INMUNOTERAPIA EN CÁNCER GÁSTRICO Y DE LA UGE: ¿DÓNDE ESTAMOS? Maria Alsina Maqueda, MD, PhD Hospital Universitario Vall d’Hebron, Barcelona
INMUNOTERAPIA EN CÁNCER GÁSTRICO Y DE LA UGE: ¿DÓNDE ESTAMOS?
Maria Alsina Maqueda, MD, PhD
Hospital Universitario Vall d’Hebron, Barcelona
Outline
• The Immune System
• Rational to develop immunotherapy in GC/GEJ
• First evidence of efficacy
• Challenges
• Conclusions
Outline
• The Immune System
• Rational to develop immunotherapy in GC/GEJ
• First evidence of efficacy
• Challenges
• Conclusions
Tumors are complex systems • Successful growth of tumors and metastasis is not determined
solely by genetic alterations in tumor cells, but also by the advantage that such mutations confer in the environment.
• Tumor formation involves the co-evolution of malignant cells together with extracellular matrix, tumor vasculature and immune cells.
Junttila Nature 2013
Tumor Antigen Transport
Lymphocyte trafficking
Acquired capacities of cancer: phenotype
Avoiding
immune
destruction
Evading
growth
suppressors
Enabling
replicative
immortality
Tumor-
promoting
inflammation
Activating
invasion &
metastasis
Genome
instability
mutation
Resisting
cell
death
Deregulating
cellular
energetics
Sustaining
proliferative
signaling
Inducing
angiogenesis
Hanahan & Weinberg Cell 2011
EGFR inhibitors
Aerobic glycolysis inhibitors
Proapoptotic BH3 mimetics
PARP inhibitors
Inhibitors of HGF/c-Met
Selective anti-inflammatory drugs
Telomerase inhibitors
Cyclin-dependent kinase inhibitors
Inhibitors of VEGF signaling
Immunotherapy
Key aspects of the Immune System
Hanahan & Weinberg Cell 2011; Dunn Nat Rev Immunol 2006
Swann & Smyth J Clin Invest 2007; Prendergast Oncogene 2008; Mapara & Sykes J Clin Oncol 2004
• The immune system recognises and destroys tumor cells
• Key features of the immune response:
• Specificity
• Memory
• Adaptability
Immunotherapy has reset survival expectations
0 12 24 36 48 60 72 84 96 108 120 0.0
0.2
0.4
0.6
0.8
1.0
4846 1786 612 392 200 170 120 26 15 5 0
Months
Pooled OS data for 1,861 patients from 10 prospective and two retrospective studies Median OS, months: 9.5 months (95% CI 9.0–10.0)
3-year OS rate: 21% (95% CI 20–22)
Ipilimumab Censored
Ipilimumab No at risk:
Schadendorf J Clin Oncol 2015
Ove
rall
surv
ival
Ipilimumab was the first immune checkpoint inhibitor to demonstrate clinical benefit in stage IV melanoma patients
The immune cycle in cancer
7. Killing of cancer cells
Anti-PD1 Anti-PDL1
Anti-CTLA-4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist)
IL-2 IL-12
Tumor
Lymph node
Blood vessel
1. Release of cancer cell antigens
2. Cancer antigen presentation
3. Priming and activation
5. Infiltration of T cells into tumors
6. Recognition of cancer cells by T cells
4. Trafficking of T cells to tumors
Vaccines IFN-α
GM-CSF Anti-CD40 (agonist)
TLR agonist
Chemotherapy Radiation therapy Targeted therapy
Anti-VEGF/VEGFR
CARs
Anti-PDL1 Anti-PD1
IDO inhibitors
Chen & Mellman Immunity 2013
The immune cycle in cancer
7. Killing of cancer cells
Anti-PD1 Anti-PDL1
Anti-CTLA-4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist)
IL-2 IL-12
Tumor
Lymph node
Blood vessel
1. Release of cancer cell antigens
2. Cancer antigen presentation
3. Priming and activation
5. Infiltration of T cells into tumors
6. Recognition of cancer cells by T cells
4. Trafficking of T cells to tumors
Vaccines IFN-α
GM-CSF Anti-CD40 (agonist)
TLR agonist
Chemotherapy Radiation therapy Targeted therapy
Anti-VEGF/VEGFR
CARs
Anti-PDL1 Anti-PD1
IDO inhibitors
Chen & Mellman Immunity 2013
T cell activation requirements
1. Antigen presentation – MHC complex
2. Co-stimulatory signal – B7 – CD28
3. Cytokines
4. Inhibitory signal – B7 – CTLA4
– PDL-1 – PD-1
Amorena Science 1978, Mueller J Immunol 1989, Walunas Immunity 1994, Krummel J Exp Med 1995, Dong Nat Med 2002; Keir Annu. Rev. Immunol. 2008
The immune checkpoint targetable receptors/ligands
Mellman Nature 2011
T cell targets for modulating activity
CD28
OX40
GITR
CD137
CD27
HVEM
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3
Activating
Receptors
Inhibitory
Receptors
T cell
stimulation
T cell
Agonistic
Antibodies
Blocking
Antibodies
Outline
• The Immune System
• Rational to develop immunotherapy in GC/GEJ
• First evidence of efficacy
• Challenges
• Conclusions
Frequency of genetic somatic mutations in cancer
Altered proteins contain new epitopes for immune recognition, providing a common denominator for cancer immunotherapy
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(/M
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22 20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49
181 231 76 88 35 335 179 121
C→T C→A C→G T→C T→A T→G
Lawrence Nature 2013
No at Risk
50%
20%
22%
9%
TCGA Nature 2014
TILs are predictive of overall survival in GC
Lee Br J Cancer 2008
Pooled OS data for 220 patients with gastric cancer surgically resected
Analysis of PDL1 expression and T cells infiltration
• 1014 GC pts – PD-L1, CD3 and CD8
• PD-L1High (TC and IC) → Better OS • CD3+ High and CD8+ High → Better OS • Close relationship between CD3+, CD8+ cell density
and PDL1 expression (TC and IC) • Patients with higher CD8 and CD3 T cell densities also
have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring
Xing ASCO GI 2017
Immune cells (IC) Tumor cells (TC)
PD-L1 74.9% 37.8%
Outline
• The Immune System
• Rational to develop immunotherapy in GC/GEJ
• First evidence of efficacy
• Challenges
• Conclusions
First evidence of efficacy
• Anti-PD1
• Pembrolizumab: KEYNOTE 0121, KEYNOTE 0592
• Nivolumab: Checkmate 0323, ONO-4538/BMS-9365584
• Anti-PDL1
• Avelumab: JAVELIN Japanese5
• Others
• Ipilimumab: Maintenance6
• New promises (other immune checkpoints and combined strategies)
1. Muro Lancet Oncol 2016, 2. Fuchs ASCO 2016, 3. Janjigian ASCO 2016, 4. Kang ASCO GI 2017;
5. Chung ASCO 2016; 6. Moehler ASCO 2016
Muro Lancet Oncol 2016
Screening: 65 of 162 (40%) patients assessed for PD-L1 expression had PD-L1-positive tumors
Patients: 19 patients from Asia and 20 patients from the rest of the world
Treatment: 10 mg/kg IV Q2W
Response assessment: Performed every 8 weeks per RECIST v1.1 by central radiology review
aAssessed in archival tumor samples using a prototype IHC assay (22C3 antibody). Positivity defined as PD-L1 staining in stroma or ≥1% of tumor cells.
Patients
• Recurrent or metastatic
adenocarcinoma of the
stomach or GEJ
• ECOG PS 0-1
• PD-L1–positive tumora
• No active brain
metastases
Pembrolizumab
10 mg/kg Q2W
Complete Response
Partial Response or
Stable Disease
Confirmed
Progressive Disease
Discontinuation
Permitted
Treat for 24 months
or until progression
or intolerable
toxicity
Discontinue
KEYNOTE-012: Gastric Cancer Cohort
Best Overall Response, RECIST v1.1
Muro Lancet Oncol 2016
Change From Baseline in Target Lesions
aOnly patients with measurable disease per RECIST v1.1 by central review at baseline and at least 1 postbaseline tumor assessment were included (n = 32).
Analysis cutoff date: March 23, 2015.
53.1% of patients experienced a decrease from
baseline
–100
–80
–60
–40
–20
0
20
40
60
80
100
Ch
ange
Fro
m B
assl
ine
, %
Maximum Change
Asia
Rest of world
Ch
ange
Fro
m B
ase
line
, %
0 8 16 24 32 40 48 56 64
–100
–75
–50
–25
0
25
50
75
100
125
150
Time, weeks
Change Over Time
Asia
Rest of world
Muro Lancet Oncol 2016
Kaplan-Meier Estimates of Survival
• OS (ITT) • 6-months OS rate: 66%
• Median OS: 11m
• (95% CI, 5.7-NR)
• Median response duration • 40w (20+ to 48+)
Analysis cutoff date: March 23, 2015.
OS
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16
Time, months
Ove
rall
Surv
ival
, %
n at risk
17 15 12 11 10 8 1 0 0 Asia
19 16 13 11 8 7 6 5 0 ROW
Asia
Rest of world
Muro Lancet Oncol 2016
KEYNOTE 059 • Ph 2 Study in 1st Line GC/GEJ pts
• Pembro 200 mg + 5-FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan)
+ cisplatin 80 mg/m2 Q3W for 6 cycles → Pembro + 5-FU (or capecitabine) for up to 2y
• 18 patients treated, median follow-up 5.5 m • No treatment-related deaths • 1 pt (6%) discontinued treatment
• Stomatitis unrelated to pembro or chemotherapy.
• 7 pts (39%) G1-2 AEs attributed to pembro • Diarrhea, dysgeusia, hyperthyroidism, nausea (n = 2 each)
• 8 pts (44%) experienced G1-2 AEs of special interest, regardless of attribution by investigator • Hyperthyroidism, hypothyroidism, infusion-related reaction, pruritus, vasculitis.
• The combination of pembro, cisplatin, and 5-FU has a manageable safety
profile as first-line therapy in patients with advanced GC
Fuchs ASCO 2016
Checkmate 032: Nivolumab +/- Ipi
• Phase I/II with a GC/GEJ/EC cohort (160 pts) • Irrespectively of PD-L1 status
• 3 different schemes of treatment
• ORR (1st End Point)
Janjigian ASCO 2016
Nivo 3 mg/kg Q2W Nivo 1 mg/kg + ipi 3 mg/kg Nivo 3 mg/kg + ipi 1 mg/kg Q3W
x 4 cycles Nivo 3 mg/kg Q2W
Checkmate 032: Nivolumab +/- Ipi
Janjigian ASCO 2016
N3 N1+I3 N3+I1
ORR 14% 26% 10%
mOS (m) (95% CI) 5.0 (3.4–12.4) 6.9 (3.6–NA) 4.8 (3.0–9.1)
• 12% of pts stopped therapy due to treatment toxicity
• Treatment-related serious AEs of any grade and Grade 3-4 occurred in 10% and 5% (N3), 43% and 35% (N1+I3), and 23% and 15% (N3+I1) of pts
• 1 Grade 5 → tumor lysis syndrome (N3+I1)
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
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
Kang ASCO GI 2017
493 patients randomized from 49 centers of Japan, Korea and Taiwan (Nov-2014 –Febr-2016)
Overall Survival
Time (months)
Pro
bab
ility
of
Surv
ival
(%
)
22 18 16 14 12 10 8 6 4 2 0
0
10
20
30
40
50
60
70
80
90
100
Hazard ratio, 0.63 (95% CI, 0.50–0.78)
P < 0.0001
0 3 5 10 19 39 57 95 142 275 330
0 1 3 3 4 10 16 32 53 121 163
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]
Kang ASCO GI 2017
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]
—
Kang ASCO GI 2017
Adverse Event Summary
Patients, n (%)
Nivolumab 3 mg/kg (n = 330)
Placebo (n = 161)
Any Grade Grade 3/4 Any Grade Grade 3/4
AEs Any Serious AEs AEs leading to discontinuation AEs leading to dose delay
300 (90.9) 131 (39.7) 23 ( 7.0) 63 (19.1)
137 (41.5) 91 (27.6) 13 ( 3.9) 40 (12.1)
135 (83.9) 75 (46.6) 12 ( 7.5) 27 (16.8)
63 (39.1) 47 (29.2) 9 ( 5.6) 17 (10.6)
AEs leading to death 35 (10.6) 25 (15.5)
TRAEs Any Serious TRAEs TRAEs leading to discontinuation TRAEs leading to dose delay
141 (42.7) 33 (10.0) 9 ( 2.7) 25 ( 7.6)
34 (10.3) 21 ( 6.4) 4 ( 1.2) 14 ( 4.2)
43 (26.7) 8 ( 5.0) 4 ( 2.5) 2 ( 1.2)
7 (4.3) 4 (2.5) 3 (1.9) 1 (0.6)
TRAEs leading to death 5 (1.5) 2 (1.2)
AE, adverse event; TRAE, treatment-related adverse event.
Kang ASCO GI 2017
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.
Kang ASCO GI 2017
Avelumab (JAVELIN JPN) • Ph 1b in GC/GEJ pts
• Irrespectively of PD-L1 status
• Treatment-related adverse events • Any grade: in 89 pts (58.9%) → Infusion-related reaction (12.6%) and fatigue (10.6%) • G3: in 15 pts (9.9%) → fatigue, asthenia, increased GGT, thrombocytopenia, and anemia • 1 treatment-related death (hepatic failure/autoimmune hepatitis)
Chung ASCO 2016
2L (n = 22) Mn (n = 52)
PD-L1+ (n = 11) PD-L1− (n = 11) PD-L1+ (n = 20) PD-L1− (n = 32)
ORR % (95% CI) 18.2
(2.3, 51.8)
9.1
(0.2, 41.3)
10.0
(1.2, 31.7)
3.1
(0.1, 16.2)
mPFS w (95% CI) 6.3
(5.4, 18.0)
10.4
(4.1, 21.9)
17.6
(6.0, 24.1)
11.6
(5.7, 14.1)
• 1st Line Maintenance (89 pts) • 2nd Line (62 pts)
Avelumab 10 mg/kg IV Q2W
Ipilimumab Mn (Ph II Trial)
• 1ary EP: irPFS • The study was stopped post-interim analysis • 143 pts screened
• Treatment-related adverse events occurred in
41/57 (72%) of ipi pts and 25/45 (56%) pts on active BSC • Pruritus (32%), diarrhea (25%), fatigue (23%), and rash
(18%)
Moehler ASCO 2016
1st Line Ttx • Ipi 10 mg/kg Q3W x4 → Ipi 10 mg/kg Q12W x3y • BSC (≈ 80% chemotherapy)
Ipilimumab Mn (Ph II Trial)
• irPFS similar between arms (HR=1.44, p=0.097)
• median OS for both arms ≈ 1 yr
Moehler ASCO 2016
Median irPFS (95% CI) Ipi 2.92 (1.6 – 5.2) BSC 4.9 (3.5-6.5)
Early progressors lost
When the immune system reacts, it reacts well, potentially even in re-introduction or 2nd L
Other immune checkpoints & combination strategies
• Atezolizumab, durvalumab
• Combined strategies
Anti-angiogenic agents Immune response
• Vasculature normalization • ↓ Interstitial pressure • ↑ Perfusion • ↑ Adhesion molecules • Preserve endothelial cell anergy
• Availability of glucose, amino acids and oxygen
• ↑ Lymphocyte infiltration • ↑ T-cell access and function
Manning Clin Ca Res 2007
Hodi Cancer Immunol Res 2014
Sznol J Clin Oncol 2015 (suppl)
Combined strategies
• Immunotherapy + anti-angiogenesis1
• Ph 1a/b trial (refractory gastric and GEJ cancer)
• Pembrolizumab + Ramucirumab
• No new safety signals and preliminary efficacy data has been reported
• Immunotherapy + palliative radiotherapy (Abscopal Effect)2
• Phase 2 trial (refractory esophageal, gastric and GEJ cancer)
• Pembrolizumab + palliative radiotherapy (30 Gy on 1ary tumor or single metastasis) → Pembrolizumab until PD
• 1ary End Point: biomarkers of immune response and ORR (RECIST1.1, irRECIST)
1. Chau ASCO GI 2017; 2. Chao ASCO GI 2017
Combined strategies
• Immunotherapy + Targeted Agents
• With anti-HER2 agents1
• Phase 1b/2 trial (HER2-pos gastric and GEJ cancer)
• Pembrolizumab + Margetuximab
• 1ary End Point: ORR (RECIST v1.1 and iRECIST) and DoR
• With anti-MMP9 agents2
• Phase 3 trial (2nd/3rd line gastric and GEJ cancer)
• Nivolumab +/- GS-5745
• 1ary End Point: ORR (RECIST v1.1)
1. Catenacci ASCO GI 2017; 2. NCT02864381
Outline
• The Immune System
• Rational to develop immunotherapy in GC/GEJ
• First evidence of efficacy
• Challenges
• Conclusions
50
25
–125
–25
Ch
ange
fro
m b
asel
ine
SPD
(%
)
–50
–75
–21 –63
Relative day from date of first dose
21 63 105 147 189 231 273 315 357
0
–100
2810
2482
2154
1826
1498
1171
843
515
–140
187
–468
SPD
(mm
2)
50
25
–125
–25
Ch
ange
fro
m b
asel
ine
SPD
(%
)
–50
–75
–21 –63
Relative day from date of first dose
21 63 105 147 189 231 273 315 357
0
–100
1272
1124
975
827
678
530
382
233
–64
85
–212
SPD
(mm
2)
N
N N
N N N
150
125
–125
75
Ch
ange
fro
m b
asel
ine
SPD
(%
)
50 25
–21 –63
Relative day from date of first dose
21 63 105 147 189 231 273 315 357
100
0
19373
17242
15111
12980
10849
8718
6587
4456
194
2325
–1937
50
25
–125
–25
Ch
ange
fro
m b
asel
ine
SPD
(%
)
–50
–75
–21 –63
Relative day from first dose
21 63 105 147 189 231 273 315 357 399 441 483 525
0
–100
153
135
117
99
82
64
46
28
–8
10
–26
SPD
(mm
2) SP
D (m
m2)
–100 –75
–50 –25
N
Response in baseline lesions
Response after initial increase in total tumor volume
‘Stable disease’ with slow, steady decline in total tumor volume
Reduction in total tumor burden after appearance of new lesions
Wolchok Clin Cancer Res 2009
Identifying patterns of response
Managing immune-related AEs
Rash
Autoimmune hepatitis Elevated transaminases
Pneumonitis
Colitis - duodenitis
Pancreatitis
Type 1 diabetes mellitus
Hypothyroidism Myositis
Myasthenia Gravis
Melero Clin Cancer Res 2013
Outline
• The Immune System
• Rational to develop immunotherapy in GC/GEJ
• First evidence of efficacy
• Challenges
• Conclusions
Conclusions
• The immune system plays an important role in GC tumorigenesis (specifically in some subtypes)
• Checkpoint inhibitors have shown encouraging preliminary efficacy
• Efforts to identify predictive biomarkers have already begun, as well as to identify the immune-pattern of response and the management of the related Aes
• The huge amount of current prospective clinical trials will validate their true role
1. Seagal ASCO 216
Ongoing phase II/III clinical trials
Adjuvant
CA209-577 Ph 3 GEJ Nivolumab vs placebo after CRT and surgery
First Line
MK-3475-062 Ph 3 PDL1 +
CDDP/FU (or CPC) vs
CDDP/FU + Pembrolizumab vs
Pembro monotherapy
EMR-100070-007 Ph 3 All (HER2 -) Avelumab (maintenance after XELOX/FOLFOX)
CA209-649 Ph 3 All (HER2 -) Nivolumab + Ipilimumab vs FOLFOX/XELOX
Second Line and beyond
MK-3475-061 Ph 3 All Pembrolizumab vs paclitaxel
GS-US-296-2013 Ph 2 All Nivolumab +/- GS-5745
EMR-100070-008 Ph 2 PDL1 + Avelumab vs investigator’s choice
CA209-358 Ph 1 EBV + Nivolumab
Neoadjuvant
NCT02730546 Ph 1b/2 GEJ Pembrolizumab
Chemoradiotherapy (carboplatin and paclitaxel)
CA209-358 Ph 1 GEJ/GC EBV+ Nivolumab vs Ipilimumab + Nivolumab
On
goin
g P
has
e I C
linic
al T
rial
s ID Ph Strategy Indication Status
NCT02443324 I Pembrolizumab plus Ramucirumab Specific cohort, 2nd or
3rd Line Recruiting
NCT02335411
(KEYNOTE 059) II
Pembrolizumab in monotherapy or in
combination with CT Different lines, HER2-
neg Recruiting
NCT02563548 I Pembrolizumab plus PEGPH20 Specific cohort, at least
2nd Line Recruiting
NCT01848834
(KEYNOTE 012) I Pembrolizumab
Specific cohort,
refractory setting Active, not recruiting
NCT02452424 I Pembrolizumab plus PLX3397 Specific cohort,
refractory setting Recruiting
NCT02318901 I/II Pembrolizumab plus trastuzumab Specific cohort, HER2-
positive Recruiting
NCT02268825 I/II Pembrolizumab plus FOLFOX Specific cohort Recruiting
NCT02340975 II Tremelimumab and/or durvalumab Refractory setting Recruiting
NCT01585987 II Ipilimumab vs FU/BSC Manteinance after 1st
Line Completed
NCT01928394 I/II Nivolumab +/- ipilimumab Specific cohort,
refractory setting Recruiting
NCT02267343 I Nivolumab Refractory setting Recruiting
NCT02488759 I/II Nivolumab EBV-positive Recruiting
NCT01772004 I Avelumab Specific cohort, 3rd Line Recruiting
NCT01943461 I Avelumab 2nd and 3rd Line,
Japanesse and Asian Recruiting
NCT01633970 I Atezolizumab montherapy or in combination
with bevacizumab or CT Basket Recruiting
NCT01375842 I Atezolizumab Basket Recruiting
NCT02471846 I Atezolizumab and GDC-0919 Specific cohort,
refractory setting Recruiting
¡Muchas gracias!