A quantitative model-based approach for adavosertib dose selection in patients with uterine serous carcinoma

Adavosertib, a WEE1 inhibitor, has been studied for safety and efficacy as monotherapy and in combination therapy. The phase 2b ADAGIO trial (NCT04590248) evaluated adavosertib monotherapy for uterine serous carcinoma with a recommended dose of 300 mg administered on days 1-5 and 8-12 of a 21-day cycle. However, reports of severe neutropaenia and dose reduction in approximately half of patients at 300 mg raised potential tolerability concerns.

We conducted a model-based benefit-risk analysis, including an exposure-safety analysis, pooling data from all AstraZeneca-sponsored monotherapy studies. Analysis focussed on the relationship between adavosertib exposure and incidence of adverse events (AEs) such as haematological and gastrointestinal toxicities. A preliminary exposure-efficacy analysis was conducted based on available efficacy data from the ADAGIO study.

A strong correlation was observed between adavosertib exposure and predicted probability of developing neutropaenia. In addition, baseline creatinine clearance (bCL_Cr) was identified as an independent factor for severe neutropaenia development. Patients with bCL_Cr ≥ 50 ml/min were less likely to experience severe neutropaenia than those with bCL_Cr < 50 ml/min. The model showed that a dose reduction from 300 to 250 mg reduced the predicted probability of neutropaenia by 55% when compared at the 95th percentile exposure range at these doses. Contrary to exposure safety, the exposure-efficacy relationship was similar across doses.

The approach identifies risk factors that can aid in the decision to use a 250-mg monotherapy dose. This regimen may manage haematological toxicities across studies. A quantitative model-based approach predicts that reducing adavosertib doses minimizes risks, underscoring the need for dose adjustment.