Dose Finding in Oncology: What is Impeding Coming of Age?

Abstract

After a drug molecule enters clinical trials, there are primarily three levers to enhance probability of success: patient selection, dose selection and choice of combination agents. Of these, dose selection remains an under-appreciated aspect in oncology drug development despite numerous peer-reviewed publications. Here, we share practical challenges faced by the biopharmaceutical industry that reduce the willingness to invest in dose finding for oncology drugs. First, randomized dose finding admittedly slows down clinical development. To reduce the size of dose finding study, trend in exposure vs. tumor-size analysis can be assessed, instead of a statistical test for non-inferiority between multiple doses. Second, investment in testing a lower dose when benefit-risk at the higher dose is sufficient for regulatory approval (i.e., efficacy at the higher dose is better than standard of care and safety is acceptable) is perceived as low priority. Changing regulatory landscape must be considered to optimize dose in pre-marketing setting as post-marketing changes in dose can be commercially costly. Third, the risk of exposing patients to subtherapeutic exposures with a lower dose should be assessed scientifically instead of assuming a monotonic relationship between dose and efficacy. Only the doses which are expected to be at the plateau of dose/exposure–response curve should be investigated in Phase 1b/2. Overall, changing the perceptions that have been impeding investment in dose finding in oncology requires pragmatic discourse among biopharmaceutical industry, regulatory agencies and academia. These perceptions should also not deter dose finding for recently emerging modalities, including BITEs and CART cell therapies.