INMUNOTERAPIA EN CÁNCER GÁSTRICO Y DE LA UGE: ¿DÓNDE … · 2017. 2. 28. · Frequency of genetic somatic mutations in cancer Altered proteins contain new epitopes for immune

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

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

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




• 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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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




• 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


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


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


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 (%)


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 (%)


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




• 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


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


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




• 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,


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,


¡Muchas gracias!

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INMUNOTERAPIA EN CÁNCER GÁSTRICO Y DE LA UGE: ¿DÓNDE … · 2017. 2. 28. · Frequency of genetic somatic mutations in cancer Altered proteins contain new epitopes for immune