special situations: patients with liver metastasis or ...€¦ · • javle et al (2016) performed...

Erika Martinelli, MD PhD

Medical Oncologist

Special situations:Patients with liver metastasis or liver primary tumor

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

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

Liver general anatomy and function

Thomson A et al (2010) Nat Rev Immunology

• Strategic location: Arterial (hepatic artery) and venous blood (portal vein) mix in the liver lowoxygen 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 toxicor waste products.

Liver: an immune-tolerant environment

Thomson A et al (2010) Nat Rev Immunology

• Hepatic regulatory mechanisms prevent the induction of immunity in order to accommodate the exposure tointestinal pathogens and innocuous antigens from the digestive system (gut-derived nutrients, aged or damagedcells, 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, thepersistence of microbial infections and tumour metastases in the liver, and the comparative immune privilege ofhepatic allografts.

• Antigen-presenting cells of the liver (liver sinusoidal endothelial cells, Kupffer cells) express high levels of inhibitoryimmune signaling molecules such as PD-L1, preferentially activate inhibitory regulatory T cells (Tregs), and produceinhibitory cytokines such as IL-10.

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

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

Greten and Sangro (2017) Journal of Hepatol

Immune based approaches in HCC

Tremelimumab at a dose of 15 mg/kg IV every90 days was administered until tumorprogression or severe toxicity. Twenty patientswere assessable for toxicity and viral responseand 17 were assessable for tumor response.Most patients were in the advanced stage and43% had an altered liver function (Child-Pughclass B).

Sangro et al (2013) Journal of Hepatol

Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles.

Tremelimumab safety data

Partial response rate was 17.6% and diseasecontrol rate was 76.4%. Time to progressionwas 6.48 months (95% CI 3.95– 9.14). OS 8.3 months (95% CI 4.64-9.14).

Significant drop-down of HCV viral load:Day 0: 3.78105 IU/mL vs day 210 1.69103 IU/mL (p= 0.017)

Tremelimumab efficacy data

Sangro et al (2013) Journal of Hepatol

Greten and Sangro (2017) Journal of Hepatol

Immune based approaches in HCC

El Khoueriry A et al (2017) Lancet

Primary endpoint: safety and tolerability Primary endpoint: efficacyas objective response rate (RECIST 1.1 criteria)

El Khoueriry A et al (2017) Lancet

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

Nivolumab related liver toxicities in CheckMate040

Nivolumab related liver toxicities

Presented by Choo at ESMO Asia Singapore 2017

El Khoueriry A et al (2017) LancetCrescenzi et al (2017) JCO (15 supp)

Nivolumab efficacy

CheckMate 040: survival update

Crescenzi et al (2017) JCO (15 supp)

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 9.1–12.1) vs 7.8 mo (6.3–8.8)

Greten and Sangro (2017) Journal of Hepatol

HCC second line treatment

El Khoueriry A et al (2017) Lancet

Biomarkers for immunotherapy in HCC

• About 20% were PDL-1 positive

• Objective responses were observed in26% of patients with PD-L1 expression onat least 1% of tumor cells (95% CI 13-44)and in 19% of patients with PD-L1 on lessthan 1% of tumour cells (95% CI 13-26)

Kudo et al (2017) Liver Cancer

Immuno checkpoint inhibitors: ongoing trials

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

Biliary tract cancers (BTCs)Potentially attractive target: chronic inflammation and conditions such as cholecystitis, sclerosing cholangitis and primary biliary cirrhosis.

Nakamura et al (2015) Nat Genetics

Nakaruma et al provided an extensivemolecularly characterization of 260 BTCs

Four clusters have been identified

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

Apinya J et al (2017) Cancer Discovery

BTCs and mismatch repair deficiency

• Gene mutations leading to defective DNA mismatch repair (MMR) areobserved in several neoplasia (eg colorectal cancer, endometrial andgastric cancer).

• Javle et al (2016) performed mutational profiling of 321 BTCs : DNA repairmutations (MSH6, BRCA1, BRCA2, ATM, MLH1 or MSH2 genes) occurred in13% intra-hepatic BTCs, 26% in extra-hepatic BTCs and 6% of gallbladdercancer cases.

• The subset of cancers with MMR system defects is very sensitive toprogrammed cell death protein 1 (PD-1) blockade using checkpointinhibitor agents like pembrolizumab.

• BTC patients with mutations in the DNA repair pathways can represent asubset where specific DNA repair inhibitors in addition to immunotherapymay be effective.

Pembrolizumab in dMMR tumors

Le et al (2017) Science

CCA =4 Keynote 016

Keynote 0158

77 pts with MSI-H non-CRC across 20 tumor types (CCA= 8)≥1 prior therapyORR 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

Ramucirumab plus pembrolizumab in previously treated advanced or metastaticbiliary tract cancer: A multi-disease phase 1 study

• Introduction: Angiogenesis and immunosuppression are implicated in the pathogenesis and progression ofinvasive biliary tract cancers, including adenocarcinomas of the gallbladder, intra- and extra- hepaticcholangiocarcinoma, and Ampulla of Vater. Beyond first-line gemcitabine-cisplatin chemotherapy there is noestablished 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 tumormicroenvironment.

• Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324; JVDF) enrolled patients with confirmedadvanced 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%) ornegative (TPS <1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. Ramucirumab was administered at 8 mg/kgon Days 1 and 8 with pembrolizumab 200 mg on Day 1 every 3 weeks. The primary objective was to assess thesafety 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 was63 years, 69% were female, 54% had ECOG PS of 1, 38% received study treatment as third or subsequent line andPD-L1 status is pending. The median duration of therapy was 2 months (interquartile range [IQR] 1.4 to 3.0) forramucirumab and 2 months (IQR 1.4 to 3.2) for pembrolizumab. Overall, 22 (85%) patients experienced atreatment-related AE (TRAE), most commonly hypertension (31%), fatigue (23%), and nausea (23%). Grade 3TRAEs 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 treatmentdue 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 notevaluable for response at the time of analysis. Median progression-free survival was 1.5 months (95% CI 1.4 to2.8) with a 4-month progression-free survival rate of 23.3% (95% CI 6.6 to 45.7). Median overall survival has notbeen reached. Nine (35%) patients remain on treatment.

• Conclusion: The safety profile of ramucirumab combined with pembrolizumab is consistent with monotherapytreatment for each drug, with no additive toxicities. In this heavily pretreated patient population with advancedor metastatic biliary tract cancer, limited antitumor activity was observed. Updated safety and efficacy data will bepresented at the meeting.

Arkenau et al (2017) ESMO WCGIC 0-019

Immunotherapies under evaluation in biliary tract cancers

Goldstein D, et al. ESMO Open 2017

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

Liver mts

Melanoma

NSCLC

PD-1 checkpoint inhibitor in dMMR tumors

Le et al (2015) New Eng J Med

CCR(2016)

Liver parenchymal tissue should be considered a unique anatomical compartment,characterized by distinct mechanisms of tolerance induction focused on the restriction ofeffector T cell function. This knowledge provides the basis for the development of newimmune 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 concernabout melanoma and NSCLC but few data, moreover their presence does not jeopardizeimmunotherapy liver related toxicities.

• In HCC patients checkpoint inhibitors might represent a novel therapeutic target andare 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 ofimmunotherapy.

Conclusions