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Alyson Haslam, Jennifer Gill and Vinay Prasad

Background: Noninferiority (NI) trials should help identify interventions that offer some benefit (eg, lower financial costs, more tolerable, or less invasive) without sacrificing noticeable effectiveness, and researchers should adhere to appropriate standards in the conduct and reporting of methods. This study describes the characteristics of a systematic sampling of NI studies from an updated search of recent published oncology trials. Methods: We performed a cross-sectional analysis of NI research published between 2014 and 2018 in the top 3 medical journals and top 3 oncology journals. We estimated the percentage of NI trials in oncology that report informative details of study, such as justification for conducting NI trial, justification of NI margin, analysis population, and alpha level. Results: There were 94 NI studies and 104 comparisons, and 59.6% (n=62) of comparisons declared NI. The median NI margin of comparisons reporting an odds or hazard ratio was 1.3 (1.05–3.2; n=64). Twenty-three percent (n=22) of studies did not provide a justification for conducting a NI study; 54.3% (n=51) of studies did not provide a justification of the margin they used in their study. Only approximately 46% (n=43) of comparisons used both an intention-to-treat (ITT) and per-protocol (PP) analysis, and 37.3% (n=35) of studies used a one-sided alpha level of >.025. There is notable variation in key elements of the conduct and reporting of NI trials, including the NI margin, the alpha level, and the population analyzed. Furthermore, a high number of studies do not provide justification for conducting a NI study or the margin used for determining NI. Conclusions: These results suggest that there is room for improvement in the reporting and conduct of NI trials in oncology.

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Antonious Hazim, Gordon Mills, Vinay Prasad, Alyson Haslam and Emerson Y. Chen

Background: As progress continues in oncology drug development, this study aimed to examine whether the previously established association between drug dose and efficacy in the era of cytotoxic therapies remains true in today’s phase I dose-escalation oncology trials. Methods: A systematic review of early-phase dose-finding trials of single-agent oncology drugs from 2015 to 2018 was conducted to examine the relationship between drug dose and objective responses. Cancer-specific trials were included if they determined maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Data related to the study drug, study design, treatment response, cancer type, dose levels, MTD, and RP2D were all collected. Dose level was categorized into 4 categories (≤40%, 41%–80%, 81%–120%, and >120% of the RP2D) and was further analyzed by class of drug. Results: A total of 175 phase I studies were identified, with a total of 7,330 patients showing a median response rate of 5% (range, 0%–83%) across trials. A total of 93 trials with 2,506 participants had response data corresponding to drug dose level. In this subset, the median response rate was 5% (range, 0%–83%) across trials. Across all participants in this subset, the response rate was 12% (57 of 491) among those in the dose range of ≤40% of RP2D, 17% (95 of 562) among those in 41% to 80% of RP2D, 23% (272 of 1,206) among those in 81% to 120% of RP2D, and 29% (71 of 247) among those in >120% of RP2D (P<.001). The response rate at ≤40% of RP2D for targeted antibody was 5%, 4% for cellular therapy, 19% for immunotherapy, and 21% for small-molecule targeted inhibitors. Conclusions: Whereas our study of published phase I trials continued to show a low response rate consistent with earlier studies, the relationship between response and dose does not always peak at 81% to 120% of RP2D anymore, likely due to the use of novel immunotherapy and targeted agents with distinct efficacy and toxicity patterns.