Liver Cancer and Immunotherapy in the Liquid Biopsy Era

Official title

Liver Cancer and Immunotherapy : Clinical Relevance of LIquid BioPSY

Overview

The goal of this prospective clinical trial is to identify a predictive biomarker in patients with advanced HCC (stage B and C) using a combinatorial approach of the liquid biopsy. The main questions it aims to answer are: * Is multi-omic liquid biopsy approach able to identify a strong predictive biomarker of immunotherapy efficiency? * Is there a correlation between tissue biopsy (PD-L1 tissue level of expression) and liquid biopsy (detection of CTC expressing PD-L1) in HCC patients? Participants blood will be collected at several time points.

Detailed description

In solid cancers, some more aggressive tumor cells actively detach from the primary lesion and then travel through the circulating compartment to reach distant organs and form micro-metastases. Detecting CTCs in the blood is also relevant for assessing tumor progression, prognosis and therapeutic follow-up. The non-invasive, highly sensitive for CTCs analysis is called "liquid biopsy". Over the past few years, a multi-analyses approach (CTCs, circulating tumor DNA, extracellular vesicles, miRNA...) of liquid biopsy has been developed.

Hepatocellular carcinoma (HCC) is the predominant pathological type of primary liver cancer. It represents the sixth most common incidence worldwide and the third most common cause of cancer mortality.

Since 2021, the gold standard treatment for patients with advanced and/or unresectable HCC is the combination of atezolizumab (anti-PD-L1) and bevacizumab (VEGF inhibitor) in cases where chemoembolization is not indicated (patients with lymph node invasion and/or distant lesions or patients with portal flow abnormality). Indeed, this therapy offers a significant benefit in overall survival (19.2 vs 13.4 months, HR 0.66, p\<0.0009) as well as in progression-free survival (6.9 vs 4.3 months, HR 0.65, p=0.0001). However, to date, there is no predictive biomarker for the efficacy of immune checkpoint inhibitors (ICI)

The purpose of this research project is to identify a predictive biomarker in patients with advanced HCC (stage B and C) using a combinatorial approach of the liquid biopsy (CTC, CTC expressing PD-L1, immune cell profiling).

Interventions

• Biological Liquid Biopsy
  30mL blood sample: * 1 x 10mL CellSave tube specifically designed for the collection and preservation of CTCs for CellSearch® analysis * 1 EDTA tube for PBMCs isolation and circulating immune cells study (5mL), * 2 EDTA tubes and 1 dry tube (15mL) for the preparation of the biobank (serum, plasma and cell).

Primary outcome measures

• Percentage of patients with CTCs-PD-L1+ by CellSearch® technique [Time frame: At inclusion]

Secondary outcome measures (9)

• Number of CTCs-PD-L1+ measured by CellSearch® technique [Time frame: At inclusion]
• Presence of CTCs at inclusion by CellSearch® technique [Time frame: At inclusion]
• Number of CTCs measured by CellSearch® technique [Time frame: At inclusion]
• Immune profiling [Time frame: 24 month follow up]
• Expression of PD-L1 by immuno-histochemical analysis of tissue samples [Time frame: At inclusion]
• Tumor control defined by mRECIST criteria [Time frame: 24 month follow up]
• Tumor control defined by RECIST criteria [Time frame: 24 month follow up]
• Overall Survival [Time frame: 24 month follow-up]
• Progression Free Survival [Time frame: 24 month follow-up]

Eligibility criteria

Inclusion criteria

• Patients of at least 18 years old,
• Patients with advanced hepatocellular carcinoma or HCC with indication for first-line PD-1 or PD-L1 immunotherapy in MDT, without prior systemic therapy,
• The diagnosis of HCC is established according to imaging criteria (LI-RADSv2018 criteria) or after histological evidence,
• Advanced HCC defined by BCLC stages B and C,
• Patients with oral consent.

Exclusion criteria

• Administration of a previous systemic anti-tumor treatment (immunotherapy or chemotherapy or targeted therapy)
• No personal history of neoplasia in the previous 5 years
• No personal history of systemic inflammatory diseases
• No immunosuppressive treatment or treatment that could modify immunity (anti-TNF...)
• No affiliation or non-beneficiary of a Social Security system;
• Vulnerable persons according to article L1121-6 of the CSP ;
• Persons of full age who are protected or unable to give their consent according to article L1121-8 of the CSP;
• Pregnant or breastfeeding women according to article L1121-5 of the CSP.
• Non-inclusion due to follow-up difficulties (transfer, insufficient motivation, poor compliance, priority associated pathology in care, etc.)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

France · 1 center

• CHU Montpellier — Montpellier

Publications

• Pantel K, Alix-Panabieres C. Tumour microenvironment: informing on minimal residual disease in solid tumours. Nat Rev Clin Oncol. 2017 Jun;14(6):325-326. doi: 10.1038/nrclinonc.2017.53. Epub 2017 Apr 11. No abstract available. PMID 28397823
• Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004 Dec 15;10(24):8152-62. doi: 10.1158/1078-0432.CCR-04-1110. PMID 15623589
• Leone K, Poggiana C, Zamarchi R. The Interplay between Circulating Tumor Cells and the Immune System: From Immune Escape to Cancer Immunotherapy. Diagnostics (Basel). 2018 Aug 30;8(3):59. doi: 10.3390/diagnostics8030059. PMID 30200242
• Alix-Panabieres C, Pantel K. Liquid Biopsy: From Discovery to Clinical Application. Cancer Discov. 2021 Apr;11(4):858-873. doi: 10.1158/2159-8290.CD-20-1311. PMID 33811121
• Alix-Panabieres C. The future of liquid biopsy. Nature. 2020 Mar;579(7800):S9. doi: 10.1038/d41586-020-00844-5. No abstract available. PMID 32214259
• Eslami-S Z, Cortes-Hernandez LE, Alix-Panabieres C. The Metastatic Cascade as the Basis for Liquid Biopsy Development. Front Oncol. 2020 Jul 21;10:1055. doi: 10.3389/fonc.2020.01055. eCollection 2020. PMID 32850309
• Mego M, Gao H, Cohen EN, Anfossi S, Giordano A, Sanda T, Fouad TM, De Giorgi U, Giuliano M, Woodward WA, Alvarez RH, Valero V, Ueno NT, Hortobagyi GN, Cristofanilli M, Reuben JM. Circulating Tumor Cells (CTC) Are Associated with Defects in Adaptive Immunity in Patients with Inflammatory Breast Cancer. J Cancer. 2016 Jun 3;7(9):1095-104. doi: 10.7150/jca.13098. eCollection 2016. PMID 27326253
• Ye L, Zhang F, Li H, Yang L, Lv T, Gu W, Song Y. Circulating Tumor Cells Were Associated with the Number of T Lymphocyte Subsets and NK Cells in Peripheral Blood in Advanced Non-Small-Cell Lung Cancer. Dis Markers. 2017;2017:5727815. doi: 10.1155/2017/5727815. Epub 2017 Dec 24. PMID 29434410

Identifiers

NCT: NCT05810402 · RECHMPL22_0514

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗