clin Oncol. 2015;33(Suppl): Abstract 4001. 2. Muro K, et al.

Lancet Oncol. 2016;17(6):717-726.

AEs of Interest Based on Immune Etiology

AEs of Interested Based on Immune Etiology

a1 case of grade 2 hypothyroidism led to treatment interruption bIncludes 1 case of grade 2 interstitial lung disease cLed to treatment infection

Analysis cut-off date March 23, 2015

1. Bang Y-J, et al. J Clin Oncol. 2015;33(Suppl): Abstract 4001. 2. Muro K, et al.

Lancet Oncol. 2016;17(6):717-726.

KEYNOTE-059 (NCT02335411) Study Design1-3

• Response assessment per RECIST v1.1: First scan 9 weeks after cycle 1, then every 6 weeks for year 1 and every 9

weeks thereafter

• Primary endpoints: 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)

a Capecitabine was administered only in Japan. b PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA, USA).

1. Fuchs CS et al. JAMA Oncol. 2018;4:e180013. 2. Wainberg Z et al. ESMO 2017. Abstract LBA28_PR. 3. Bang Y-J et al.

Pembrolizumab

200 mg/kg Q3W

Cohort 1

≥2 Prior lines of therapy

N = 259

Pembrolizumab (200 mg/kg Q3W)

+ cisplatin (80 mg/m2 Q3W)

+ 5-FU (800 mg/m2 Q3W) or

capecitabine (1,000 mg/m2 BID Q3W)a

Cohort 2

No prior therapy

N = 25

Pembrolizumab

200 mg/kg Q3W

Cohort 3

No prior therapy

PD-L1+b

Treat for 35 cycles or

until progression,

intolerable toxicity

ASCO 2017. Abstract 4012.

1. Fuchs CS et al. ASCO 2017. Abstract 4003.

KEYNOTE-059: ORR by PD-L1 Expression Status1

a Only confirmed responses are included. b No assessment represents patients who had a baseline assessment but no post-

baseline assessment at the time of the data cutoff date. Reasons for no assessment include missing, treatment discontinuation, or

death before the first post-baseline radiologic imaging study. c No progressive disease at last assessment.

Best Overall

Responsea

PD-L1 Positive (n = 148) PD-L1 Negative (n = 109)

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

Objective

response (CR

+ PR)

23 15.5 (10.1-

22.4)

7 6.4 (2.6-12.8)

Disease control 49 33.1 (25.6-

41.3)

21 19.3 (12.3-

27.9)

(CR + PR + SD ≥2

mo)

CR 3 2.0 (0.4-5.8) 3 2.8 (0.6-7.8)

PR 20 13.5 (8.5-20.1) 4 3.7 (1.0-9.1)

SD 26 17.6 (11.8-

24.7)

16 14.7 (8.6-22.7)

PD 79 53.4 (45.0-

61.6)

65 59.6 (49.8-

68.9)

Nonevaluable 3 2.0 (0.4-5.8) 3 2.8 (0.6-7.8)

No assessmentb 17 11.5 (6.8-17.8) 18 16.5 (10.1-

24.8)

Duration of

response,

median (range),

mo

16.3 (1.6c to 17.3c) 6.9 (2.4 to 7.0c)

KEYNOTE-059: Pembrolizumab in Refractory Gastric Cancer—Cohort 11

• Objective response rate 11.6%

• MSI-H 4/7; 57.1%; non–MSI-H 15/167; 9.0%

• Median duration of response: 8.4 months

Best Change From Baseline in SLD Duration of Exposure

and First Confirmed Response

1. Fuchs CS et al. JAMA Oncol. 2018;4:e180013.

KEYNOTE-059: ORR by MSI Status1

or death before the first post-baseline radiologic imaging study. c No progressive disease at last assessment.

1. Fuchs CS et al. ASCO 2017. Abstract 4003.

a Only confirmed responses are included. b No assessment represents patients who had a baseline assessment but no post-

baseline assessment at the time of the data cutoff date. Reasons for no assessment include missing, treatment discontinuation,

Best

Overall

Respons

ea

MSI High (n = 7) Non–MSI High (n = 167)

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

Objective

response (CR

+ PR)

4 57.1 (18.4-

90.1)

15 9.0 (5.1-14.4)

Disease control 5 71.4 (29.0-

96.3)

37 22.2 (16.1-

29.2)

(CR + PR + SD ≥2

mo)

CR 1 14.3 (0.4-57.9) 4 2.4 (0.7-6.0)

PR 3 42.9 (9.9-81.6) 11 6.6 (3.3-11.5)

SD 1 14.3 (0.4-57.9) 23 13.8 (8.9-19.9)

PD 0 0 (0.0-41.0) 102 61.1 (53.2-

68.5)

Nonevaluable 0 0 (0.0-41.0) 4 2.4 (0.7-6.0)

No assessmentb 2 28.6 (3.7-71.0) 23 13.8 (8.9-19.9)

Duration of

response,

median (range),

mo

NR (5.3c to 14.1c) 8.4 (2.4 to 19.4c)

a The table lists events that occurred in ≥5% of patients. There were 0 grade 4-5 events.

1. Fuchs CS et al. JAMA Oncol. 2018;4:e180013.

• 7.7% discontinued due to an AE (N = 259)

KEYNOTE-059: Safety: TRAEs1,a

Event Any Grade, n (%) Grade 3, n (%)

Fatigue 49 (18.9) 6 (2.3)

Pruritus 23 (8.9) 0

Rash 22 (8.5) 2 (0.8)

Hypothyroidism 20 (7.7) 1 (0.4)

Decreased appetite 19 (7.3) 0

Anemia 18 (6.9) 7 (2.7)

Nausea 18 (6.9) 2 (0.8)

Diarrhea 17 (6.6) 3 (1.2)

Arthralgia 15 (5.8) 1 (0.4)

Pembrolizumab is not approved in Gastric Cancer Indication

• PD-L1 expression in gastric cancer is determined by combined positive

score (CPS) No. of PD-L1 staining cells (tumor cells, lymphocytes,

macrophages) Total no. of viable tumor cells

• A specimen is considered to have positive PD-L1 expression if CPS ≥1

PD-L1 Expression IHCa

CPS = × 100

PD-L1 Negative PD-L1 Positive

a 22C3 pharmDx kit, Agilent Technologies, Carpinteria, CA.

PD-L1 Positive Negative

Detectable by IHC

Detectable on tumor cells and immune

cells

• Results may be different depending on the antibody/assay

• Which is more important?

• Fluidity – when do we check?

• Cut-off for positivity (1%, 5%, 10%)?

• Primary tumor vs metastatic lesions

Nivolumab vs BSC in Refractory GastricCancer Study Design and Endpoints

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

R

2:1

1

Nivolumab

3 mg/kg IV

q2w

Placebo

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

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

Kang Y-K, et al. J Clin Oncol. 2017;35(Suppl 4): Abstract 2.

ATTRACTION-2: Nivolumab for Gastric Cancer After Standard Treatment1,2 (Cont’d)

Significant OS benefit in Asian patients

(MST +1.2 ms, 1 y OS 26.6%, HR = 0.63)

Well tolerated in pretreated GC patients

(d/c by AE 7% same with placebo)

ORR: 11% Any tumor shrinkage: 37%

Patients with tumor reduction 37.3%

1. Kang YK et al. Lancet. 2017;390:2461-2471. 2. Kang YK et al. ASCO GI 2017. Abstract 2.

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

(%) l va

urvi S of y t i l bi

roba P

0

10

20

30

40

50

60

Placebo (n=52) 4.2 (3.0–6.9) 70

80

90

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

ONO-

4538

Placeb o

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

Nivolumab (n=16) 5.2 (2.8–9.4)

3.8 (0.8–5.0) Placebo (n=10)

Ove

rall

Su

rviv

al (%

)

umab 114 10

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

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

16 15 10 7 5 4

10 8 4 2 1 1

4 2 2 0 0 0 0 0 0

1 0 0 0 0 0 0 0 0

Nivol

Plac

Months Months No. at Risk

Median OS, months (95% CI)

Nivolumab (n=114) 6.1 (4.8–8.6)

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

ATTRACTION-02: Nivolumab Overall Survival by PD-L1 Expression <1% vs ≥1%

100

PD-L1 <1% PD-L1 ≥1%

Median OS, months (95% CI)

Among PD-L1–evaluable patients, baseline characteristics between nivolumab and placebo arms were similar

Boku N, et al. ESMO 2017

Evaluable for PD-L1 expression, n (%)

≥1% vs <1%

≥5% vs <5%

Nivo: 130 (39)

16 (12) vs 114 (88)

10 (8) vs 120 (92)

Placebo: 62 (38)

10 (16) vs 52 (84)

7 (11) vs 55 (89)

KEYNOTE-061 Phase 3 Trial1

Pembrolizumab

200 mg Q3W

n = 196

Eligibility criteria

• Unresectable or metastatic

G/GEJ adenocarcinoma

• Progression on or after

platinum + fluoropyrimidine

• Measurable disease

• ECOG PS 0-1

• Tumor sample for PD-L1

analysis

N = 720

R

1:1

Outcomes

• Primary: PFS in PD-L1+ by per RECIST v1.1 blinded central

review, OS in PD-L1+ tumors

• Secondary: PFS by central review and investigator assessment,

PFS by immune response criteria, OS, TTP, ORR

Paclitaxel

80 mg/m2 days 1, 8, 15

of 4-week cycle

n = 199

Continued for 24

months or until

progression or

intolerable toxicity

Continued until

progression or

intolerable toxicity

1. https://clinicaltrials.gov/ct2/show/NCT02370498. Accessed May 31, 2018.

Shitara K, et al. Lancet 2018

Pembrolizumab is not approved in Gastric Cancer Indication

1. Fuchs CS et al. ASCO 2018. Abstract 4062.

KEYNOTE-061 Outcomes1,a

a Data as reported in abstract form. b Assessed per RECIST v1.1 by blinded, independent central review.

Pembrolizumab (n = 196) Paclitaxel (n = 199)

OS

Median (95% CI), mo 9.1 (6.2-10.7) 8.3 (7.6-9.0)

HR (95% CI) 0.82 (0.66-

1.03)

P .042

PFSb

Median (95% CI), mo 1.5 (1.4-2.0) 4.1 (3.1-4.2)

HR (95% CI) 1.27 (1.03-

1.57)

P .98

ORR,b % (95% CI) 15.8 (11.0-21.7) 13.6 (9.1-19.1)

DOR,b median (range) 18.0 (1.4+ to 26.0+) 5.2 (1.3+ to 16.8)

≥12 mo, % 59.5 29.5

Shitara K, et al. Lancet 2018

Shitara K, et al. Lancet 2018

Phase 3 JAVELIN Gastric 3001

Avelumab

10 mg/kg Q2W

+ BSC

• Eligibility criteria

• Unresectable, recurrent, locally

advanced, or metastatic G/GEJ

• Progression on ≥2 prior

therapies

• Unselected for PD-L1

expression

• N ~ 330

• Outcomes

• Primary: OS

Secondary: PFS, ORR, safety, PROs/QoL

R

1:1 BSC + physician's choice of

chemotherapy (or BSC

alone if ineligible for CT)

Press release, early 2018:

Study did not meet endpoint

of improving survival2

Continued until

confirmed disease

progression,

unacceptable

toxicity, or

withdrawal

1. https://clinicaltrials.gov/ct2/show/NCT02625623. Accessed June 1, 2018.

2. http://www.ascopost.com/News/58303. Accessed June 1, 2018.

CheckMate-032 Gastric Cohort1,2

Nivolumab

3 mg/kg Q2W Eligibility Criteria

• Unresectable or advanced

G/GEJ cancer

• Histologically confirmed

adenocarcinoma

• ≥2 prior lines of therapy

and refractory to/intolerant

of standard therapy

N = 160

Outcomes

• Primary: ORR

• Secondary: OS, PFS, TTR, DOR, safety

• Exploratory: PD-L1 expression

R

1:1:1

1. Janjigian YY et al. ASCO 2017. Abstract 4014. 2. https://clinicaltrials.gov/ct2/show/NCT01928394. Accessed May 30, 2018.

Nivolumab 3 mg/kg

+ ipilimumab 1 mg/kg Q3W

Nivolumab 1 mg/kg

+ ipilimumab 3 mg/kg Q3W

CheckMate-032: Nivolumab + Ipilimumab for Gastric Cancer1

Nivo 3 Nivo 1 + Ipi 3 Nivo 3 + Ipi 1

ORR by PD-L1

PD-L1 ≥1%: 19%

PD-L1 <1%: 12%

ORR by PD-L1

PD-L1 ≥1%: 40%

PD-L1 <1%: 22%

ORR by PD-L1

PD-L1 ≥1%: 23%

PD-L1 <1%: 0%

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

Nivo 3

Nivo 1 + ipi 3

Nivo 3 + ipi 1

a Investigator review. b Patients with a best overall response of CR, PR, or SD.

1. Janjigian YY et al. ASCO 2017. Abstract 4014.

Benefit for which patients? Phase 3 is

ongoing (CheckMate-649)

CHECKMATE-032 PD-L1 Expression and Response

Janjigian YY, et al. J Clin Oncol. 2016;

34(Suppl): Abstract 4010.

• PD-L1 expression appears to be numerically associated

with higher objective response rate (ORR)

PD-L1 Expression

Cutoffa

Objective Response

Rate, n/N

(%)

95% CI

1%

expression

<1% 3/25 (12) 3–31

≥1%b 4/15 (27) 8–55

5%

expression

<5% 5/34 (15) 5–31

≥5% 2/6 (33) 4–78

Anti-PD-1 + anti-CTLA-4 Ab: • Grade 3/4 toxicities are substantially increased

with adding anti-CTLA-4 Ab:

– 17% in nivolumab-only arm

– 27% in nivo 3/ipi 1 arm

– 45% in nivo 1/ipi 3 arm [diarrhea, AST, ALT in

>10%]

Checkmate 032, Janjigian, J Clin Oncol 2016;34:4010 [abstr]

KEYNOTE-059 Cohort 2: Treatment-Naïve Patients1

Pembrolizumab (200 mg/kg Q2W)

+ cisplatin (80 mg/m2 Q3W)

+ 5-FU (800 mg/m2 Q3W)

or capecitabine (1000 mg/m2 BID Q3W)

Cohort 23

No prior therapy

N = 25 Treat for 35 cycles

or until progression,

intolerable toxicity

Outcomes

• Primary: Safety

• Secondary: ORR, DOR, DCR, PFS, OS, OS in PD-L1+

Eligibility criteria

• Recurrent or metastatic

G/GEJ cancer

• No prior therapy

• Measurable disease

• HER2 negative

• ECOG PS 0-1

1. Bang Y-J et al. ASCO 2017. Abstract 4012 . Pembrolizumab is not approved in Gastric Cancer Indication

KEYNOTE-059 Cohort 2: Tumor Response and Duration of Response1

Change in Tumor Size From Baseline Duration of Response

Median (range) time to response, mo: 2 (2-4)

Median (range) duration of response, mo: 5 (3-18+)

1. Bang Y-J et al. ASCO 2017. Abstract 4012 .

1. Bang Y-J et al. ASCO 2017. Abstract 4012 .

Event Grades

3-4 n

(%)

Neutropenia 16 (64)

Stomatitis 5 (20)

Anemia 2 (8)

Decreased appetite 2 (8)

Fatigue 2 (8)

PPE syndrome 2 (8)

Thrombocytopenia 2 (8)

Discontinuations because of a chemotherapy-related AE, n

(%)

3 (12)

Discontinuations because of a pembrolizumab-related AE, n 0

Interruptions because of a chemotherapy-related AE, n (%) 21 (84)

Interruptions because of a pembrolizumab-related AE, n (%) 5 (20)

Deaths because of a treatment-related AE, n 0

KEYNOTE-059 Cohort 2: Safety of Pembrolizumab + Chemotherapy1

1. Wainberg Z et al. ESMO 2017. Abstract LBA28_PR.

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

KEYNOTE-059 Cohort 2: Immune-Mediated Adverse Events1,a

a Based on a list of terms specified by the sponsor and included regardless of attribution to study treatment

or immune relatedness by the investigator.

Event, n (%) n

All Grades in

>2 Patients

= 25

Grade 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-062 – Phase III Trial of Pembrolizumab in First-Line Therapy

Pembrolizumab is not approved in Gastric Cancer Indication

Ongoing Trials • Esophageal

– Adjuvant nivolumab vs docetaxel/paclitaxel

– CheckMate577 adjuvant nivolumab vs placebo

– KEYNOTE-181 second-line pembrolizumab vs taxane/irinotecan

• Gastric/GEJ

– Adjuvant nivolumab

– First-line

• KEYNOTE-062 pembrolizumab monotherapy and in combination with cisplatin + 5-FU

• CheckMate649 nivolumab + ipilimumab vs XELOX/FOLFOX

Conclusions

• Anti PD-1 therapy clearly has activity in

gastroesophageal cancers

– Studies ongoing in first-line and curative

settings, single agent and combination

• Anti CTLA-4 Abs are minimally active

• Combination of Anti CTLA -4 and anti PD

1 Abs maybe more active but with more

toxicity

Conclusions

• PD-L1 is a likely predictive marker, but is

inadequate for patient selection

• MSI is a significant positive predictor of

response, higher frequency in GEC than CRCs-

should be tested routinely

• Future rests on:

- Biomarker development

- Combination approaches with chemotherapy,

radiotherapy and targeted agents are likely

to improve outcomes

Thank you