Molecular-based targeted therapies in patients with hepatocellular carcinoma and hepato-cholangiocarcinoma refractory to atezolizumab/bevacizumab

J Hepatol. 2023 Dec;79(6):1450-1458. doi: 10.1016/j.jhep.2023.08.017. Epub 2023 Aug 28.

Abstract

Background & aims: The "French Medicine Genomic program 2025" has been designed to give patients with cancers that are refractory to systemic treatments access to off-label therapies adapted to their specific genomic profile. Herein, we reported the results of this program in patients with advanced hepatocellular carcinoma (HCC) and hepato-cholangiocarcinoma (H-CCK).

Methods: In one center, all patients with HCC or H-CCK who progressed under atezolizumab/bevacizumab with available tumor frozen samples benefited from whole-genome/-exome and RNA sequencing. Targeted therapies were matched to genomic alterations following the recommendations of a molecular tumor board and radiological response and overall survival were assessed.

Results: Among 135 patients with HCC and H-CCK treated by atezolizumab/bevacizumab, 20 patients benefited from genomic analysis after progression (16 HCC; 4 H-CCK). Nineteen patients had analyzable data, 70% were male, median age was 57 years, 65% had metastatic disease and 45% had vascular invasion. Among these 19 patients, 14 patients (76%) harbored at least one actionable genomic alteration and 9/14 received an adapted targeted therapy (45%). One patient with H-CCK showing CDK4 amplification was treated with palbociclib and achieved a partial radiological response for 16 months. Another patient with H-CCK, high HER2 overexpression and a high homologous recombination score was treated with trastuzumab/olaparib and had stable disease. One patient with an HCC and bi-allelic inactivation of TSC2 achieved a complete radiological response under everolimus. The remaining six treated patients (all HCC) had progressive disease, including three patients treated with trametinib, two with everolimus and one with olaparib.

Conclusion: Molecular-based guided therapy is feasible in patients with HCC/H-CCK progressing under atezolizumab/bevacizumab and may be useful in a small subset of patients.

Impact and implications: The use of whole-genome/-exome and RNA sequencing in clinical practice has not been reported in patients with hepatocellular carcinoma and hepato-cholangiocarcinoma. Herein, we performed a pilot study which suggested that whole-genome/-exome and RNA sequencing is feasible on tumor biopsies from patients refractory to atezolizumab/bevacizumab, with a small subset of patients exhibiting at least one actionable genomic alteration and receiving an adapted targeted therapy. This proof-of-concept study suggests that this clinical strategy could benefit a small subset of patients. Finally, validation of this approach will be required in a larger cohort of patients.

Keywords: hepatocellular carcinoma; hepatocholangiocarcinoma; next generation sequencing; precision medicine; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Bevacizumab / therapeutic use
  • Bile Duct Neoplasms* / drug therapy
  • Bile Duct Neoplasms* / genetics
  • Bile Ducts, Intrahepatic
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Cholangiocarcinoma* / drug therapy
  • Cholangiocarcinoma* / genetics
  • Everolimus
  • Female
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Pilot Projects
  • Precision Medicine

Substances

  • atezolizumab
  • Bevacizumab
  • Everolimus
  • Antineoplastic Agents