INMUNOTERAPIA EN CÁNCER GÁSTRICO Y DE LA UGE: DÓNDE ESTAMOS? Maria Alsina Maqueda, MD, PhD Hospital Universitario Vall d Hebron, Barcelona

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1 INMUNOTERAPIA EN CÁNCER GÁSTRICO Y DE LA UGE: DÓNDE ESTAMOS? Maria Alsina Maqueda, MD, PhD Hospital Universitario Vall d Hebron, Barcelona

2 Outline The Immune System Rational to develop immunotherapy in GC/GEJ First evidence of efficacy Challenges Conclusions

3 Outline The Immune System Rational to develop immunotherapy in GC/GEJ First evidence of efficacy Challenges Conclusions

4 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. Tumor Antigen Transport Lymphocyte trafficking Junttila Nature 213

5 Hanahan & Weinberg Cell 211 Acquired capacities of cancer: phenotype Aerobic glycolysis inhibitors EGFR inhibitors Deregulating cellular energetics Sustaining proliferative signaling Inhibitors of VEGF signaling Inducing angiogenesis Evading growth suppressors Cyclin-dependent kinase inhibitors Proapoptotic BH3 mimetics Resisting cell death Avoiding immune destruction Immunotherapy PARP inhibitors Genome instability mutation Activating invasion & metastasis Tumorpromoting inflammation Enabling replicative immortality Telomerase inhibitors Inhibitors of HGF/c-Met Selective antiinflammatory drugs

6 Key aspects of the Immune System The immune system recognises and destroys tumor cells Key features of the immune response: Specificity Memory Adaptability Hanahan & Weinberg Cell 211; Dunn Nat Rev Immunol 26 Swann & Smyth J Clin Invest 27; Prendergast Oncogene 28; Mapara & Sykes J Clin Oncol 24

7 Overall survival Immunotherapy has reset survival expectations 1. Ipilimumab was the first immune checkpoint inhibitor to demonstrate clinical benefit in stage IV melanoma patients.8 Pooled OS data for 1,861 patients from 1 prospective and two retrospective studies Median OS, months: 9.5 months (95% CI 9. 1.) year OS rate: 21% (95% CI 2 22).2. No at risk: Ipilimumab Ipilimumab Censored Months Schadendorf J Clin Oncol 215

8 Chen & Mellman Immunity 213 The immune cycle in cancer 3. Priming and activation Anti-PD1 Anti-PDL1 Anti-CTLA-4 Anti-CD137 (agonist) Anti-OX4 (agonist) Anti-CD27 (agonist) IL-2 IL Trafficking of T cells to tumors 5. Infiltration of T cells into tumors 2. Cancer antigen presentation Vaccines IFN-α GM-CSF Anti-CD4 (agonist) TLR agonist Lymph node Blood vessel Tumor Anti-VEGF/VEGFR 6. Recognition of cancer cells by T cells CARs 1. Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy 7. Killing of cancer cells Anti-PDL1 Anti-PD1 IDO inhibitors

9 Chen & Mellman Immunity 213 The immune cycle in cancer 3. Priming and activation Anti-PD1 Anti-PDL1 Anti-CTLA-4 Anti-CD137 (agonist) Anti-OX4 (agonist) Anti-CD27 (agonist) IL-2 IL Trafficking of T cells to tumors 5. Infiltration of T cells into tumors 2. Cancer antigen presentation Vaccines IFN-α GM-CSF Anti-CD4 (agonist) TLR agonist Lymph node Blood vessel Tumor Anti-VEGF/VEGFR 6. Recognition of cancer cells by T cells CARs 1. Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy 7. Killing of cancer cells Anti-PDL1 Anti-PD1 IDO inhibitors

10 Amorena Science 1978, Mueller J Immunol 1989, Walunas Immunity 1994, Krummel J Exp Med 1995, Dong Nat Med 22; Keir Annu. Rev. Immunol. 28 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

11 The immune checkpoint targetable receptors/ligands T cell targets for modulating activity Activating Receptors Inhibitory Receptors CD28 OX4 GITR CD137 CD27 HVEM T cell CTLA-4 PD-1 TIM-3 BTLA VISTA LAG-3 Agonistic Antibodies T cell stimulation Blocking Antibodies Mellman Nature 211

12 Outline The Immune System Rational to develop immunotherapy in GC/GEJ First evidence of efficacy Challenges Conclusions

13 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 213

14 5% 9% 22% 2% TCGA Nature 214

15 TILs are predictive of overall survival in GC Pooled OS data for 22 patients with gastric cancer surgically resected Lee Br J Cancer 28

16 Analysis of PDL1 expression and T cells infiltration 114 GC pts PD-L1, CD3 and CD8 Immune cells (IC) PD-L1 74.9% 37.8% Tumor cells (TC) PD-L1 High (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 217

17 Outline The Immune System Rational to develop immunotherapy in GC/GEJ First evidence of efficacy Challenges Conclusions

18 First evidence of efficacy Anti-PD1 Pembrolizumab: KEYNOTE 12 1, KEYNOTE 59 2 Nivolumab: Checkmate 32 3, ONO-4538/BMS Anti-PDL1 Avelumab: JAVELIN Japanese 5 Others Ipilimumab: Maintenance 6 New promises (other immune checkpoints and combined strategies) 1. Muro Lancet Oncol 216, 2. Fuchs ASCO 216, 3. Janjigian ASCO 216, 4. Kang ASCO GI 217; 5. Chung ASCO 216; 6. Moehler ASCO 216

19 KEYNOTE-12: Gastric Cancer Cohort Complete Response Discontinuation Permitted Patients Recurrent or metastatic adenocarcinoma of the stomach or GEJ ECOG PS -1 PD-L1 positive tumor a No active brain metastases Pembrolizumab 1 mg/kg Q2W Partial Response or Stable Disease Treat for 24 months or until progression or intolerable toxicity Confirmed Progressive Disease Discontinue Screening: 65 of 162 (4%) patients assessed for PD-L1 expression had PD-L1-positive tumors Patients: 19 patients from Asia and 2 patients from the rest of the world Treatment: 1 mg/kg IV Q2W Response assessment: Performed every 8 weeks per RECIST v1.1 by central radiology review a Assessed in archival tumor samples using a prototype IHC assay (22C3 antibody). Positivity defined as PD-L1 staining in stroma or 1% of tumor cells. Muro Lancet Oncol 216

20 Best Overall Response, RECIST v1.1 Muro Lancet Oncol 216

21 Change From Bassline, % Change From Baseline in Target Lesions Change From Baseline, % Maximum Change Change Over Time 15 1 Asia Asia Rest of world 125 Rest of world % of patients experienced a decrease from baseline Time, weeks a Only 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, 215. Muro Lancet Oncol 216

22 Overall Survival, % Kaplan-Meier Estimates of Survival 1 OS OS (ITT) 6-months OS rate: 66% Median OS: 11m (95% CI, 5.7-NR) 1 Asia Rest of world Time, months n at risk Asia ROW Median response duration 4w (2+ to 48+) Analysis cutoff date: March 23, 215. Muro Lancet Oncol 216

23 Ph 2 Study in 1 st Line GC/GEJ pts KEYNOTE 59 Pembro 2 mg + 5-FU 8 mg/m 2 (or capecitabine 1 mg/m 2 in Japan) + cisplatin 8 mg/m 2 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 216

24 Checkmate 32: Nivolumab +/- Ipi Phase I/II with a GC/GEJ/EC cohort (16 pts) Irrespectively of PD-L1 status 3 different schemes of treatment 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 ORR (1 st End Point) Janjigian ASCO 216

25 Checkmate 32: Nivolumab +/- Ipi 12% of pts stopped therapy due to treatment toxicity Treatment-related serious AEs of any grade and Grade 3-4 occurred in 1% and 5% (N3), 43% and 35% (N1+I3), and 23% and 15% (N3+I1) of pts 1 Grade 5 tumor lysis syndrome (N3+I1) N3 N1+I3 N3+I1 ORR 14% 26% 1% mos (m) (95% CI) 5. ( ) 6.9 (3.6 NA) 4.8 (3. 9.1) Janjigian ASCO 216

26 Nivolumab (ONO-4538/BMS ) as Salvage Treatment After Second- or Later-Line Chemotherapy for Advanced Gastric or Gastroesophageal Junction Cancer (AGC): A Double-Blinded, Randomized, Phase 3 Trial Key eligibility criteria: Age 2 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 or 1 R 2:1 Nivolumab 3 mg/kg IV Q2W Stratification based on: Country (Japan vs Korea vs Taiwan) ECOG PS ( vs 1) Number of organs with metastases (< 2 vs 2) Placebo Primary endpoint: OS Secondary endpoints: Efficacy (PFS, BOR, ORR, TTR, DOR, DCR) Safety Exploratory endpoint: Biomarkers 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 493 patients randomized from 49 centers of Japan, Korea and Taiwan (Nov-214 Febr-216) Kang ASCO GI 217

27 Probability of Survival (%) Overall Survival At risk: Nivolumab 33 Placebo Patients, n 1 12 Time (months) Events, n Median OS [95% CI], months Hazard ratio,.63 (95% CI,.5.78) P < Month OS Rate [95% CI], % Nivolumab [ ] 26.6 [ ] Placebo [ ] 1.9 [ ] 22 Kang ASCO GI 217

28 RECIST Response and Disease Control ORR, n (%) [95% CI] P value BOR, n (%) Complete response Partial response Stable disease Progressive disease DCR, n (%) [95% CI] P value Nivolumab 3 mg/kg (n = 268) 3 (11.2) [ ] <.1 3 (11.2) 78 (29.1) 124 (46.3) 18 (4.3) [ ].36 Placebo (n = 131) [ 2.8] 33 (25.2) 79 (6.3) 33 (25.2) [ ] Median TTR (range), months 1.61 (1.4 7.) Median DOR, months [95% CI] 9.53 [ ] Kang ASCO GI 217

29 Adverse Event Summary Patients, n (%) AEs Any Serious AEs AEs leading to discontinuation AEs leading to dose delay Nivolumab 3 mg/kg (n = 33) Placebo (n = 161) Any Grade Grade 3/4 Any Grade Grade 3/4 3 (9.9) 131 (39.7) 23 ( 7.) 63 (19.1) 137 (41.5) 91 (27.6) 13 ( 3.9) 4 (12.1) 135 (83.9) 75 (46.6) 12 ( 7.5) 27 (16.8) AEs leading to death 35 (1.6) 25 (15.5) 63 (39.1) 47 (29.2) 9 ( 5.6) 17 (1.6) TRAEs Any Serious TRAEs TRAEs leading to discontinuation TRAEs leading to dose delay 141 (42.7) 33 (1.) 9 ( 2.7) 25 ( 7.6) 34 (1.3) 21 ( 6.4) 4 ( 1.2) 14 ( 4.2) 43 (26.7) 8 ( 5.) 4 ( 2.5) 2 ( 1.2) TRAEs leading to death 5 (1.5) 2 (1.2) 7 (4.3) 4 (2.5) 3 (1.9) 1 (.6) AE, adverse event; TRAE, treatment-related adverse event. Kang ASCO GI 217

30 Treatment-Related Adverse Events Patients, n (%) Nivolumab 3 mg/kg (n = 33) Placebo (n = 161) Any Grade Grade 3/4 Any Grade Grade 3/4 Any TRAE 141 (42.7) 34 (1.3) 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 3 (9.1) 23 (7.) 19 (5.8) 18 (5.5) 16 (4.8) 14 (4.2) 13 (3.9) 11 (3.3) 1 (3.) 8 (2.4) 7 (2.1) ALT, alanine aminotransferase; AST, aspartate aminotransferase. 2 (.6) 2 (.6) 4 (1.2) 2 (.6) 1 (.3) 1 (.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 (.6) 3 (1.9) 1 (.6) 2 (1.2) 1 (.6) Kang ASCO GI 217

31 Avelumab (JAVELIN JPN) Ph 1b in GC/GEJ pts Irrespectively of PD-L1 status 1 st Line Maintenance (89 pts) 2 nd Line (62 pts) Avelumab 1 mg/kg IV Q2W Treatment-related adverse events Any grade: in 89 pts (58.9%) Infusion-related reaction (12.6%) and fatigue (1.6%) G3: in 15 pts (9.9%) fatigue, asthenia, increased GGT, thrombocytopenia, and anemia 1 treatment-related death (hepatic failure/autoimmune hepatitis) ORR % (95% CI) mpfs w (95% CI) 2L (n = 22) Mn (n = 52) PD-L1+ (n = 11) PD-L1 (n = 11) PD-L1+ (n = 2) PD-L1 (n = 32) (2.3, 51.8) (.2, 41.3) (1.2, 31.7) (.1, 16.2) (5.4, 18.) (4.1, 21.9) (6., 24.1) (5.7, 14.1) Chung ASCO 216

32 Ipilimumab Mn (Ph II Trial) 1st Line Ttx Ipi 1 mg/kg Q3W x4 Ipi 1 mg/kg Q12W x3y BSC ( 8% chemotherapy) 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 216

33 Ipilimumab Mn (Ph II Trial) irpfs similar between arms (HR=1.44, p=.97) median OS for both arms 1 yr Median irpfs (95% CI) Ipi 2.92 ( ) BSC 4.9 ( ) When the immune system reacts, it reacts well, potentially even in re-introduction or 2nd L Early progressors lost Moehler ASCO 216

34 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 27 Hodi Cancer Immunol Res 214 Sznol J Clin Oncol 215 (suppl)

35 Combined strategies Immunotherapy + anti-angiogenesis 1 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 (3 Gy on 1 ary tumor or single metastasis) Pembrolizumab until PD 1 ary End Point: biomarkers of immune response and ORR (RECIST1.1, irrecist) 1. Chau ASCO GI 217; 2. Chao ASCO GI 217

36 Combined strategies Immunotherapy + Targeted Agents With anti-her2 agents 1 Phase 1b/2 trial (HER2-pos gastric and GEJ cancer) Pembrolizumab + Margetuximab 1 ary End Point: ORR (RECIST v1.1 and irecist) and DoR With anti-mmp9 agents 2 Phase 3 trial (2 nd /3 rd line gastric and GEJ cancer) Nivolumab +/- GS ary End Point: ORR (RECIST v1.1) 1. Catenacci ASCO GI 217; 2. NCT

37 Outline The Immune System Rational to develop immunotherapy in GC/GEJ First evidence of efficacy Challenges Conclusions

38 Change from baseline SPD (%) Change from baseline SPD (%) Change from baseline SPD (%) Change from baseline SPD (%) Identifying patterns of response Response in baseline lesions Relative day from first dose SPD (mm 2 ) Stable disease with slow, steady decline in total tumor volume Relative day from date of first dose SPD (mm 2 ) Response after initial increase in total tumor volume N Relative day from date of first dose SPD (mm 2 ) Reduction in total tumor burden after appearance of new lesions 21 N N N N N N Relative day from date of first dose SPD (mm 2 ) Wolchok Clin Cancer Res 29

39 Managing immune-related AEs Myositis Myasthenia Gravis Hypothyroidism Pneumonitis Autoimmune hepatitis Elevated transaminases Pancreatitis Colitis - duodenitis Type 1 diabetes mellitus Rash Melero Clin Cancer Res 213

40 Outline The Immune System Rational to develop immunotherapy in GC/GEJ First evidence of efficacy Challenges Conclusions

41 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

42 Ongoing phase II/III clinical trials Adjuvant CA Ph 3 GEJ Nivolumab vs placebo after CRT and surgery MK Ph 3 PDL1 + Neoadjuvant NCT Ph 1b/2 GEJ Pembrolizumab Chemoradiotherapy (carboplatin and paclitaxel) CA Ph 1 GEJ/GC EBV+ Nivolumab vs Ipilimumab + Nivolumab First Line CDDP/FU (or CPC) vs CDDP/FU + Pembrolizumab vs Pembro monotherapy EMR-17-7 Ph 3 All (HER2 -) Avelumab (maintenance after XELOX/FOLFOX) CA Ph 3 All (HER2 -) Nivolumab + Ipilimumab vs FOLFOX/XELOX Second Line and beyond MK Ph 3 All Pembrolizumab vs paclitaxel GS-US Ph 2 All Nivolumab +/- GS-5745 EMR-17-8 Ph 2 PDL1 + Avelumab vs investigator s choice CA Ph 1 EBV + Nivolumab

43 Ongoing Phase I Clinical Trials ID Ph Strategy Indication Status NCT I Pembrolizumab plus Ramucirumab Specific cohort, 2 nd or 3 rd Line Recruiting NCT Pembrolizumab in monotherapy or in Different lines, HER2- II (KEYNOTE 59) combination with CT neg Recruiting NCT I Pembrolizumab plus PEGPH2 Specific cohort, at least 2 nd Line Recruiting NCT Specific cohort, I Pembrolizumab (KEYNOTE 12) refractory setting Active, not recruiting NCT I Pembrolizumab plus PLX3397 Specific cohort, refractory setting Recruiting NCT I/II Pembrolizumab plus trastuzumab Specific cohort, HER2- positive Recruiting NCT I/II Pembrolizumab plus FOLFOX Specific cohort Recruiting NCT II Tremelimumab and/or durvalumab Refractory setting Recruiting NCT II Ipilimumab vs FU/BSC NCT I/II Nivolumab +/- ipilimumab Manteinance after 1 st Line Specific cohort, refractory setting Completed Recruiting NCT I Nivolumab Refractory setting Recruiting NCT I/II Nivolumab EBV-positive Recruiting NCT17724 I Avelumab Specific cohort, 3rd Line Recruiting NCT I Avelumab NCT I Atezolizumab montherapy or in combination with bevacizumab or CT 2nd and 3rd Line, Japanesse and Asian Basket Recruiting Recruiting NCT I Atezolizumab Basket Recruiting NCT I Atezolizumab and GDC-919 Specific cohort, refractory setting Recruiting

44 Muchas gracias!