LAUSR

I read with interest the study by CasadeiGardini et al who compared the effects of sorafenib and lenvatinib as firstline treatment of hepatocellular carcinoma (HCC) in the reallife setting, through inverse probability of treatment weighting (IPTW) methodology which weights patient characteristics and measured outcomes of each patient in both treatment arms.1 They found that in the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI: 0.701.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.621.07) even in the presence of balanced baseline characteristics. However, they found that lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69). The study adds to the dilemma that has arisen since the REFLECT trial about the choice of firstline therapy for HCC. This dilemma is the result of a noninferiority study, which owing to its intrinsic characteristics never allows to establish the best therapeutic option for the patient. In recent years superiority trials have often been replaced by equivalence or noninferiority trials. This reflects a switch from the search for better drugs to the acceptance of drugs that are similar to, or not worse than, those already on the market. This shift is questionable for some reasons. Firstly, it is conceptually difficult to establish the limits that define a drug as equivalent or not inferior. Then, equivalence or noninferiority designs in clinical trials also reflect economic considerations. Marketing authorization is easier to obtain when researchers have tested for and show equivalence rather than tested for and not shown superiority. In addition, trials that do not aim to show superiority require smaller sample sizes as they include in the ‘equivalence range’ therapeutic differences that may well be clinically relevant if measured with the appropriate statistical precision. The use of noninferiority studies should not be approved in oncology as already influentially reported.2 The limitations of the REFLECT study have been partly blunted by the interesting study by CasadeiGardini et al which however still keeps open the debate on the best choice in the firstline setting of HCC treatment. It is desirable that new emerging therapies under investigation in the next few years are no longer evaluated with noninferiority studies to avoid that the potential benefit of new agents is rendered meaningless by studies that demonstrate not the best choice but the nonworst option.3