The oral WEE1 inhibitor adavosertib (AZD1775) has demonstrated meaningful antitumor activity in patients with recurrent or persistent uterine serous carcinoma (USC), according to findings from the phase 2b ADAGIO trial (NCT04590248). However, significant tolerability issues may limit its clinical utility in its current formulation.
Among 104 evaluable patients, adavosertib achieved an objective response rate (ORR) of 26.0% per blinded independent central review (BICR), including one complete response and 26 partial responses. The median duration of response was 4.7 months (95% CI, 3.8-8.3), and median progression-free survival (PFS) reached 2.8 months (95% CI, 2.6-3.9).
"The scientific rationale for exploring WEE1 inhibition as a potential treatment target for uterine serous carcinoma remains of interest, despite the narrow therapeutic window for adavosertib," noted Dr. Joyce F. Liu of Dana-Farber Cancer Center and colleagues in their publication in the Journal of Clinical Oncology.
Disease Context and Unmet Need
Uterine serous carcinoma represents a particularly aggressive subtype of endometrial cancer. While USC accounts for a relatively small proportion of endometrial cancer cases, it is responsible for a disproportionately high number of relapses and cancer-related deaths, highlighting the urgent need for effective treatment options.
The ADAGIO trial enrolled patients aged 18 years and older with histologically confirmed recurrent or persistent USC who had previously received at least one platinum-based chemotherapy regimen. The study population was heavily pretreated, with a median of three prior lines of therapy (range, 0-8).
Treatment Protocol and Safety Profile
Adavosertib was administered at a dose of 300 mg once daily on days 1-5 and 8-12 of 21-day cycles. This dosing regimen, however, proved challenging for many patients.
Treatment-related adverse events (TRAEs) occurred in 97.2% of patients, with the most common being diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). Grade 3 or higher TRAEs affected 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) being the most frequent severe events.
The safety challenges led to dose reductions in 60.6% of patients and treatment interruptions in 76.1%. Ultimately, 17.4% of patients discontinued adavosertib due to adverse events. Four patients (3.7%) died from adverse events, including sepsis (n=2), cardiac disorder (n=1), and respiratory failure (n=1).
Efficacy Across Patient Subgroups
The ADAGIO trial also examined efficacy in various patient subgroups. In patients previously treated with PD-1/PD-L1 inhibitors, the ORR was 17.9%, compared to 28.9% in those who were naive to these immunotherapies. The median duration of response was 5.0 months (95% CI, 4.4-not calculated) in the PD-1/PD-L1 pretreated group versus 4.2 months (95% CI, 3.2-not calculated) in the naive group.
At the 6-month mark, 11 patients (18.1%) remained progression-free. The median overall survival was 9.6 months, with 6-month and 12-month survival rates of 73.0% and 46.8%, respectively.
Biomarker Analysis and Future Directions
Exploratory biomarker studies conducted as part of the ADAGIO trial sought to identify factors that might predict response to adavosertib. While no single predictive alteration was definitively identified, there was a trend suggesting that CCNE1 amplification or high cyclin E1 protein expression could be associated with better response to WEE1 inhibition in USC.
"This finding warrants further investigation in future studies," the researchers noted. "Future studies could explore combination therapies or alternative dosing schedules to improve the balance between efficacy and safety."
Clinical Implications
The ADAGIO results build upon a previous phase 2 study (NCT03668340) that showed a 29.4% ORR with adavosertib monotherapy in recurrent USC. The consistent activity across studies reinforces the potential of targeting the WEE1 pathway in this difficult-to-treat cancer.
However, the significant toxicity profile presents a substantial challenge to clinical implementation. The high rates of dose modifications and treatment discontinuations suggest that alternative dosing strategies or combination approaches may be necessary to optimize the therapeutic window.
For patients with USC, who face limited treatment options after progression on platinum-based chemotherapy, these findings represent both promise and challenge. While adavosertib demonstrates meaningful activity in a subset of patients, improving its tolerability profile will be crucial for advancing this therapeutic approach in clinical practice.
