Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma.

Background & Aims

Immune checkpoint inhibitors (ICIs) alone or in combination with other ICIs or vascular endothelial growth factor pathway inhibitors are therapeutic options in unresectable/metastatic hepatocellular carcinoma (HCC). Whether antibiotic (ATB) exposure affects outcome remains unclear.

Methods

This study retrospectively analysed an FDA database including 4,098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or in combination (n = 584), tyrosine kinase inhibitor (TKI) (n = 1,968), vascular endothelial growth factor pathway inhibitors (n = 480), or placebo (n = 808) as part of nine international clinical trials. Exposure to ATB within 30 days before or after treatment initiation was correlated with overall survival (OS) and progression-free survival (PFS) across therapeutic modality before and after inverse probability of treatment weighting (IPTW).

Results

Of 4,098 patients with unresectable/metastatic HCC, of which 39% were of hepatitis B aetiology and 21% were of hepatitis C aetiology, 83% were males with a median age of 64 years (range 18-88), a European Collaborative Oncology Group performance status of 0 (60%), and Child-Pugh A class (98%). Overall, ATB exposure (n = 620, 15%) was associated with shorter median PFS (3.6 months in ATB-exposed

Conclusions

Unlike other malignancies where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with worse outcomes in this study across different therapies for HCC including placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut-liver axis remains to be demonstrated in translational studies.

Impact and Implications

A growing body of evidence suggests the host microbiome, frequently altered by antibiotic treatment, as an important outcome predictor in the context of immune checkpoint inhibitor therapy. In this study, we analysed the effects of early antibiotic exposure on outcomes in almost 4,100 patients with hepatocellular carcinoma treated within nine multicentre clinical trials. Interestingly, early exposure to antibiotic treatment was associated with worse outcomes not only in patients treated with immune checkpoint inhibitors but also in those treated with tyrosine kinase inhibitors and placebo. This is in contrast to data published in other malignancies, where the detrimental effect of antibiotic treatment may be more prominent in immune checkpoint inhibitor recipients, highlighting the uniqueness of hepatocellular carcinoma given the complex interplay between cirrhosis, cancer, risk of infection, and the pleiotropic effect of molecular therapies for this disease.

Informations de copyright

© 2023 The Author(s).

Déclaration de conflit d'intérêts

DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, EISAI, BMS, and Roche; travel expenses from BMS and Bayer Healthcare; and consulting fees for Mina Therapeutics, DaVolterra, Mursla, IPSEN, Exact Sciences, Avamune, EISAI, Roche, and Astra Zeneca. DJP received research funding (to institution) from MSD, GSK, and BMS. BS received travel support from AbbVie, Gilead, and Ipsen. AC received consulting fees from MSD, Astra Zeneca, Roche, and BMS. He also received speaker fees from Novartis, Astra Zeneca, and EISAI. AD received educational grant support for conference attendance by Roche. There are no other personal or financial conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.