Pooled Individual Patient-Data Analysis of Clinical Trials on Second-line Multikinase Inhibitors Following Immunotherapy in Hepatocellular Carcinoma.

BACKGROUND: Three prospective clinical trials from Asia have been published on the efficacy of second-line multikinase inhibitors (MKIs) following first-line immunotherapy. We aim to study the outcomes of second-line MKIs via combined analyses of the three studies. We also aim to identify prognostic factors after immunotherapy which will inform future clinical trial design. METHODS: Individual patient-data were pooled from the three Asian clinical trials on second-line cabozantinib, lenvatinib and regorafenib. Median progression-free survival (PFS) and overall survival (OS) were computed for the overall population and those treated with first-line atezolizumab plus bevacizumab-based regimens. Prognostic factors for survival of second-line MKIs were investigated in patients treated with prior atezolizumab plus bevacizumab-based regimens. RESULTS: 117 patients were included in this pooled analysis. 103 patients were treated with prior atezolizumab plus bevacizumab-based regimens. Patients receiving second-line MKIs following prior first-line immunotherapy had a median PFS of 4.2 months (95%CI: 3.5-5.3 months) and OS of 10.6 months (95%CI: 9.1-15.4 months) respectively. Median PFS and OS of second-line MKIs following prior atezolizumab plus bevacizumab-based regimens were 4.2 months (95%CI: 3.5-5.3 months) and 10.6 months (95%CI: 8.9-15.4 months) respectively. Macrovascular invasion (MVI) is the only prognostic factor of OS for second-line MKIs after multivariable adjustment (HR 3.55, 95%CI 1.89-6.67, p<0.001). Previous response to immunotherapy, presence of extrahepatic spread (EHS), and baseline liver function are not associated with survival. CONCLUSION: The current study provides the largest prospective data on second-line MKIs in patients with HCC who had prior first-line immunotherapy. Given the strong prognostic signal of MVI observed in this analysis, our data suggest considering MVI, rather than prior response to immunotherapy or EHS, as a stratification factor for future second-line trials.