Post on 13-Sep-2020
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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