L6.3 Molecular Characterization and Pre-Screening Process in Early Drug Clinical Development of PI3K-Pathway Inhibitors

Abstract

The efficacy of targeted therapies in patient populations selected on the basis of the molecular features of their tumors is shifting the current focus of treatment to biomarker-driven clinical trials. Phase 1 trials provide an arena for early hypothesis testing, evaluating target engagement and the potential predictive biomarkers. Based on preclinical data, the best-case scenario for proof-of-concept in the early development of PI3K-pathway inhibitors seems to be treating patients with PTEN loss or mutations in the PIK3CA gene. Different approaches in order to enrich phase 1 trials with patients harboring these aberrations are possible, considering the limitations of relying on retrospective analysis of tumor samples. Modern genotyping platforms are relatively inexpensive and provide results rapidly, what prevents delay from time of progression on standard therapy to enrollment in phase 1 trial with matched targeted agents. In addition to the more practical pre-screening strategy that focuses on molecular profiling of patients referred to early clinical trials, a broader approach can be performed on site with the analysis of archived tumor samples from patients with metastatic diseases known to harbor PIK3CAmutations. This latter strategy allows not-heavily pretreated patients to be enrolled in clinical trials with PI3K inhibitors. Nevertheless, screening of patients that may never enter a clinical trial could take place. Furthermore, upfront molecular profiling is not covered by insurance companies or study budgets, requiring additional funding. On the other hand, the option of sending a patient's tumor sample to a central lab supported by the sponsor immediately before considering inclusion in a trial has many disadvantages, including the usual long time-frame to receive the results and define eligibility of phase 1 trial candidates and issues with the limited amount of tissue left on site for further molecular analysis. In conclusion, to potentially optimize benefit for individual patients and speed up the regulatory approval of new anticancer drugs, a biomarker-driven setting for clinical trials is the most rational approach. The different strategies of pre-screening tumors from patients eligible for early clinical trials have pros and cons, but are an impor­tant step in the drug development of PI3K pathway inhibitors.