Tumores esófago-gástricos,

¿tiene algo que decir la inmunoterapia?

Dr. Fernando Rivera Herrero

Hospital Universitario Marqués de Valdecilla.

Santander

Finantial disclosure

• Consultor: CELGENE

• Research fundings: AMGEN., MERCK-SERONO, ROCHE, SANOFI, BAYER, LILLY, MSD

• Advisories: BMS, MSD, AMGEN., MERCK-SERONO, ROCHE, SANOFI, BAYER, LILLY, SERVIER, BAXALTA

9%

20 %

21%

50%

Gastric Cancer: Comprehensive Molecular Characterization

9%

21%

20 %

50%

Adapted from Shah. J Clin Oncol 2015

3-4m

8-10m

10-11m

2nd Line therapy : chemo +/- ramucirumab

Systemic treatment in AGC

in HER2 + (1st line) 16m

17m

Immunotherapy in Esophago-Gastric Cancer

◼ Immunomodulation→ Immune “check points”

◼ Other

Immunotherapies

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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C→TC→AC→GT→CT→AT→G

Lawrence Nature 2013

No at Risk

Cambiando la Práctica Clínica

Nivolumab approved for the Treatment

of Patients with Unresectable Advanced

or Recurrent Gastric Cancer Which Has

Progressed After Chemotherapy1

Pembrolizumab approved for Previously

Treated Patients with Recurrent Locally

Advanced or Metastatic Gastric or

Gastroesophageal Junction Cancer Whose

Tumors Express PD-L1 (CPS≥ 1)2

1. https://news.bms.com/press-release/corporatefinancial-news/japan-ministry-health-labor-and-welfare-approves-opdivo-nivolu . 2.http://investors.merck.com/news/press-release-details/2017/FDA-Approves-Mercks-KEYTRUDA-pembrolizumab-for-Previously-Treated-Patients-with-Recurrent-Locally-Advanced-or-Metastatic-Gastric-or-Gastroesophageal-Junction-Cancer-Whose-Tumors-Express-PD-L1-CPS-Greater-Than-or-Equal-to-1/default.aspx

Cambiando la Práctica Clínica: Biomarcadores

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.2.2018. © National Comprehensive Cancer

Network, Inc. 2018. All rights reserved. Accessed June 13, 2018.

4% of AdGC

Immuno Checkpoint Inh in AdGC

1st line manteinance 2nd line ≥ 3rd line

KN 059. Coh 1

ATTRACTION-02

CM 032. Coh 1

Javelin 300

KN 061

KN 062

KN 059 Coh 2, 3

CM 032. Coh 2,3

Ipi manteinance

KN 811

CM 649

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Ipi

Javelin manteinance

Promising P. II

Rand P. II-III +

Rand P. II-III -

Ongoing P III

KN 859

F II-III ATTRACTION 04

Nivolumab (Anti PD-1)

A positive asian P III in refractory disease

1.- Kang YK, et al. ASCO-GI 2017 . Abst 1 ;

2.- Boku N et al, ESMO 2017

P. III ATTRACTION-02 / ONO-4538 1, 2

Advanced Gastric cancer, refractory to standard therapy (> 2 lines)

→ 493 pts (rand 2/1)

PlaceboNivolumab 3 mg/kg / 14 d Primary Endpoint:OS

OS (median) 5.3 m HR 0,62 p< 0,0001 4.1 m

12 m 27 % 12 %

PFS(median) 1,6 m HR 0,60 p<0,0001 1,4 m

RR 12 % p<0,0001 0%

1.- Boku N et al, ESMO 2017

P. III ATTRACTION-02 / ONO-4538 1

Subgroup analysis : PD-L1 expression

Retrospective determination of tumor PD-L1 expression,

defined as positive if staining in ≥1% (or ≥5%) of tumor

cells, was performed in a central laboratory using

immunohistochemistry (28-8 pharmDx assay) for patients with available tumor samples

PD-L1 ≥ 1% : 14 % ptsPD-L1 ≥ 5% : 7 % pts

Checkmate 032: Nivolumab +/- Ipi• Phase I/II with a GC/GEJ/EC cohort (160 pts) ; Western pts; Irrespectively of PD-L1

status

Ott P et al. ESMO GI 2017

Nivo 3 mg/kg Q2WNivo 1 mg/kg + ipi 3 mg/kg Q3WNivo 3 mg/kg + ipi 1 mg/kg Q3W

x 4 cycles Nivo 3 mg/kg Q2W

42 pts EG adenocarcinoma ≥ 2 previous lines

RR: 17% DC: 33%OS (median) 8.5 m

(1 y OS) 44%PFS (median) 1.4 m

(6m PFS) 20%

Similar response and OS regardless of P-L1 status

Checkmate 032: Nivolumab +/- Ipi

Janjigian ASCO 2017

Nivo 3 mg/kg Q2WNivo 1 mg/kg + ipi 3 mg/kg Q3WNivo 3 mg/kg + ipi 1 mg/kg Q3W

x 4 cycles Nivo 3 mg/kg Q2W

Similar response regardless of P-L1 status

ORR (1st End Point)

mOS 6.2 (3.4, 12.4) 6.9 ( 3.7, 11.5) 4.8 (3.0, 8.4)

NIVO 3

NIVO 1+IPI 3

NIVO 3 + IPI 1

OS

NIVO 3

NIVO 1+IPI 3

NIVO 3 + IPI 1

PFS

Nivolumab in 1st line AGC

P. II/III ATTRACTION-04. Japan & South Corea. ~100% PD-L1 available

Part 1

1:1

PatientsPreviously untreated patients with unresectable advanced or recurrent gastric cancer

SOX therapyNIVO (360 mg IV Q3W)

+ SOX therapya

CapeOX therapy NIVO (360 mg IV Q3W)+ CapeOX therapyb

R

N = 30

Adapted from Kang YK et al. ESMO 2017.

Ongoing P III trials with nivolumab in 1st line AGC

P. III CM-649

1st line Advanced G/EGJ adenoca

HER 2 -;

→ 1 266 pts

Nivolumab + Ipilimumab

1º Endpoint: OS / PFS Nivolumab + Chemotherapy

Chemotherapy

P. III ATTRACTION-04

1st line Advanced G/EGJ adenoca

HER 2 -;

→ 680 pts

Chemo + Nivolumab1º Endpoint: OS/PFS

Chemo+ placebo

Immuno Checkpoint Inh in AdGC

1st line manteinance 2nd line ≥ 3rd line

KN 059. Coh 1

ATTRACTION-02

CM 032. Coh 1

Javelin 300

KN 061

KN 062

KN 059 Coh 2, 3

CM 032. Coh 2,3

Ipi manteinance

KN 811

CM 649

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Ipi

Javelin manteinance

Promising P. II

Rand P. II-III +

Rand P. II-III -

Ongoing P III

KN 859

F II-III ATTRACTION 04

Pembrolizumab (Anti PD-1)

1- Fucks CS et al, JAMA Oncol, 2018;

P II KEYNOTE 059 1 (Cohort 1: Pembro in GC ≥ 3rd line)

259 pts (PD-L1 + 57%; EGJ 51%; >3 lines 48%; Asian 13% )

RR 12%, DC 27% Dur of Resp: 8.4 m

Higher activity in PD-L1+ vs PD-L1- and in 3rd line vs > 3rd and in MSI-H (4% of pts)

RR: 15% 6% 16% 6% 57%

DC 33% 19% 71%

Dur of Resp 16,3 m 6,9 m

PD-L1 positive was defined as combined positive score (CPS)

≥1 (previously reported as and equivalent to CPS ≥1%), where

.CPS = the number of PD-L1–positive cellsb (tumor cells,

lymphocytes, and macrophages) divided by the total number of

tumor cells × 100

- PD-L1 IHC 22C3 pharmDx (Agilent Technologies)

1 y OS: 26%

Pembrolizumab (Anti PD-1)

1..- Fucks et al, Lancet Oncol. 2018 2.- Muro K, ASCO-GI 2018

P II KEYNOTE 059 1,2 (Cohort 1: Pembro in GC ≥ 3rd line)

RR: Asian 7% Non-Asian: 12%

Pembrolizumab in 2nd line AGCA recently comunicated negative P III in 2nd line

1.- Fuchs CS. ASCO 2018

P. III KN 0611

2nd line Advanced Gastric canc

→ 592 pts

PaclitaxelPembrolizumab 200 mg /21 d Primary Endpoint:

PFS and OS in PD-L1+ (CPS >1) OS (median) 9.1 m vs 8.3 m HR 0.82 (0.66-1.03 ) p 0.042 (0.0135)

PFS (median) 1.5 m vs 4.1 m HR 1.37 (1.03-1.57) p NS

P. III KN 0611

1.- Fuchs CS. ASCO 2018

33% of pts 18% of pts67% of pts

Overall Survivalby PD-L1 (CPS)

P. III KN 0611

1.- Fuchs CS. ASCO 2018

27 pts

RR

Pembrolizumab in 1st line AGC

1.- Weinberg et al, ESMO 2017

P II KEYNOTE 059 1 (Cohort 3: Pembro in PD-L1+ AG/EGJC 1st line)

30 pts PD-L1 + (CPS>1) RR 26%, DC 89% , mOS 20.7 m

PD-L1 positive was defined as combined positive score (CPS) ≥1

(previously reported as and equivalent to CPS ≥1%), where

.CPS = the number of PD-L1–positive cellsb (tumor cells,

lymphocytes, and macrophages) divided by the total number of

tumor cells × 100

- PD-L1 IHC 22C3 pharmDx (Agilent Technologies

Pembrolizumab + CT in 1st line AGC

1.- Bang YJ, et al, ASCO 2017

P II KEYNOTE 059 1 (Cohort 2: Pembro-Cis-Fu/Xeloin AG/EGJC 1st line)

25 pts PD-L1 + (CPS>1) 64% , RR 60%, DC 80%

Higher activity in PD-L1+ vs PD-L1-

RR: 69% 38%

DC 81% 75%

P III Pembrolizumab in 1st line AGC

P. III KN 062

1st line Advanced G/EGJ canc

HER 2 -; PD-L1 + (CPS >1)

→ 750 pts

Platin-FU Placebo

Pembrolizumab

200 mg /21 d 1º Endpoint: OS / PFS

Platin-FU

Pembrolizumab

P. III KN 811

1st line Advanced G/EGJ C

HER 2 + → pts

CT-Herceptin

Pembrolizumab

CT-Herceptin

P. III KN 859

1st line Advanced G/EGJ canc

HER 2 -; PD-L1 + (CPS >1)

→ 750 pts

Platin-FU Placebo

Pembrolizumab

200 mg /21 d 1º Endpoint: OS / PFS Platin-FU

Pembrolizumab

1º Endpoint: OS / PFS

Immuno Checkpoint Inh in AdGC

1st line manteinance 2nd line ≥ 3rd line

KN 059. Coh 1

ATTRACTION-02

CM 032. Coh 1

Javelin 300

KN 061

KN 062

KN 059 Coh 2, 3

CM 032. Coh 2,3

Ipi manteinance

KN 811

CM 649

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Ipi

Javelin manteinance

Promising P. II

Rand P. II-III +

Rand P. II-III -

Ongoing P III

KN 859

F II-III ATTRACTION 04

Avelumab (Anti PD-L1)

Avelumab (Anti PD-L1)

Immuno Checkpoint Inh in AdGC

1st line manteinance 2nd line ≥ 3rd line

KN 059. Coh 1

ATTRACTION-02

CM 032. Coh 1

Javelin 300

KN 061

KN 062

KN 059 Coh 2, 3

CM 032. Coh 2,3

Ipi manteinance

KN 811

CM 649

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Ipi

Javelin manteinance

Promising P. II

Rand P. II-III +

Rand P. II-III -

Ongoing P III

KN 859

F II-III ATTRACTION 04

Ipilimumab Mn (Ph II Trial)

Moehler ASCO 2016

1st Line Ttx107 pts

• Ipi 10 mg/kg Q3W x4 → Ipi 10 mg/kg Q12W x3y• BSC (≈ 80% chemotherapy)

1º endpoint PFS

Median irPFS (95% CI)✓ Ipi 2.92 (1.6 – 5.2)✓ BSC 4.9 (3.5-6.5)

median OS for both arms ≈ 1 yr

PD-L1: predictive value in AGC

• Pembrolizumab (CPS >1: 40-57%) – Más actividad (Rta, Dur Rta) en PD-L1+

– …pero tbn hay actividad en PD-L1-

– KN-061: ¿Sólo beneficio en CPS>10??

• Nivolumab (Tumor cells > 1%: 14-33%)– No valor predictivo

PD-L1 positive was defined as combined positive score (CPS) ≥1

(previously reported as and equivalent to CPS ≥1%), where

.CPS = the number of PD-L1–positive cellsb (tumor cells,

lymphocytes, and macrophages) divided by the total number of

tumor cells × 100

- PD-L1 IHC 22C3 pharmDx (Agilent Technologies)

Retrospective determination of tumor PD-L1

expression, defined as positive if staining in ≥1%

(or ≥5%) of tumor cells, was performed in a central

laboratory using immunohistochemistry (28-8

pharmDx assay) for patients with available tumor samples

50%

20%

22%

9%

TCGA Nature 2014

Slide 15

Treatment optionsin Resectable Gastric/EGJ Adencoca

Gastric Adenoca

- Postoperative Chemotherapy-Postoperative Chemo-Radiotherapy- Perioperative Chemotherapy

- Preoperative Chemo-RT

E-EGJ Adenoca

DANTE Perioperative G/EGJ R II FLOT 295 DFS/PFS

NCT03421288 FLOT + Atezolizumab

Selected Ongoing trials with Inmunotherapy in resectable G/EGJ Adenoca

-Nivolumab : - only one + P III in asian pts (ATTRACTION,; refractory)

-Promissing P II in western pts (CM 032; refractory)

-Promising P II with Nivo-Ipi (CM 032; refractory)

-Ongoing P III in 1st line (ATTRACTION-4,;CM 649)

-Pembrolizumab : - Promissing P II (KN 059; refractory pembro: 1st line pembro and pembro-CT)

-2nd line: PIII negative? (KN 061…Benefit only in MSI / CPS>10??)

-Ongoing P III in 1st line (KN 062 and KN 859 in HER2-; KN 811 in HER2+)

-Avelumab : - A negative? trial in refractory pts (Javelin 300)

- Manteinance: ongoing P III (Javelin mant)

-Ipilimumab : -A negative trial in manteinance

-Selection of pts: MSI, PD-L1? (CPS?) , EBV?, TMB?...-Ongoing P III trials in resectable disease

Inmnotherapy in Advanced Gastric Cancer

Muchas gracias