The phase IIb ADAGIO trial has revealed that the Wee1 inhibitor adavosertib shows limited efficacy with high toxicity rates in patients with recurrent or persistent uterine serous carcinoma, according to findings published in the Journal of Clinical Oncology by Liu et al.
The international study evaluated 104 patients who had previously received platinum-based chemotherapy, enrolled from clinical sites across Canada, France, Germany, Italy, Spain, and the United States between December 2020 and November 2021. Participants received adavosertib at a dose of 300 mg once daily on days 1 to 5 and 8 to 12 of 21-day cycles, with objective response assessed by blinded independent central review as the primary endpoint.
Efficacy Results Show Modest Activity
Among the 104 evaluable patients, objective responses were observed in 27 patients (26.0%, 95% confidence interval [CI] = 17.9%–35.5%), with only one patient achieving a complete response. The median duration of response was 4.7 months (95% CI = 3.8–8.3 months), while the median progression-free survival was limited to 2.8 months (95% CI = 2.6–3.9 months).
Dr. Joyce F. Liu, MD, MPH, of the Department of Medical Oncology at Dana-Farber Cancer Institute and corresponding author of the study, noted that while the drug showed some antitumor activity, the results were tempered by tolerability concerns.
Safety Profile Raises Concerns
Treatment-related adverse events were nearly universal, affecting 97.2% of patients. The most common side effects included diarrhea and nausea (both 59.6%) and anemia (58.7%). More concerning was the high rate of grade 3 or higher treatment-related adverse events, reported in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) being the most frequent serious toxicities.
The safety profile ultimately led to treatment discontinuation in 14.7% of patients, highlighting significant tolerability challenges with the current dosing regimen of 300 mg once daily.
Biomarker Analysis Provides Future Direction
An exploratory biomarker analysis conducted on archival tissue from 77 patients yielded potentially valuable insights for future drug development. While no single alteration definitively predicted response to adavosertib, researchers observed trends toward higher likelihood of response associated with CCNE1 amplification (40%) and high cyclin E1 protein expression (32%).
"Exploratory biomarker studies suggest CCNE1/cyclin E1 expression may enrich for response to Wee1 inhibition in uterine serous carcinoma," the investigators concluded in their report.
Implications for Future Development
Although adavosertib is no longer under clinical development, the findings from the ADAGIO trial may inform the development of other Wee1 inhibitors. The identification of potential biomarkers of response could help guide patient selection in future trials, potentially improving the therapeutic index of this drug class.
Uterine serous carcinoma represents an aggressive subtype of endometrial cancer with limited treatment options after progression on platinum-based chemotherapy. The ADAGIO results underscore the continued need for novel therapeutic approaches for this challenging malignancy, while suggesting that alternative dosing strategies or more selective patient populations might be necessary to optimize the benefit-risk profile of Wee1 inhibition in this setting.
