Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma

Abstract

Background and Aims: Immunotherapies have altered the treatment paradigm in HCC. Surrogate and modified endpoints are used to assess early success in clinical studies and guide clinical practice. We sought to determine whether surrogate endpoints and modifications to the conventional criteria for tumor response (RECIST), including modified RECIST (mRECIST) and immune-modified RECIST (imRECIST), are valid measures to predict overall survival (OS) in HCC treated with immunotherapies. Approach and Results: We performed an individual-level post hoc analysis of patients treated with atezolizumab and bevacizumab in the IMbrave150 trial (N = 279) and a cross-sectional analysis of a multicenter real-world patient cohort treated with immunotherapy (N = 328). Landmark analyses showed that objective response rates by RECIST were associated with greater OS including among Child-Pugh A and B patients and among patients treated with immunotherapies in the first- or second-line setting (IMbrave150: HR 0.24, 95% CI, 0.17–0.33; RW: HR 0.25, 95% CI, 0.15–0.43). Objective response rates by mRECIST or imRECIST were not associated with the greater predictive power of OS benefit (mRECIST: HR 0.30, 95% CI, 0.22–0.42; imRECIST: HR 0.36, 95% CI, 0.30–0.51). Progression-free survival determined by RECIST was only moderately correlated with OS, and this association was not improved using mRECIST or imRECIST. Conclusions: Our results clarify the utility of surrogate and modified endpoints in HCC treated with immunotherapies and support the use of RECIST objective response rates as an appropriate signal-finding measure for the evaluation of emerging treatments. Contrary to their intended purpose, mRECIST and imRECIST did not provide meaningful improvements in predicting OS benefits.

Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab–bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study

“…The use of progression-free survival as a surrogate marker of overall survival in patients with advanced hepatocellular carcinoma has been challenged. [23][24][25][26] Several trials investigating different systemic therapies, such as REFLECT or COSMIC-312, 27,28 showed significantly longer median progression-free survival but did not find an improvement in median overall survival.…”

From Conversion to Resection for Unresectable Hepatocellular Carcinoma: A Review of the Latest Strategies

“…Many scholars believe that patients with HCC that cannot be resected initially should accept surgery as soon as they meet the criteria of surgery after conversion therapy. However, one study showed that overall survival after resection in HCC patients was correlated with the objective response rate (ORR) of RECIST [34]. Patients with an objective response had longer postoperative OS.…”

Impact of radiological response and pattern of progression in patients with hepatocellular carcinoma treated by atezolizumab- bevacizumab

“…Several retrospective studies have compared the prognostic ability of RECIST 1.1 criteria and mRECIST criteria in patients with HCC treated with sorafenib, 10–14 and a recent systematic review that included 34 RCTs highlighted that mRECIST criteria have a better correlation with overall survival (OS) than RECIST 1.1 criteria 15 . In addition, a recent individual-level post hoc analysis of the IMbrave 150 trial and cross-sectional analysis of an international real-world cohort assessed surrogacy of ORR using RECIST, mRECIST, and imRECIST in patients treated with ICI (atezolizumab-bevacizumab, nivolumab, and pembrolizumab) showing that ORR is a good surrogate endpoint for OS in this group of patients as well demonstrating that prognostic performance of mRECST and imRECIST criteria is not higher than that of RECIST 16 . In the IMBrave 150 trial, which led to the worldwide approval of the combination of atezolizumab and bevacizumab (AtezoBev) as the new first-line standard of care for patients with unresectable HCC, 8,17 slightly higher ORR values are reported for mRECIST criteria compared with RECIST 1.1 criteria (33.2 vs. 27.3).…”

“…[15] In addition, a recent individuallevel post hoc analysis of the IMbrave 150 trial and cross-sectional analysis of an international real-world cohort assessed surrogacy of ORR using RECIST, mRECIST, and imRECIST in patients treated with ICI (atezolizumab-bevacizumab, nivolumab, and pembrolizumab) showing that ORR is a good surrogate endpoint for OS in this group of patients as well demonstrating that prognostic performance of mRECST and imRE-CIST criteria is not higher than that of RECIST. [16] In the IMBrave 150 trial, which led to the worldwide approval of the combination of atezolizumab and bevacizumab (AtezoBev) as the new first-line standard of care for patients with unresectable HCC, [8,17] slightly higher ORR values are reported for mRECIST criteria compared with RECIST 1.1 criteria (33.2 vs. 27.3). However, the prognostic ability of the two criteria has never been directly compared in patients treated with this combination of systemic treatments.…”