The SOUND Randomized Clinical Trial Results—Reply

Abstract

carcinoma. The noninferiority margin of 1.08 is clearly clinically justifiable. It is based on the data from the 2 sorafenib trials in first-line hepatocellular carcinoma (HCC), namely the SHARP trial. 2 Using the 95% CI lower limit method on log hazard ratio (HR) as described in Rothmann et al, 3 the noninferiority margin corresponding to 60% retention of the sorafenib effect vs placebo was calculated as 1.08. Given the consistent survival improvement of sorafenib vs placebo demonstrated in the SHARP and Asia-Pacific trials, and the fact that, at the time the BGB-A317-301 study was designed, no other monotherapy treatment was able to show superiority compared with sorafenib since its approval in 2007, a margin of 1.08 derived from 2 wellconducted phase 3 pivotal trials was statistically persuasive. Notably, the same margin was used in other noninferiority monotherapy HCC trials, namely the REFLECT (lenvatinib) and HIMALAYA (durvalumab) trials. 4,5 HRs are a well-established parameter to quantify overall survival difference, widely used in pivotal clinical trials, and accepted by regulatory agencies worldwide. The acceptability of using HRs to characterize overall survival between the arms in BGB-A317-301 was confirmed by regulatory agencies during scientific consultations before initiation of the trial. The duration of response, as per its definition, is based on responders only and is also a well-accepted clinical end point in oncology trials.Noninferiority active control study design is an established scientific concept accepted by health authorities worldwide. In addition, as indicated in the RATIONALE-301 documentation, 6 a test sequence starting with noninferiority and followed with a superiority test was prespecified in this study. While superiority is desirable, the demonstration of noninferiority in efficacy with improvement in safety and quality of life reflects a meaningful clinical benefit provided by the investigational treatment. Those were both achieved with tislelizumab monotherapy.