Special situations: Patients with liver metastasis or liver primary tumor. Erika Martinelli, MD PhD Medical Oncologist

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1 Special situations: Patients with liver metastasis or liver primary tumor Erika Martinelli, MD PhD Medical Oncologist

2 Outline: Liver (anatomy, basic functions) Liver Immuno-landscape Immuno-landscape in HCC -preclinical and translational studies - HCV/HBV/cirrhosis -tremelimumab -nivolumab -future directions Immuno-landscape in biliary tract -translational subgroups -pembrolizumab -future directions Liver metastasis

3 Outline: Liver (anatomy, basic functions) Liver Immuno-landscape Immuno-landscape in HCC -preclinical and translational studies - HCV/HBV/cirrhosis -tremelimumab -nivolumab -future directions Immuno-landscape in biliary tract -translational subgroups -pembrolizumab -future directions Liver metastasis

4 Liver general anatomy and function Strategic location: Arterial (hepatic artery) and venous blood (portal vein) mix in the liver low oxygen tension, low perfusion pressure and slow and irregular blood flow within sinusoids. Metabolic functions: in lipid, carbohydrate and protein sintesis and in the degradation of toxic or waste products. Thomson A et al (2010) Nat Rev Immunology

5 Liver: an immune-tolerant environment Hepatic regulatory mechanisms prevent the induction of immunity in order to accommodate the exposure to intestinal pathogens and innocuous antigens from the digestive system (gut-derived nutrients, aged or damaged cells, metabolic products of detoxification of alcohol or drugs). The tolerogenic properties of the liver are exemplified by its roles in oral tolerance and portal venous tolerance, the persistence of microbial infections and tumour metastases in the liver, and the comparative immune privilege of hepatic allografts. Antigen-presenting cells of the liver (liver sinusoidal endothelial cells, Kupffer cells) express high levels of inhibitory immune signaling molecules such as PD-L1, preferentially activate inhibitory regulatory T cells (Tregs), and produce inhibitory cytokines such as IL-10. Thomson A et al (2010) Nat Rev Immunology

6 Outline: Liver (anatomy, basic functions) Liver Immuno-landscape Immuno-landscape in HCC -preclinical and translational studies - HCV/HBV/cirrhosis -tremelimumab -nivolumab -future directions Immuno-landscape in biliary tract -translational subgroups -pembrolizumab -future directions Liver metastasis

7 Immune cells involved in tumor tolerance in hepatocellular cancer (HCC) The inability of the immune system to recognize liver cancer cells is also explained by increase in regulatory T-cell (Tregs) impairment of CD4+ T-cell functions suppression of natural killer (NK) cells recruitment of immunosuppressive cells (monocyte and neutrophils) upregulation of immune checkpoint pathways (CTLA-4, PD-1, LAG-3, Tim3 and its ligand) Raufi A. and Tirona M (2017) Cancer Man and Res

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10 Immune based approaches in HCC Greten and Sangro (2017) Journal of Hepatol

11 Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B).

12 Tremelimumab safety data Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Sangro et al (2013) Journal of Hepatol

13 Tremelimumab efficacy data Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI ). OS 8.3 months (95% CI ). Significant drop-down of HCV viral load: Day 0: IU/mL vs day IU/mL (p= 0.017) Sangro et al (2013) Journal of Hepatol

14 Immune based approaches in HCC Greten and Sangro (2017) Journal of Hepatol

15 Primary endpoint: safety and tolerability Primary endpoint: efficacy as objective response rate (RECIST 1.1 criteria) El Khoueriry A et al (2017) Lancet

16 Nivolumab related liver toxicities in CheckMate040 AST/ALT about 20% but G3/G4 only in 5% AEs comparable in infected and HCV or HBV cohorts, immunorelated hepatitis requiring steroids occurred rarely El Khoueriry A et al (2017) Lancet

17 Nivolumab related liver toxicities Presented by Choo at ESMO Asia Singapore 2017

18 Nivolumab efficacy El Khoueriry A et al (2017) Lancet Crescenzi et al (2017) JCO (15 supp)

19 CheckMate 040: survival update Crescenzi et al (2017) JCO (15 supp)

20 HCC second line treatment BRISK-PS= Brivanib ; negative (Llovet et al 2013 JCO) EVOLVE= Everolimus; negative (Zhu et al 2014 JAMA) REACH= Ramucirumab; negative (Zhu et al 2015 Lancet Oncol) RESORCE= Regorafenib; positive (Bruix et al 2017 Lancet) 10.6 mo (95% CI ) vs 7.8 mo ( ) Greten and Sangro (2017) Journal of Hepatol

21 Biomarkers for immunotherapy in HCC About 20% were PDL-1 positive Objective responses were observed in 26% of patients with PD-L1 expression on at least 1% of tumor cells (95% CI 13-44) and in 19% of patients with PD-L1 on less than 1% of tumour cells (95% CI 13-26) El Khoueriry A et al (2017) Lancet

22 Immuno checkpoint inhibitors: ongoing trials Kudo et al (2017) Liver Cancer

23 Outline: Liver (anatomy, basic functions) Liver Immuno-landscape Immuno-landscape in HCC -preclinical and translational studies - HCV/HBV/cirrhosis -tremelimumab -nivolumab -future directions Immuno-landscape in biliary tract -translational subgroups -pembrolizumab -future directions Liver metastasis

24 Biliary tract cancers (BTCs) Potentially attractive target: chronic inflammation and conditions such as cholecystitis, sclerosing cholangitis and primary biliary cirrhosis. Nakaruma et al provided an extensive molecularly characterization of 260 BTCs Four clusters have been identified Nakamura et al (2015) Nat Genetics

25 Cluster 4 showed: poorest prognosis enrichment for genes involved in the immune, cytokine activity and antiapoptotic genes. Enrichment in hypermutated cases, where the high mutation load created abundant tumor-specific neoantigens. Higher expression of targetable immunosuppressive molecules ICMs, including PD-L1 (CD274) Nakamura et al (2015) Nat Genetics

26 Apinya J et al (2017) Cancer Discovery

27 BTCs and mismatch repair deficiency Gene mutations leading to defective DNA mismatch repair (MMR) are observed in several neoplasia (eg colorectal cancer, endometrial and gastric cancer). Javle et al (2016) performed mutational profiling of 321 BTCs : DNA repair mutations (MSH6, BRCA1, BRCA2, ATM, MLH1 or MSH2 genes) occurred in 13% intra-hepatic BTCs, 26% in extra-hepatic BTCs and 6% of gallbladder cancer cases. The subset of cancers with MMR system defects is very sensitive to programmed cell death protein 1 (PD-1) blockade using checkpoint inhibitor agents like pembrolizumab. BTC patients with mutations in the DNA repair pathways can represent a subset where specific DNA repair inhibitors in addition to immunotherapy may be effective.

28 Keynote 016 Pembrolizumab in dmmr tumors CCA =4 Le et al (2017) Science Keynote pts with MSI-H non-crc across 20 tumor types (CCA= 8) 1 prior therapy ORR 37.7% (n = 29 [23 confirmed and 6 unconfirmed]; 95% CI 26.9%-49.4%) Median OS was not reached, with 6-mo OS 73% Diaz et al (2017) ESMO 386p

29 Ramucirumab plus pembrolizumab in previously treated advanced or metastatic biliary tract cancer: A multi-disease phase 1 study Introduction: Angiogenesis and immunosuppression are implicated in the pathogenesis and progression of invasive biliary tract cancers, including adenocarcinomas of the gallbladder, intra- and extra- hepatic cholangiocarcinoma, and Ampulla of Vater. Beyond first-line gemcitabine-cisplatin chemotherapy there is no established standard of care following progression. This is the first study to combine ramucirumab (anti-vegfr-2) with pembrolizumab (anti-pd-1) to simultaneously target angiogenesis and immunosuppression in the tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT ; JVDF) enrolled patients with confirmed advanced or metastatic biliary tract cancer with prior progression on systemic therapy, measurable disease, baseline tumor tissue, and ECOG PS 0-1. PD-L1 was assessed as positive (tumor proportion score [TPS] 1%) or negative (TPS <1%) using the DAKO PD-L1 22C3 IHC pharmdx assay. Ramucirumab was administered at 8 mg/kg on Days 1 and 8 with pembrolizumab 200 mg on Day 1 every 3 weeks. The primary objective was to assess the safety and tolerability of ramucirumab plus pembrolizumab; preliminary efficacy will be examined. Results:As of 21-Nov-2016, 26 patients with biliary tract cancer were enrolled (intrahepatic cholangiocarcinoma [42%], extrahepatic cholangiocarcinoma [31%], gallbladder carcinoma [15%], and other [12%]). Median age was 63 years, 69% were female, 54% had ECOG PS of 1, 38% received study treatment as third or subsequent line and PD-L1 status is pending. The median duration of therapy was 2 months (interquartile range [IQR] 1.4 to 3.0) for ramucirumab and 2 months (IQR 1.4 to 3.2) for pembrolizumab. Overall, 22 (85%) patients experienced a treatment-related AE (TRAE), most commonly hypertension (31%), fatigue (23%), and nausea (23%). Grade 3 TRAEs occurred in nine (35%) patients (hypertension [n = 5], diarrhea, duodenal ulcer, hematemesis, neutropenia, and transaminases increased). No Grade 4-5 TRAEs occurred. One patient discontinued treatment due to an adverse event (transaminases increased). One patient had a partial response (unconfirmed), 8 (31%) patients had stable disease, and 12 (46%) patients had progressive disease. A further five patients were not evaluable for response at the time of analysis. Median progression-free survival was 1.5 months (95% CI 1.4 to 2.8) with a 4-month progression-free survival rate of 23.3% (95% CI 6.6 to 45.7). Median overall survival has not been reached. Nine (35%) patients remain on treatment. Conclusion: The safety profile of ramucirumab combined with pembrolizumab is consistent with monotherapy treatment for each drug, with no additive toxicities. In this heavily pretreated patient population with advanced or metastatic biliary tract cancer, limited antitumor activity was observed. Updated safety and efficacy data will be presented at the meeting. Arkenau et al (2017) ESMO WCGIC 0-019

30 Immunotherapies under evaluation in biliary tract cancers Goldstein D, et al. ESMO Open 2017

31 Outline: Liver (anatomy, basic functions) Liver Immuno-landscape Immuno-landscape in HCC -preclinical and translational studies - HCV/HBV/cirrhosis -tremelimumab -nivolumab -future directions Immuno-landscape in biliary tract -translational subgroups -pembrolizumab -future directions Liver metastasis

32 Liver mts

33 Melanoma NSCLC

34 PD-1 checkpoint inhibitor in dmmr tumors Le et al (2015) New Eng J Med

35 CCR(2016)

36 Conclusions Liver parenchymal tissue should be considered a unique anatomical compartment, characterized by distinct mechanisms of tolerance induction focused on the restriction of effector T cell function. This knowledge provides the basis for the development of new immune therapies that enhance or break local immunoregulatory circuits in the liver. DO LIVER METASTASIS OR LIVER PRIMARY TUMOR REPRESENT A SPECIAL SITUATION? Liver metastasis do respond as well to treatment in dmmr tumors, some concern about melanoma and NSCLC but few data, moreover their presence does not jeopardize immunotherapy liver related toxicities. In HCC patients checkpoint inhibitors might represent a novel therapeutic target and are not contraindicated in patients with HBV or HCV infections. Checkpoint inhibitors showed preliminary activity in CCA. Combination therapy strategy will provide information to improve efficacy of immunotherapy.

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