Tumores esófago-gástricos, tiene algo que decir la inmunoterapia? Dr. Fernando Rivera Herrero Hospital Universitario Marqués de Valdecilla.

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1 Tumores esófago-gástricos, tiene algo que decir la inmunoterapia? Dr. Fernando Rivera Herrero Hospital Universitario Marqués de Valdecilla. Santander

2 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

3 9% 21% 20 % 50%

4 Gastric Cancer: Comprehensive Molecular Characterization 50% 9% 21% 20 %

5 Systemic treatment in AGC 3-4m 8-10m 10-11m in HER2 + (1st line) 16m 2 nd Line therapy : chemo +/- ramucirumab 17m Adapted from Shah. J Clin Oncol 2015

6 Immunotherapy in Esophago-Gastric Cancer Immunomodulation Immune check points Other Immunotherapies

7 Rhabdoid tumour Ewing sarcoma Thyroid Acute myeloid leukaemia Medulloblastoma Carcinoid Neuroblastoma Prostatre Chronic lymphocytic leukaemia Low-grade glioma Breast Pancreas Multiple myeloma Kidney clear cell Kidney papillary cell Ovarian Glioblastoma multiforme Cervical Diffuse large B-cell lymphoma Head and neck Colorectal Esophageal adenocarcinoma Stomach Bladder Lung adenocarcinoma Lung squamous cell carcinoma Melanoma Somatic mutation frequency (/Mb) Frequency of genetic somatic mutations in cancer No at Risk C T C A C G T C T A T G Altered proteins contain new epitopes for immune recognition, providing a common denominator for cancer immunotherapy Lawrence Nature 2013

8 Cambiando la Práctica Clínica Nivolumab approved for the Treatment of Patients with Unresectable Advanced or Recurrent Gastric Cancer Which Has Progressed After Chemotherapy 1 Pembrolizumab approved for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-L1 (CPS 1) 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

9 Cambiando la Práctica Clínica: Biomarcadores 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Gastric Cancer V National Comprehensive Cancer Network, Inc All rights reserved. Accessed June 13, 2018.

10 4% of AdGC

11 Ipi Ave Nivolumab Pembrolizumab Immuno Checkpoint Inh in AdGC 1st line manteinance 2nd line 3rd line KN 059 Coh 2, 3 KN 062 KN 859 KN 811 F II-III ATTRACTION 04 CM 649 Javelin manteinance Ipi manteinance KN 061 KN 059. Coh 1 ATTRACTION-02 CM 032. Coh 1 CM 032. Coh 2,3 Javelin 300 Ongoing P III Promising P. II Rand P. II-III + Rand P. II-III -

12 Nivolumab (Anti PD-1) A positive asian P III in refractory disease P. III ATTRACTION-02 / ONO , 2 Advanced Gastric cancer, refractory to standard therapy (> 2 lines) 493 pts (rand 2/1) Primary Endpoint:OS Nivolumab 3 mg/kg / 14 d Placebo OS (median) 5.3 m HR 0,62 p< 0, 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.- Kang YK, et al. ASCO-GI Abst 1 ; 2.- Boku N et al, ESMO 2017

13 P. III ATTRACTION-02 / ONO 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% : PD-L1 5% : 14 % pts 7 % pts 1.- Boku N et al, ESMO 2017

14 Checkmate 032: Nivolumab +/- Ipi Phase I/II with a GC/GEJ/EC cohort (160 pts) ; Western pts; Irrespectively of PD-L1 status Nivo 3 mg/kg Q2W Nivo 1 mg/kg + ipi 3 mg/kg Q3W Nivo 3 mg/kg + ipi 1 mg/kg Q3W 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% x 4 cycles Nivo 3 mg/kg Q2W Similar response and OS regardless of P-L1 status Ott P et al. ESMO GI 2017

15 Nivo 3 mg/kg Q2W Nivo 1 mg/kg + ipi 3 mg/kg Q3W Nivo 3 mg/kg + ipi 1 mg/kg Q3W ORR (1 st End Point) Checkmate 032: Nivolumab +/- Ipi x 4 cycles Nivo 3 mg/kg Q2W mos 6.2 (3.4, 12.4) 6.9 ( 3.7, 11.5) 4.8 (3.0, 8.4) OS PFS NIVO 3 NIVO 1+IPI 3 NIVO 3 + IPI 1 NIVO 3 NIVO 1+IPI 3 NIVO 3 + IPI 1 Similar response regardless of P-L1 status Janjigian ASCO 2017

16 Nivolumab in 1st line AGC P. II/III ATTRACTION-04. Japan & South Corea. ~100% PD-L1 available N = 30 Part 1 Patients Previously untreated patients with unresectable advanced or recurrent gastric cancer R 1:1 SOX therapy NIVO (360 mg IV Q3W) + SOX therapy a CapeOX therapy NIVO (360 mg IV Q3W) + CapeOX therapy b Adapted from Kang YK et al. ESMO 2017.

17 Ongoing P III trials with nivolumab in 1st line AGC P. III ATTRACTION-04 1st line Advanced G/EGJ adenoca HER 2 -; 680 pts 1º Endpoint: OS/PFS Chemo + Nivolumab Chemo+ placebo P. III CM-649 1st line Advanced G/EGJ adenoca HER 2 -; pts 1º Endpoint: OS / PFS Nivolumab + Nivolumab + Ipilimumab Chemotherapy Chemotherapy

18 Ipi Ave Nivolumab Pembrolizumab Immuno Checkpoint Inh in AdGC 1st line manteinance 2nd line 3rd line KN 059 Coh 2, 3 KN 062 KN 859 KN 811 F II-III ATTRACTION 04 CM 649 Javelin manteinance Ipi manteinance KN 061 KN 059. Coh 1 ATTRACTION-02 CM 032. Coh 1 CM 032. Coh 2,3 Javelin 300 Ongoing P III Promising P. II Rand P. II-III + Rand P. II-III -

19 Pembrolizumab (Anti PD-1) P II KEYNOTE (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 cells b (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells PD-L1 IHC 22C3 pharmdx (Agilent Technologies) 1 y OS: 26% 1- Fucks CS et al, JAMA Oncol, 2018;

20 Pembrolizumab (Anti PD-1) P II KEYNOTE 059 1,2 (Cohort 1: Pembro in GC 3rd line) RR: Asian 7% Non-Asian: 12% 1..- Fucks et al, Lancet Oncol Muro K, ASCO-GI 2018

21 P. III KN Pembrolizumab in 2nd line AGC A recently comunicated negative P III in 2nd line 2nd line Advanced Gastric canc 592 pts Primary Endpoint: Pembrolizumab 200 mg /21 d Paclitaxel PFS and OS in PD-L1+ (CPS >1) OS (median) 9.1 m vs 8.3 m HR 0.82 ( ) p (0.0135) PFS (median) 1.5 m vs 4.1 m HR 1.37 ( ) p NS 1.- Fuchs CS. ASCO 2018

22 P. III KN Fuchs CS. ASCO 2018 Overall Survival by PD-L1 (CPS) 33% of pts 67% of pts 18% of pts

23 P. III KN pts RR 1.- Fuchs CS. ASCO 2018

24 Pembrolizumab in 1st line AGC P II KEYNOTE (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 cells b (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells PD-L1 IHC 22C3 pharmdx (Agilent Technologies 1.- Weinberg et al, ESMO 2017

25 Pembrolizumab + CT in 1st line AGC P II KEYNOTE (Cohort 2: Pembro-Cis-Fu/Xelo in 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% 1.- Bang YJ, et al, ASCO 2017

26 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 1º Endpoint: OS / PFS Pembrolizumab 200 mg /21 d Platin-FU Placebo Platin-FU Pembrolizumab P. III KN 859 1st line Advanced G/EGJ canc HER 2 -; PD-L1 + (CPS >1) 750 pts 1º Endpoint: OS / PFS P. III KN 811 1st line Advanced G/EGJ C HER 2 + pts Pembrolizumab 200 mg /21 d Platin-FU Placebo Platin-FU Pembrolizumab 1º Endpoint: OS / PFS CT-Herceptin CT-Herceptin Pembrolizumab

27 Ipi Ave Nivolumab Pembrolizumab Immuno Checkpoint Inh in AdGC 1st line manteinance 2nd line 3rd line KN 059 Coh 2, 3 KN 062 KN 859 KN 811 F II-III ATTRACTION 04 CM 649 Javelin manteinance Ipi manteinance KN 061 KN 059. Coh 1 ATTRACTION-02 CM 032. Coh 1 CM 032. Coh 2,3 Javelin 300 Ongoing P III Promising P. II Rand P. II-III + Rand P. II-III -

28 Avelumab (Anti PD-L1)

29 Avelumab (Anti PD-L1)

30 Ipi Ave Nivolumab Pembrolizumab Immuno Checkpoint Inh in AdGC 1st line manteinance 2nd line 3rd line KN 059 Coh 2, 3 KN 062 KN 859 KN 811 F II-III ATTRACTION 04 CM 649 Javelin manteinance Ipi manteinance KN 061 KN 059. Coh 1 ATTRACTION-02 CM 032. Coh 1 CM 032. Coh 2,3 Javelin 300 Ongoing P III Promising P. II Rand P. II-III + Rand P. II-III -

31 Ipilimumab Mn (Ph II Trial) 1st Line Ttx 107 pts Ipi 10 mg/kg Q3W x4 Ipi 10 mg/kg Q12W x3y BSC ( 80% chemotherapy) 1º endpoint PFS median OS for both arms 1 yr Median irpfs (95% CI) Ipi 2.92 ( ) BSC 4.9 ( ) Moehler ASCO 2016

32 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?? 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 cells b (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells PD-L1 IHC 22C3 pharmdx (Agilent Technologies) Nivolumab (Tumor cells > 1%: 14-33%) No valor predictivo 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

33 50% 9% 22% 20% TCGA Nature 2014

34 Slide 15

35 Treatment options in Resectable Gastric/EGJ Adencoca E-EGJ Adenoca - Preoperative Chemo-RT - Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy Gastric Adenoca

36 Selected Ongoing trials with Inmunotherapy in resectable G/EGJ Adenoca DANTE Perioperative G/EGJ R II FLOT 295 DFS/PFS NCT FLOT + Atezolizumab

37 Inmnotherapy in Advanced Gastric Cancer -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

38 Muchas gracias