DOI: 10.25934/pr00007809
title: The prognostic impact of early antibiotics exposure on Overall Survival and Progression Free Survival of patients affected by unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab or sorafenib within the IMbrave 150 trial.

description: 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.