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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.

Although prior studies have shown underuse of appropriate therapy in patients with hepatocellular carcinoma (HCC), no studies to date have assessed the prevalence and clinical impact of therapeutic delays among patients with HCC. The goal of this study was to characterize and identify factors associated with underuse and delays in treatment of these patients. A retrospective cohort study was conducted of patients with cirrhosis diagnosed with HCC at a large urban safety net hospital between January 2005 and June 2012. Dates for HCC diagnosis and any treatments were recorded. Univariate and multivariate analysis was used to determine factors associated with treatment underuse and delayed treatment, which was defined as time from diagnosis to treatment exceeding 3 months. The authors identified 267 treatment-eligible patients with HCC, of whom only 62% received HCC therapy. On multivariate analysis, tumor stage (odds ratio [OR], 0.48; 95% CI, 0.36-0.65), Child-Pugh class (OR, 0.49; 95% CI, 0.28-0.84), and black race (OR, 0.55; 95% CI, 0.31-0.99) were associated with lower rates of treatment use. The median time to treatment was 1.7 months, with 31% of patients experiencing delayed treatment. Delayed treatment was associated with the presence of ascites (hazard ratio [HR], 2.8; 95% CI, 1.3-6.1) and current treatment with transarterial chemoembolization (HR, 4.8; 95% CI, 1.8-12.5). After adjusting for tumor stage and Child-Pugh class, treatment underuse (HR, 0.33; 95% CI, 0.24-0.46) and delayed treatment (HR, 0.50; 95% CI, 0.30-0.84) were both associated with significantly worse survival. Results showed that, in addition to one-third of patients not receiving HCC-directed therapy, another 30% experienced significant therapeutic delays, leading to worse survival.