The document describes a case study of a 72-year-old male patient with metastatic gastric cancer who showed a partial response after 20 months of treatment with pembrolizumab immunotherapy, with reduction in tumor size of multiple lesions of over 70%. It then reviews the KEYNOTE-012 trial which found that pembrolizumab achieved an objective response rate of 33% in patients with advanced gastric cancer. Ongoing trials are investigating nivolumab as a potential treatment for gastric cancer patients who have progressed on two or more prior chemotherapy regimens.

1. Cáncer Gástrico Metastásico
Inmunoterapia
Dr. Daniel Agüero V
Residente Oncología Médica
Pontificia Universidad Católica
Abril 2017

2. Hoja de Ruta
• Caso Clínico
• Introducción
• Biología Molecular
• Keynote 012
• (ONO-4538/BMS-
936558)
• Ongoing Trials
• Conclusiones

3. Caso Clínico
• Iniciales: R.M.V
• Sexo: Masculino
• Edad: 72 años
• Procedencia: Santiago

4. • Antecedentes personales:
o Médicos: HTA – Depresión
o Quirúgicos: Colecistectomizado 2009
o Fármacos:
o Cordiax D Forte 80/12.5mg día
o Sertralina 50mg dia
o Domperidona 10 mg día
o Polivitaminico 1 día
o Lansoprazol 30 mg dia
o Tabaco: No Refiere OH: No Refiere Alergia: (-)
• Antecedentes Familiares:
o No Refiere
Caso Clínico

5. 2010 Extra UC:
Dolor Abdominal tipo
Cólico y Baja de Peso
EDA + Biopsia:
Adenocarcinoma
Gástrico. HER2 (+++)
FISH (+)
Gastrectomia
Parcial
Caso Clínico
Biopsia Qx:
Adenoca. Tubular Moderada Diferenciado
Serosa (+) PVL y PN (+) Epiplon: (+)
Higado: (+) LN: 43/59
TAC TAP: Adenopatias
Retroperitoneales y Cervicales.
(máx 2 cm)

6. Caso Clínico
Cáncer Gástrico pT4N3M1
Etapa IV

7. Caso Clínico
- 1ª Linea:
- Epirrubicina-Oxaliplatino-
Capecitabina-Trastuzumab
2ciclos.
- 2ª Linea:
- 5FU-Leucovorina-
Oxaliplatino-Trastuzumab
7ciclos
- 3ª Línea:
- Docetaxel-Trastuzumab
3ciclos
- PET CT (06.05.2015)
- Progresión Enfermedad en
Número, Tamaño y
Actividad Metabólica de
Múltiples Adenopatias
Infradiafragmáticas
(>35 mm)
- Junio 2015 Ingresa a Centro
Cáncer UC.
- Inicia Inmunoterapia
Pembrolizumab

8. Actividad Pembrolizumab:
Baseline 2015
20 Meses Tratamiento
- Hombre 72 años con Progresión a EOX, FOLFOX,
Docetaxel, Trastuzumab
- Inicia Pembrolizumab 200 mg cada 3s.
- Ha Completado 30 dosis – TC Control Febrero
2017
10 semanas Tratamiento

9. Caso Clínico
- Actualmente en Dosis Nº 32 con
Pembrolizumab.
- Hipotiroidismo 2º en control
- RECIST Respuesta Parcial

10. Pembrolizumab Respuesta Clínica:
Baseline 2015 Control 2017
Hombre 72 años con Progresión a QMT y Trastuzumab

11. Lesión Medible Basal 2015 2017
Supraclavicular 34 mm 5 mm
Latero Ao. Izq. 23 mm 9 mm
Intercavo Ao 21 mm 11 mm
Masa Mesenterica 41 mm 11 mm
Criterio Respuesta Parcial
% 70%
RECIST

12. • 5ª Enfermedad Maligna Más Común
• 3ª causa más común de Muerte por Cáncer
• Sobrevida a 5 años 5-20%
• Mediana SG 10 m
• Amplia variación geográfica
Cáncer Gastrico :
20/100000
<10/100000
10 - 20/100000
Incidence

13. Etapa IV:
0
5
10
15
20
25
30
C. Paliativos Paclitaxel Paclitaxel +
Ramucirumab
Inmunoterapia
Mediana Sobrevida Global y Respuesta con
Segunda Línea
3,8
7,4
9,6
meses
16%
28%
mOS
RR
11,4
22%

14. 14

16. 16

17. 17

19. +
-
-

20. Checkpoint Inmunes
Ipilimumab
Tremelimumab
Nivolumab,
Pembrolizumab
Atezolizumab
Avelumab
Durvalumab

21. Pembrolizumab

22. Inhibidores Checkpoint
 Las moléculas Checkpoint son la forma del Sistema
Inmune de Autorregular
 El bloqueo de estas moléculas puede mejorar la
actividad de las células T
 Objetivos Checkpoint:
- CTLA 4 (células T activadas)
- PD-1 (células T y B activadas)
- PDL-1 (puede expresarse en células tumorales)
DCR = disease control rate; PR = partial response.
aRalph et al, 2010; bTabernero et al, 2013; cSegal et al, 2014; dBang et al, 2015.

23. KEYNOTE-012
 Multicenter, multicohort open-label phase Ib trial
 Outcomes:
• Primarios: Seguridad/tolerabilidad, respuesta (RECIST v 1.1).
• Secundarios: duración de respuesta, sobrevida libre de progresión (PFS),
sobrevida global (OS), biomarcadores de eficacia (PD-L1, genes IFN-g).
Pts with PD-L1–positive
recurrent or metastatic
adenocarcinoma
of the stomach or
gastroesophageal junction;
ECOG PS 0-1; no active
brain metastases
(N=39)
Pembrolizumab
10 mg/kg IV q 2 w
Pembrolizumab 10 mg/kg IV q 2 w
for 24 mo or until progression or
intolerable toxicity
Bang Y, et al , Lancet 2016

24. KEYNOTE-012
 4/24 pacientes (17%) tenían MSI
 4/39 1ª Linea
 Mediana seguimiento 10,8 meses.
 85% descontinuaron:
- 32 pacientes por progresión
- 1 por enfermedad pulmonar
intersticial.
N: 39
Edad 63
Hombres 72%
Asiaticos y No 49% - 49%
ECOG 1 56%
Gastrectomizados 51%
Sin Ady. O Neo 72%
Del Resto (28%) 42% (3 – 4 Linea)
Tamaño Basal 9.2 cm
Bang Y, et al , Lancet 2016

25.  Respuesta objetiva: 33% (investigador), 22 % (central)
Bang Y, et al , Lancet 2016
KEYNOTE-012
Outcomes
Response
Investigator
Review
(n = 39)
Central
Review
(n = 36)
ORR, % (95% CI) 33 (19-50) 22 (10-39)
Best response, n (%)
 CR 0 0
 PR 13 (33) 8 (22)
 SD 3 (8) 5 (14)
 PD 23 (59) 19 (53)
 No assessment 0 1 (3)
 Not determined 0 3 (8)
 TTR (weeks) 8 8
 DOR (weeks) 40 40

26. KEYNOTE-012
Maximum Percentage Change From Baseline in Tumor Size
(RECIST v1.1, Central Review)
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaselinein
SumofLongestDiameter
ofTargetLesion(%)
53.1% of pts experienced a
decrease in target lesions
Bang Y, et al , Lancet 2016

27. 0 162 4 6 8 10 12 140 142 4 6 8 10 12
100
80
60
40
20
0
100
80
60
40
20
0
KEYNOTE-012:
 6-mo PFS rate: 26%
 Median PFS: 1.9 mos
(95% CI: 1.8-3.5)
 6-mo OS rate: 66%
 12 mo OS rate: 42%
 Median OS: 11.4 mos
(95% CI: 5.7-NR)
PFS
PFS(%)
MosPts at
Risk, n 36 14 12 9 7 5 1 0
OS
OS(%)
MosPts at
Risk, n 36 31 25 22 18 15 7 05
Bang Y, et al , Lancet 2016

28. KEYNOTE-012:
 Pocas Reacciones G ≥ 3
 Toxicidad parecida a otros
trabajos con pembrolizumab
 Sin Muertes
 Colitis, hepatitis, Tiroiditis
Autoinmune 1 pcte C/U
– Todos G 1 o 2
 2 descontinuaron Tto
– Hipotiroidismo, n = 1
– Pneumonitis, n = 1
Pembrolizumab-Associated AE (N = 39), n (%)
Any toxicity
 Grade 3/4
26 (67)
5 (13)
Fatigue, any
 Grade 3
7 (18)
2 (5)
Hypothyroidism, any
 Grade 3
5 (13)
1 (3)
Pruritus 5 (13)
Arthralgia 4 (10)
Hyperthyroidism 3 (8)
Nausea 3 (8)
Peripheral neuropathy, any
 Grade 3
3 (8)
1 (3)
Grade 3 pemphigoid 1 (3)
Grade 4 pneumonitis 1 (3)
Bang Y, et al , Lancet 2016

29. Nivolumab (ONO-4538/BMS-936558) as Salvage
Treatment After Second- or Later-Line
Chemotherapy for Advanced Gastric or
Gastroesophageal Junction Cancer (AGC):
A Double-Blinded, Randomized, Phase 3 Trial
Yoon-Koo Kang,1 Taroh Satoh,2 Min-Hee Ryu,1 Yee Chao,3 Ken Kato,4 Hyun Cheol Chung,5
Jen-Shi Chen,6 Kei Muro,7 Won Ki Kang,8 Takaki Yoshikawa,9 Sang Cheul Oh,10 Takao Tamura,11
Keun-Wook Lee,12 Narikazu Boku,4 Li-Tzong Chen13
1Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 2Frontier Science for Cancer and Chemotherapy, Osaka University
Graduate School of Medicine, Suita, Japan; 3Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Gastrointestinal Medical Oncology, National Cancer
Center Hospital, Tokyo, Japan; 5Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Song Dang Institute for Cancer Research, Yonsei
University College of Medicine, Yonsei University Health System, Seoul, Korea; 6Division of Hematology/Oncology, Department of Internal Medicine, Linkou Chang Gung
Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; 7Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 8Division of Hematology-Oncology,
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 9Gastrointestinal Surgery, Kanagawa Cancer Center,
Yokohama, Japan; 10Division of Hematology/Oncology, Internal Medicine Department, College of Medicine, Korea University, Seoul, Korea; 11Medical Oncology, Kindai
University, Faculty of Medicine, Osakasayama, Japan; 12Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul
National University College of Medicine, Seongnam, Korea; 13National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

30. 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.
R
2:1
Nivolumab
3 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

31. Baseline Characteristics
Characteristic
Nivolumab 3 mg/kg (n =
330)
Placebo (n = 163)
Median age (range), years
< 65 years, n (%)
62 (20–83)
189 (57.3)
61 (26–83)
95 (58.3)
Male, n (%) 229 (69.4) 119 (73.0)
Country, n (%)
Japan
Korea
Taiwan
152 (46.1)
146 (44.2)
32 ( 9.7)
74 (45.4)
74 (45.4)
15 ( 9.2)
ECOG PS, n (%)
0
1
95 ( 28.8)
235 ( 71.2)
48 ( 29.4)
115 ( 70.6)
Primary site of disease, n (%)
Gastric
Gastroesophageal junction
Unknown
272 (82.4)
30 ( 9.1)
28 ( 8.5)
135 (82.8)
12 ( 7.4)
16 ( 9.8)
Prior gastrectomy, n (%)
No
Yes
133 (40.3)
197 (59.7)
58 (35.6)
105 (64.4)
Organs with metastases (≥ 2), n (%) 246 (74.5) 119 (73.0)
Prior treatment regimens, n (%)
2
3
≥ 4
69 (20.9)
137 (41.5)
124 (37.6)
29 (17.8)
62 (38.0)
72 (44.2)
Any prior therapy, n (%)
Fluoropyrimidine
Platinum
Taxane
Irinotecan
Ramucirumab
330 (100)
329 (99.7)
311 (94.2)
284 (86.1)
247 (74.8)
35 (10.6)
163 (100)
163 (100)
157 (96.3)
140 (85.9)
123 (75.5)
22 (13.5)

32. Overall Survival
Time (months)
ProbabilityofSurvival(%)
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,
n
Events,
n
Median OS
[95% CI], months
12-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]

33. 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]

34. Progression-Free Survival
Time (months)
ProbabilityofProgression-FreeSurvival(%)
20181614121086420
0
10
20
30
40
50
60
70
80
90
100
0024819314683131330
011224791741163
Nivolumab
Placebo
At risk:
Nivolumab
Placebo
Hazard ratio, 0.60 (95% CI, 0.49–0.75)
P < 0.0001
Median Progression-Free Survival
1.61 months
1.45 months
Patients,
n
Events,
n
Median PFS
[95% CI], months
12-Month PFS Rate
[95% CI], %
Nivolumab 330 253 1.61 [1.54–2.30] 7.6 [4.2–12.2]
Placebo 163 145 1.45 [1.45–1.54] 1.5 [0.3–4.8]

35. RECIST Response and Disease Control
Nivolumab 3 mg/kg
(n = 268)
Placebo
(n = 131)
ORR, n (%)
[95% CI]
P value
30 (11.2)
[7.7–15.6]
< 0.0001
0
[0–2.8]
—
BOR, n (%)
Complete response
Partial response
Stable disease
Progressive disease
0
30 (11.2)
78 (29.1)
124 (46.3)
0
0
33 (25.2)
79 (60.3)
DCR, n (%)
[95% CI]
P value
108 (40.3)
[34.4–46.4]
0.0036
33 (25.2)
[18.0–33.5]
—
Median TTR (range),
months
1.61 (1.4–7.0) —
Median DOR, months
[95% CI]
9.53
[6.14–9.82]
—

36. Maximum Reduction in Tumor Burden From Baseline
Nivolumab Placebo
MaximumReductionFromBaseline
inTargetLesions(%)
-100
-80
-60
-40
-20
0
20
40
60
80
100
-100
-80
-60
-40
-20
0
20
40
60
80
100
a
a Patients with a change in tumor burden that exceeds 100%.
a
Patients with Tumor reduction: 37.3% Patients with Tumor reduction: 12.4%

37. Treatment-Related Adverse Events
Patients, n (%)
Nivolumab 3
mg/kg
(n = 330)
Placebo
(n = 161)
Any
Grade
Grade
3/4
Any
Grade
Grade
3/4
Any TRAE 141 (42.7) 34 (10.3) 43 (26.7) 7 (4.3)
TRAEs in > 2% of
patients treated with
nivolumab
Pruritus
Diarrhea
Rash
Fatigue
Decreased appetite
Nausea
Malaise
AST increased
Hypothyroidism
Pyrexia
ALT increased
30 (9.1)
23 (7.0)
19 (5.8)
18 (5.5)
16 (4.8)
14 (4.2)
13 (3.9)
11 (3.3)
10 (3.0)
8 (2.4)
7 (2.1)
0
2 (0.6)
0
2 (0.6)
4 (1.2)
0
0
2 (0.6)
0
1 (0.3)
1 (0.3)
9 (5.6)
3 (1.9)
5 (3.1)
9 (5.6)
7 (4.3)
4 (2.5)
6 (3.7)
3 (1.9)
1 (0.6)
3 (1.9)
1 (0.6)
0
0
0
2 (1.2)
1 (0.6)
0
0
0
0
0
0
ALT, alanine aminotransferase; AST, aspartate aminotransferase.

38. Trial Name
(Phase)
Therapy Study Design N Completion
Date
Outcome
Measures
NCT02314117
(RAINFALL)
Eli Lilly
ramucirumab +
capecitibine/cisplatin vs
placebo
+capecitabine/cisplatin
Randomized double-
blind phase 3 study
616 January 2017 PFS/OS
NCT01630083
(IMAB362)
Ganymed
IMAB362 800/600mg/m2
OR 1000mg/m2 +
Epirubicin+ Oxaliplatin +
Capecitabine (EOX) vs
EOX
Randomized open-label
phase 2 study
252 September 2018 PFS
NCT02545504
Gilead
GS-5745 + mFOLFOX6 vs
placebo + mFOLFOX6
Randomized double-
blind phase 3 study
430 September 2018 OS
NCT02625610
(JAVELIN
GASTRIC 100)
Merck/EMD
Avelumab vs (Oxaliplatin+
5-FU + leucovorin +
capecitabine)
Randomized open-label
phase 3 study
666 November 2018 OS
NCT02494583
(KEYNOTE-062)
Merck
Pembrolizumab vs pembro
+ cisplatin + 5-FU vs
placebo + cisplatin + 5-FU
Randomized, active-
controlled, partially
blinded, biomarker
select phase 3 study
750 July 2019 PFS/OS
NCT02658214
AstraZeneca
FOLFOX + durvalumab +
tremelimumab
Open-label, parallel
phase 1b study
60 May 2018 Safety
NCT02340975
MedImmune
MEDI4736+ tremelimumab
vs
MEDI4736/tremelimumab
Randomized, open-
label, parallel phase
1b/2 study (For 1L to
135 August 2018 AEs/DLTs/OR
R/PFS
Ongoing Trials 1L

39. Trial Name
(Phase)
Therapy Study Design N Completio
n Date
Outcome
Measures
NCT01924533
AstraZeneca
Olaparib+ paclitaxel vs
placebo + paclitaxel
Randomized, double-
blinded placebo-controlled
phase 3 study
664 April 2016 OS
NCT02335411
(KEYNOTE-059)
Merck
Pembrolizumab (previously
treated) vs pembro + cisplatin +
5-Fu + capecitabine (treatment-
naïve) vs pembro (treatment-
naïve)
Non-randomized open-
label, phase 2 study
253 January 2017 AE/ORR
NCT02318277
(ECHO-203)
Incyte
Epacadostat +
durvalumab
Open-label, phase 1/2
study
185 March 2017 ORR/AE
NCT02689284
MacroGenics/Mer
ck
Margetuximab +
pembrolizumab
Open-label, dose
escalation phase 1b/2
study
52 September
2017
MTD/ORR
NCT02340975
MedImmune
Tremelimumab +/-
durvalumab in 4 arms
Open label phase 1b/2
study
236 November
2017
AE/DLT/
ORR/PFS
NCT02370498
(KEYNOTE-061)
Merck
Pembrolizumab vs
paclitaxel
Randomized, open-label
phase 3 study
720 December
2017
PFS/OS
NCT02514551
Eli Lilly
Ramucirumab +
paclitaxel (standard
dose vs alternative dose
of ramucirumab)
Randomized , open-label
phase 2 study
240 March 2018 PFS
Ongoing Trials 2L

40. Trial Name (Phase) Therapy Study Design N Completion Date Outcome Measures
NCT01772004
(JAVELIN Solid Tumor)
Pfizer/EMD
Avelumab Open-label phase 1 study 1700 May 2018 DLT/ORR
NCT02443324
(KEYNOTE-098)
Merck/Eli Lilly
Pembrolizumab +
ramucirumab
Randomized multicohort
phase 3 study
41 June 2018 DLT
ORR, Disease control
rate, median time to
response
NCT03019588
(KEYNOTE-063)
Merck
Pembrolizumab vs paclitaxel Randomized, open-label
phase 3 study
360 January 2019
(primary completion)
OS, PFS
NCT02572687
Eli Lilly
Ramucirumab (LY3009806)
Plus MEDI4736
Open label, parallel phase 1
study
114 August 2017 Number of patients
with DLT
NCT02876224
Hoffman-La Roche
Cobimetinib +
atezolizumab+ bevacizumab
Open-label, parallel phase 1b
study
33 September 2018 % of patients with AEs
NCT02918162 Pembrolizumab, SOC Phase 2 study 40 June 2019 (primary
completion)
24 month disease free
survival rate (DFS)
NCT02625623
(JAVELIN Gastric 300)
Pfizer/EMD
Avelumab +BSC vs
physician’s choice
chemotherapy +BSC
Randomized, open-label
phase 3 study
330 August 2017 OS
NCT02689284
Macrogenomics
Pembrolizumab +
margetuximab
Randomized, dose-escalation
phase 1b/2 study
52 March 2020 Maximum tolerated
dose
Ongoing Trials 2L

41. Conclusiones
 Inhibidores de Checkpoint (IC) son
seguros en este grupo de pacientes.
 IC Respuestas Sostenidas.
 IC Beneficio SG y PFS
 Inmunoterapia representa el Futuro en
Ca. Gastrico Avanzado

42. Cáncer Gástrico Metastásico
Inmunoterapia
Dr. Daniel Agüero V
Residente Oncología Médica
Pontificia Universidad Católica
Abril 2017