Inmunoterapia en tumores digestivos no colorrectales

Transcription

1 Inmunoterapia en tumores digestivos no colorrectales Santander, 13 de Julio del 2017 Maria Alsina, MD PhD Hospital Universitari Vall d Hebron

2 Outline Introduction Hepatocarcinoma Pancreatic Cancer Gastric Cancer Conclusions

3 Outline Introduction Hepatocarcinoma Pancreatic Cancer Gastric Cancer Conclusions

4 Introduction 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 neoplastic cells together with extracellular matrix, tumor vasculature and immune cells. Tumor Antigen Transport Lymphocyte trafficking Junttila Nature 2013

5 Introduction: Therapeutic approaches to target the cancer immunity cycle Lymph node Blood vessel Tumor Chen & Mellman Immunity 2013, Moehler Eur J Can 2016

6 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) Introduction 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

7 Outline Introduction Hepatocarcinoma Gastric Cancer Pancreatic Cancer Conclusions

8 HCC: microenvironment and immune landscape HCC is an immunogenic cancer which express tumor-associated antigens and neo-antigens arising from gene mutations The 90% of the HCC are associated with prolonged hepatitis the immune microvenvironment has pivotal role in its pathogenesis The presence of immune infiltrates is asssociated with a better prognosis Antitumor immune responses are subverted by a variety of stromal cells and multiple immunoinhibitory molecules Chronic HBV and HCV infection are associated with PD-1 and PD-L1 upregulation Koontongkaew, 2013

9 Nivolumab in HCC Melero GI ASCO 2017, El-Khoureiy Lancet 2017

10 Melero GI ASCO 2017, El-Khoureiy Lancet 2017 Nivolumab in HCC

11 Nivolumab in HCC Melero GI ASCO 2017

12 Checkpoint Blockade in advanced HCC 1. Sangro Hepatology El Khouelry Lancet Wainberg ASCO 2017 # Kelley ASCO 2017 # 4074

13 Future in HCC

14 Outline Introduction Hepatocarcinoma Pancreatic Cancer Gastric Cancer Conclusions

15 Immunotherapy for pancreatic cancer The microenvironment of PC is unique

16 Immunotherapy for pancreatic cancer PC is non-immunogenic secondary to immunosuppressive elements, low mutational burden, and paucity of T cells Single agent therapeutic approaches with immune checkpoint inhibitors or vaccines have not been encouraging Combinatorial approaches appear key Overcome T-cell immunologic endpoints Royal J Immunother 2010; Topalian NEJM 2012

17 Immunotherapy for pancreatic cancer

18 Targeting tumor infiltrating macrophages (TAMs) and myeloid derived suppressor cells Targeting macrophage signaling (CCR2) will block myeloid monocyte/macrophage recruitment to tumor microenvironment, which would improve cytotoxic efficacy and increase antitumor T-cell response. Sideras Can Treat Reviews 2013; Lesokhin Cancer Res 2011, Mitchem Cancer Res 2013 Nywering Lancet Oncol 2016

19 Outline Introduction Hepatocarcinoma Pancreatic Cancer Gastric Cancer Conclusions

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

21 TILs are predictive of overall survival in GC Pooled OS data for 220 patients with gastric cancer surgically resected Lee Br J Cancer 2008

22 PDL1 expression and T cells infiltration in GC 1014 GC pts Immune cells (IC) Tumor cells (TC) PD-L1 74.9% 37.8% CD3+ High and CD8+ High Better OS PD-L1 High (TC and IC) 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

23 Anti-CTLA-4 therapy in GC Tremelimumab Ph 2 in 2 nd Line, not randomized Ipilimumab Ph 2 for maintenance after 1 st Line, randomized Stopped after interim analysis Ralph Clin Cancer Res 2012; Moehler ASCO & World GI 2016

24 Anti-PD1 & anti-pd-l1 therapies in GC Anti-PD1 Pembrolizumab: KEYNOTE 012, KEYNOTE 059 Nivolumab: Checkmate 032, ATTRACTION-2 (ONO-4538/BMS ) Anti-PDL1 Avelumab: JAVELIN Japanese Atezolizumab 1 Durvalumab 2 Only old activity reported, from Ph 1 basket trials Herbst JCO 2013; Segal Ann Oncol 2014

25 KEYNOTE 012 Pembrolizumab in GC Bang 2015 ASCO Annual Meeting

26 Change From Bassline, % Change From Baseline, % KEYNOTE 012 Pembrolizumab in GC Asia Rest of world Maximum Change 53.1% of patients experienced a decrease from baseline Change Over Time Asia Rest of world Time, weeks OS (ITT) 6-months OS rate: 66% mos: 11m Bang YJ et al. Proc ESMO GI 2015

27 KEYNOTE 059 Pembrolizumab in GC ORR All patients: 11.6% PD-L1 pos: 15.5% (vs 6.4% in PD-L1 neg) 3 rd Line: 16.4% (vs 6.4% in > 3 rd L) MSI-H: 57.1% (vs 9% in non MSI-H) Fuchs ASCO 2017

28 KEYNOTE 059 Pembrolizumab in GC 31 pts, all PD-L1 positive ORR (1 ary End Point): 25.8% 1 pt with complete response mpfs: 3,3m (95% CI ) mos: not reached Yoon-Koo Kang ESMO World Congress on Gastrointestinal Cancer 2017

29 KEYNOTE 059 Pembrolizumab in GC

30 Checkmate 032 Nivolumab in GC Janjigian ASCO 2016 & ASCO 2017

31 ATTRACTION-2 Nivolumab in 3 rd Line ORR, n (%) [95% CI] P value Nivolumab 3 mg/kg (n = 268) 30 (11.2) [ ] < Placebo (n = 131) 0 [0 2.8] BOR, n (%) Complete response Partial response Stable disease Progressive disease 0 30 (11.2) 78 (29.1) 124 (46.3) (25.2) 79 (60.3) Overall Survival DCR, n (%) [95% CI] P value 108 (40.3) [ ] (25.2) [ ] Median TTR (range), months 1.61 ( ) Median DOR, months 9.53 [95% CI] [ ] Kang ASCO GI 2017

32 Avelumab in GC Ph 1b in GC/GEJ pts Irrespectively of PD-L1 status ORR % (95% CI) mpfs w (95% CI) 2L (n = 22) Mn (n = 52) PD-L1+ (n = 11) PD-L1 (n = 11) PD-L1+ (n = 20) PD-L1 (n = 32) (2.3, 51.8) (0.2, 41.3) (1.2, 31.7) (0.1, 16.2) (5.4, 18.0) (4.1, 21.9) (6.0, 24.1) (5.7, 14.1) Chung ASCO 2016

33 Which biomarker? PD-L1 IHC Different positivity rate (57.1% in KEYNOTE 059, 31% in Checkmate 032) IHC test not standardized Different Ab, different positivity criteria Other issues: sampling time, simple type (heterogeneity) Trend of higher activity in PDL1+ Gene expression signature IFN-γ signature (18 gene) as a predictor for inefficacy Usefulness not evident: much overlap Shankaran V et al. Abstract Presented at the 2015 ASCO

34 Which biomarker? MSI MSI-High rate is quite low ( 5% in incidence) Very high activity in MSI-high (KEYNOTE 059) Useful for clinical practice P =.046 Seruca Int J Can 1995 Hye Seung Lee Mod Pathol 2002

35 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)

36 Combined strategies Immunotherapy + anti-angiogenesis Pembrolizumab + Ramucirumab 1 Immunotherapy + radiotherapy (Abscopal Effect) Pembrolizumab + palliative radiotherapy (30 Gy on 1 ary tumor or single metastasis) Pembrolizumab until PD 2 Immunotherapy + targeted agents With anti-her2 agents (margetuximab) 3 With anti-mmp9 agents (GS-5745) 4 With PARP-inhibitors (Olaparib) 5 1. Chau ASCO GI 2017; 2. Chao ASCO GI 2017;3, Catenacci ASCO GI 2017; 4. NCT ; 5. NCT

37 The future in GC

38 Outline Introduction Hepatocarcinoma Pancreatic Cancer Gastric Cancer Conclusions

39 Conclusions Pancreatic Cancer PC is an immune privileged tumor Still too early for immunotherapy, but many opportunities using rational combinations HCC Activity for anti-ctla-4 and anti-pd1 Efficacy observed irrespective of HCV, HBV or PDL1 status

40 Conclusions Esophago-Gastric Cancer Single agent anti-ctla4 no activity Very interesting activity with single agent anti-pd1 and anti-pd-l1 Dual PD-1/CTLA-4 (nivo/ipi) may be more active, but with higher toxicity Biomarkers PD-L1 IHC: multiple technical factors, response in PDL1 negative patients Gene expression profiles, MSI/EBV status, mutational load Combinatorial strategies

41 Take home messages Activity in subset of patients, particularly in esophago-gastric tumors 25% long term survivors Pembrolizumab as a standard in MSI+ patients Combination strategies may improve the efficacy Biomarkers beyond MSI are crucial Need to further understand the immune-pattern of response and how to manage related adverse events

42 Muchas gracias!