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. Second-line 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 ~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.