Quantitative Systems Pharmacology in Late Stage Oncology Drug Development– New Horizons to Dose Optimization
Dose guidance for a novel combination therapy to treat head and neck squamous cell carcinoma (HNSCC) for patients with HRAS/PIK3CA variants using QSP model
Executive DIrector Clinical Pharmacology Boston, Massachusetts, United States
Disclosure(s): No financial relationships to disclose
Disclosure(s):
Amitava Mitra, PhD: No financial relationships to disclose
Oncogenic mutations in HRAS and PI3K have been reported in HNSCC. Overactive crosstalk between HRAS and PI3K pathways is known to sustain tumor survival signaling. Using a QSP model, we evaluated the dual inhibition of HRAS and PI3K as a treatment option for recurrent/metastatic HNSCC patients with several genotypes such as PIK3CA mutant, PIK3CA amplified, HRAS overexpressed. The logic-gated QSP model was calibrated using preclinical in-vitro cell signaling and mouse xenograft data. Finally, translation was done to human QSP model using clinical tumor response data from HNSCC patients treated with tipifarnib monotherapy and alpelisib monotherapy. In this case study details of the model development and verification will be presented. The case study will then discuss the applications of the model to characterize the tumor response to the combination therapy and guide dose optimization for phase 2 study.
