Lenvatinib, toripalimab plus FOLFOX chemotherapy in hepatocellular carcinoma patients with extrahepatic metastasis: A biomolecular exploratory, phase II trial (LTSC)
Mené sur 30 patients atteints d'un carcinome hépatocellulaire avec métastases extra-hépatiques, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression à 6 mois, et la toxicité d'un traitement combinant lenvatinib, toripalimab et chimiothérapie de type FOLFOX en fonction du sous-type des hépatocytes
Purpose: To investigate the efficacy, safety, and biomarkers of systemic chemotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX) in combination with lenvatinib and toripalimab as the first-line treatment for advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis. Patients and Methods: In this biomolecular exploratory, phase II trial, eligible patients underwent the triple combination therapy of lenvatinib, toripalimab, plus FOLFOX chemotherapy. Primary endpoint was progression-free survival (PFS) rate at 6 months by RECIST v1.1. Single-nucleus RNA sequencing (snRNA-seq) of tumor biopsy samples was performed for exploratory biomarker analyses. Results: Between November 19, 2019 and July 4, 2021, 30 patients were enrolled. The primary endpoint was a 6-month PFS rate of 66.7%, with a median PFS of 9.73 months (95%CI: 2.89-16.58). The median overall survival (OS) was 14.63 months (95%CI: 11.77-17.50), with an objective response rate of 43.3%. Twenty-four (80.0%) patients exhibited high-risk features, among whom the median OS and PFS were 13.7 months (95%CI: 9.24-18.16) and 8.3 months (95%CI: 3.02-13.58), respectively. The most common adverse events were neutropenia, increased aspartate aminotransferase and alanine aminotransferase levels. Exploratory analyses of snRNA-seq profiles suggested that patients with higher abundance of tumor-infiltrating immune cells were more likely to benefit from this combination. Additionally, two subtypes of hepatocytes (AKR1C2+ and CFHR4+ malignant hepatocytes) were associated with reduced clinical benefits. Conclusions: FOLFOX chemotherapy in combination with lenvatinib and toripalimab showed promising antitumor activity with manageable toxicities in advanced HCC with extrahepatic metastasis. AKR1C2+ and CFHR4+ hepatocyte subtypes may be predictive biomarkers of resistance to the combination therapy.