The following is a summary of the “Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study,” published in the January 2023 issue of Hepatology by Kudo, et al.

Overall survival (OS) surrogate endpoints that have been validated are crucial for speeding up clinical research and drug development. Therefore, our study’s primary purpose was to verify that objective response is an independent predictor of OS in patients with unresectable hepatocellular carcinoma (HCC) treated with systemic anti-angiogenic treatment.

In REFLECT, a phase III research comparing lenvatinib and sorafenib, we looked into the connection between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST, and RECIST v1.1) and OS. They analyzed OS by objective response using landmark analyses at 2, 4, and 6 months post-randomization (Simon-Makuch). Responders (as assessed by investigators using mRECIST) had a median OS of 21.6 months (95% CI 18.6-24.5), while non-responders had a median OS of 11.9 months (95% CI 10.7-12.8) (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; P< 0.001). 

The connection with OS was corroborated by the objective response as measured by the intention-to-treat ratio (IRR) according to mRECIST and RECIST v1.1 (HR 0.61; 95% CI 0.51-0.72; P< 0.001 and HR 0.50; 95% CI 0.39-0.65; p 0.001, respectively). Around 2-month (HR 0.61; 95% CI 0.49-0.76; P< 0.001), four-month (HR 0.63; 95% CI 0.51-0.80; p 0.001), and six-month (HR 0.68; 95% CI 0.54-0.86; P<0.001) OS were substantially longer for responders compared to non-responders (investigator-assessed mRECIST). Incidence rate ratio (IRR) evaluations using mRECIST or RECIST v1.1 yielded comparable results. 

Objective response as measured by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; P<0.0001) or IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; P< 0.0001) was found to be an independent predictor of OS in patients with unresectable HCC in an exploratory multivariate Cox regression analysis. Those with unresectable HCC had a better chance of surviving the study period if they had an objective response, but more research is needed to confirm surrogacy. A complete or partial response as measured by mRECIST or RECIST v1.1 was associated with significantly improved survival compared to stable/progressive/non-evaluable illness.

Source: sciencedirect.com/science/article/pii/S0168827822031117