Assessing the translational value of pre-clinical studies for clinical response rate in oncology: an exploratory investigation of 42 FDA-approved small-molecule targeted anticancer drugs.

PURPOSE: To assess the translational value of anticancer preclinical models, we retrospectively investigated the relationships between preclinical data and clinical response rate for 42 small-molecule targeted anticancer drugs approved by the US FDA from 2001 to 2018.
METHODS: For 42 FDA-approved drugs, relevant pre-clinical (IC50, mouse PK/efficacy) and clinical (overall response rates [ORR], PK) data were extracted from the public domain. Relationships were investigated overall and separately by mechanism of action and solid vs liquid tumors. Binomial-normal regression analysis was performed using R.
RESULTS: A significant correlation was found between the ratio of free human average plasma concentration (hCave) at the approved clinical dose to biochemical IC50 and ORR for kinase inhibitors with solid tumor indications (KIST). We also identified that, for KIST, the ratios of (i) total and (ii) free human-to-mouse average plasma concentration at efficacious doses were correlated to ORR ((i) R2 = 0.72, n = 10; (ii) R2 = 0.78, n = 10)).
CONCLUSION: Relationships were identified for ratios of efficacious clinical exposures to typical preclinical pharmacology data and ORR for KIST in this retrospective analysis. Although the obtained datasets are limited, the relationships demonstrate that a systemic exposure relative to established pre-clinical pharmacology experiments for an investigational KIST could be used as a reference to assess if desired efficacy could be achieved. This approach may assist selection of the recommended phase 2 dose (RP2D) of an investigational drug.