Relationship Between Response and Dose in Published, Contemporary Phase I Oncology Trials

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  • 1 School of Medicine,
  • 2 Division of Hematology Oncology, Knight Cancer Institute,
  • 3 Department of Public Health and Preventive Medicine, and
  • 4 Center for Health Care Ethics, Oregon Health & Science University, Portland, Oregon.
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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.

Submitted July 1, 2019; accepted for publication October 29, 2019.

Previous presentation: Data from this manuscript was deemed publication-only at the 2019 ASCO Annual Meeting; May 31–June 4, 2019; Chicago, Illinois. Abstract e14583.

Disclosures: Dr. Mills has disclosed that he is a scientific advisor for AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Medimmune, Nuevolution, Pfizer, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda; has stock options for Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda; has received grant/research support from Abbvie, Adelson AstraZeneca, Critical Outcomes Technology, Illumina, Ionis, Immunomet, Karus Therapeutics, Pfizer, Nanostring, Takeda/Millennium Pharmaceuticals, and Tesaro; and has licensed technology to Nanostring and Myriad Genetics. Dr. Prasad has disclosed that he receives grant/research support from Arnold Ventures; is a consultant for UnitedHealthcare; has received honoraria from Medscape; and that his podcast is supported by Patreon. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was funded by the Knight Cancer Institute and the Laura and John Arnold Foundation.

Correspondence: Emerson Y. Chen, MD, Division of Hematology Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. Email:

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