Objective response to systemic therapy linked to overall survival in unresectable HCC

Objective response to first-line systemic therapy with lenvatinib or sorafenib independently predicts overall survival (OS) in individuals with unresectable hepatocellular carcinoma (HCC), as shown by the subanalysis of the REFLECT study.

“Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival [than] those with stable/progressive/nonevaluable disease,” said the researchers, led by Masatoshi Kudo from the Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Kudo and his team explored the relationship between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study comparing lenvatinib with sorafenib. They also performed landmark analysis of OS by objective response at 2, 4, and 6 months after randomization.

Responders had significantly longer median OS than nonresponders (21.6 vs 11.9 months; hazard ratio [HR], 0.61, 95 percent confidence interval [CI], 0.49‒0.76; p<0.001). Objective response by IRR per mRECIST and RECIST v1.1 correlated with OS (HR, 0.61, 95 percent CI, 0.51‒0.72; p<0.001 and HR, 0.50, 95 percent CI, 0.39‒0.65; p<0.001, respectively). [J Hepatol 2023;78:133-141]

OS was significantly extended for responders than for nonresponders at 2 (HR, 0.61, 95 percent CI, 0.49‒0.76; p<0.001), 4 (HR, 0.63, 95 percent CI, 0.51‒0.80; p<0.001), and 6 months (HR, 0.68, 95 percent CI, 0.54‒0.86; p<0.001). Results were consistent when assessed by IRR, with both mRECIST and RECIST v1.1.

On multivariate analysis, objective response by investigator-assessed mRECIST (HR, 0.55, 95 percent CI, 0.44‒0.68; p<0.0001) and IRR-assessed RECIST v1.1 (HR, 0.49, 95 percent CI, 0.38‒0.64; p<0.0001) was found to be independently predictive of OS in patients with unresectable HCC.

“However, additional studies, such as individual-patient pooled data analyses from several trials, are needed to further validate the association between objective response to systemic therapy and OS,” the researchers said.

“Although this study also suggests that objective response may be a potential surrogate endpoint for OS in early-phase trials, its validity as a potential surrogate endpoint requires confirmation in additional prospective studies,” they added.

The association between objective response by mRECIST and OS was supported by the results of earlier studies. One such study was a time-dependent multivariate analysis that used data from the phase III BRISK-PS study and showed that objective response by mRECIST was independently predictive of OS in patients with advanced HCC. [J Hepatol 2017;66:1166-1172]

Moreover, an analysis of two phase II studies of patients with advanced HCC who received either nintedanib or sorafenib revealed that response by mRECIST or RECIST v1.0 correlated with improved survival. [Liver Int 2017;37:1047-1055]

Other independent predictors of OS by mRECIST per investigator assessment were as follows: increase in Child-Pugh score to ≥7, sex, macroscopic portal vein invasion, baseline alpha-fetoprotein level, number of tumour sites at baseline, presence of HCC in the liver, hepatitis B virus aetiology, and treatment with lenvatinib.

“Given the large difference in the number of responders versus nonresponders in the overall REFLECT population, more research is needed to validate these predictors,” the researchers said.