Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma

Background No trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC). Objectives Conduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib. Methods The CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared. Results In the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9–17.0] versus 10.6 [9.1–12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9–7.3] versus 3.1 [2.8–4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib ( p ≤ 0.001). Conclusions Cabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.