The predictive role of concomitant antibiotics in patients treated with immunotherapy or oral treatment for unresectable hepatocellular carcinoma (HCC)

Lead Investigator: David James Pinato, Imperial College, London
Title of Proposal Research: The predictive role of concomitant antibiotics in patients treated with immunotherapy or oral treatment for unresectable hepatocellular carcinoma (HCC)
Vivli Data Request: 7809
Funding Source: None
Potential Conflicts of Interest: DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; received research funding (to institution) from MSD and BMS.
The study will not receive any external fundings.

Summary of the Proposed Research:

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is the fourth cause of cancer-related death worldwide. Sorafenib (an oral treatment that inhibits cancer growth by blocking blood vessels formation) has been the only available option for more than a decade for patients with advanced HCC. In 2020, the combination of atezolizumab (an immune checkpoint inhibitor [ICI], a type of treatment that helps the immune system seek out and destroy cancer) and bevacizumab ((a targeted therapy that starves tumors by preventing new blood vessels from growing) has demonstrated significant survival advantage over sorafenib as first line for advanced HCC. More recently, the association of combined immune checkpoint inhibitors, durvalumab plus tremelimumab, performed better than sorafenib in the same setting. Despite these positive results, there is still a consistent percentage of patients who fail to respond to ICI-based treatments, and prognostic factors are urgently required.

Necessity of the research:
In the last few years, several factors have been investigated for their potential ability to modulate ICIs response by a direct or indirect influence on host immunity. Our group has already demonstrated that early antibiotics exposure in patients affected by advanced HCC does not impact overall survival (OS) nor overall response rate (ORR), whilst being associated with delayed cancer progression (progression free survival: defined as the time from treatment start to radiological progression or death) [1]. These findings were not confirmed by Cheung et al. [2], who found that patients receiving antibiotics during immunotherapy for advanced HCC had a shorter survival.

How the research will be conducted:
In this proposal, we aim to analyze the impact of antibiotic exposure on treatment outcomes in patients treated within the IMbrave 150 study.

What design and methods you have you chosen and why:
The effect of antibiotic exposure in HCC recipients will be analysed in patients treated with atezolizumab plus bevacizumab and in a control cohort treated with sorafenib, allowing therefore to distinguish between a potential predictive and prognostic role of early antibiotic exposure in HCC patients treated in first-line.
Since recent evidence suggest a possible role of other common concomitant medications in influencing outcomes of patients receiving ICIs [3, 4], as ancillary hypothesis, we will investigate the impact of beta-blockers, steroids, proton pump inhibitors (PPI), anti-diabetic medications and statins on OS and PFS in both arms (atezolizumab plus bevacizumab and sorafenib).

How the research will add to medical science or patient care:
Access to the IMbrave150 dataset is likely to be highly contributory to topic of antibiotics and ICI outcomes, providing high quality data to define predictive and prognostic factors in HCC patients.

Statistical Analysis Plan:

The sample size was calculated based on the expected number of patients receiving antibiotics in the atezolizumab plus bevacizumab group. Based on previous literature findings [18,19], we hypothesized that about 30% of patients had received antibiotics treatment during the study. We assumed a 17% reduction in 12 months survival rate in patients receiving antibiotics. With a probability of type I error of 0.05 and type II error of 0.20, a sample size of 307 patients in the atezolizumab plus bevacizumab group is required [24]. Baseline characteristics of the 2 groups (antibiotics treated and not) across the 2 cohorts (atezolizumab plus bevacizumab and sorafenib) will be descriptively reported and expressed as percentage, median values and interquartile range (IQR) for each group. Differences among baseline continuous variables will be analysed using the Kruskal-Wallis test assuming a non-parametric distribution, and Chi-squared test will be adopted for categorial variables. Median PFS and OS will be estimated with Kaplan-Meier method with 95% confidence interval (CIs), and two-sided log-rank test will be used to assess the prognostic role of antibiotics exposure across the atezolizumab plus bevacizumab and sorafenib cohorts. The correlation between antibiotics exposure (yes or not) and the ORR will be explored by the Chi-square tests. The prognostic role of antibiotics exposure on PFS and OS will be estimated using univariate and multivariate Cox-regression models to obtain hazard ratios (HR) with 95% CIs. In the case of a significant prognostic impact on OS and PFS in both the cohorts, the HR for OS and PFS will be compared. A pooled multivariable model of the two cohorts will be constructed, using all the baseline clinical characteristics already investigated within the IMbrave150 trial as covariates (gender; age; geographic region; ECOG PS; Barcelona Clinic Liver Cancer stage; alpha-fetoprotein; macrovascular invasion; extrahepatic spread; aetiology; prior local therapy). An initial multivariable analysis without interactions will be carried out and then the interaction term between the treatment modality (atezolizumab plus bevacizumab) and the variable of interest (antibiotics exposure) will be tested in separate models. The two-tailed alfa level for all analyses is set at 0.05.
Missing data will be excluded from the analyses.
All analyses will be carried out with R Studio Desktop 1.4.1717.

Requested Studies:

A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
Sponsor: Roche
Study ID: NCT03434379
Sponsor ID: YO40245

Public Disclosures:

Claudia A.M. Fulgenzi, Cian Murphy, Antonio D’Alessio, Bernhard Scheiner, Matthias Pinter, Alessio Cortellini, David J. James Pinato. Effect of early antibiotic exposure on survival of patients receiving atezolizumab plus bevacizumab but not sorafenib for unresectable HCC: A sub-analysis of the phase III IMbrave150 study. J Clin Oncol 41, 2023 (suppl 4; abstr 597). doi: 10.1200/JCO.2023.41.3_suppl.597.