Background and importance Regorafenib, ramucirumab and cabozantinib are used as secondline therapy in patients with hepatocarcinoma and alfa-fetoprotein value ≥400 ng/mL (HCC-AP ≥400). There are no direct comparisons among them.

Aim and objectives To establish whether regorafenib, ramucirumab and cabozantinib are equivalent therapeutic alternatives (ATE) in the secondline treatment of HCC-AP ≥400 through an indirect treatment comparison (ITC) using a common comparator.

Material and methods A search was conducted to identify phase III clinical trials with similar populations (secondline treatment of HCC-AP ≥400), duration and endpoints. If more than one study of the same drug was found, the results were combined in a meta-analysis (Joaquim Primo calculator). ITC was made according to Bucher’s method. The variable selected to determine clinical equivalence was overall survival (OS). Delta value (Δ), maximum acceptable difference as a clinical criterion of non-inferiority, was set at 0.750 (and its inverse, 1.33), the value used in trials to calculate sample size. To establish positioning, the criteria of the ATE guide were applied. If 95% CI deviated from the delta margin, this probability was calculated using the Shakespeare method.

Results Four clinical trials were found, ramucirumab (n=2), regorafenib (n=1) and cabozantinib (n=1). Limitations found: included population (only patients with alpha-fetoprotein ≥400 ng/mL versus all patients, then subgroup data were used for ITC) and previous therapy as firstline (only sorafenib vs other treatments allowed, in small percentages). Ramucirumab trials were pooled, resulting in HR 0.71 (95% CI 0.58 to 0.86). The results of the ITC are shown in table 1.

According to the ATE guide, there was a likely clinical equivalence. The probability that the result exceeded the delta margin above and below was, respectively, 12.45% and 5.76% for cabozantinib–regorafenib, 9.57% and 3.71% for ramucirumab–regorafenib, and 5% and 4.86% for ramucirumab–cabozantinib.

Conclusion and relevance The ITC showed no statistically significant differences in OS among the drugs. The 95% CI showed a certain grade of uncertainty, exceeding the equivalence margin. According to the ATE guide, there was clinical equivalence among the drugs due to the small percentage of 95% CI outside the equivalence margin.

References and/or acknowledgements No conflict of interest.