A quantitative model‐based approach for adavosertib dose selection in patients with uterine serous carcinoma
Aims
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.
Methods
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.
Results
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.
Conclusion
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.