Regorafenib vs. cabozantinib as second-line treatment for advanced hepatocellular carcinoma: an anchored matching-adjusted indirect comparison of efficacy and safety

Introduction: The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments. Methods: We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Secondline HCC patients with prior sorafenib exposure of >= 3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs) occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs. Results: After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80 [95% CI: 0.54, 1.20]) and similar to 3-month longer RMST over cabozantinib (RMST difference, 2.76 months [95% CI: -1.03, 6.54]), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00 [95% CI: 0.68, 1.49]) and no clinically meaningful difference based on RMST analyses (RMST difference, -0.59 months [95% CI: -1.83, 0.65]). Regorafenib showed significantly lower incidence of discontinuation (risk difference, -9.2% [95% CI: -17.7%, -0.6%]) and dose reductions (-15.2% [95% CI: -29.0%, -1.5%]) due to treatment-related AEs (any grade). Regorafenib was also associated with lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, -7.1% [95% CI: -14.7%, 0.4%]) and fatigue (-6.3% [95% CI: -14.6%, 2.0%]). Conclusion: This indirect treatment comparison suggests, relative to cabozantinib, regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.