Adavosertib Active in Uterine Cancer, But Tolerability Limits Use
The Wee1 inhibitor adavosertib shows activity in recurrent uterine serous carcinoma, but the drug’s tolerability remains a challenge.
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Adavosertib (AZD1775), an oral Wee1 inhibitor, exhibited some antitumor activity in patients with recurrent or persistent uterine serous carcinoma (USC); however, the treatment's tolerability presented challenges, impacting its overall effectiveness, according to findings from the phase 2b ADAGIO trial (NCT04590248).
The study's findings indicated an objective response rate (ORR) of 26.0% of 104 evaluable patients treated with adavosertib. Specifically, there was 1 complete response and 26 partial responses. Despite this, the median duration of response (DOR) was 4.7 months (95% CI, 3.8-8.3) and the median progression-free survival (PFS) was 2.8 months (95% CI, 2.6-3.9), highlighting the need for further improvements in treatment strategies.
ADAGIO also revealed significant challenges related to the tolerability of adavosertib. Most patients experienced treatment-related adverse events (TRAEs), and the most common included diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). More severe, grade ≥3 TRAEs occurred in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) being the most frequent. Notably, 17.4% of patients discontinued adavosertib treatment due to AEs.
“Nonetheless, the experience in ADAGIO suggests that, despite the narrow therapeutic window for adavosertib, the scientific rationale for exploring Wee1 inhibition as a potential treatment target for USC remains of interest,” Joyce F. Liu, MD, MPH, Dana-Farber Cancer Center, et al, wrote in the study published in the Journal of Clinical Oncology.
USC represents a significant challenge in gynecologic oncology. While it accounts for a smaller proportion of endometrial cancer cases, it is responsible for a disproportionately high number of relapses and cancer-related deaths. Given its aggressive nature, there is a pressing need to identify effective therapies for this subtype of endometrial cancer.
About ADAGIO
The ADAGIO trial enrolled patients aged 18 years and older with histologically confirmed recurrent/persistent USC who had previously received at least 1 platinum-based chemotherapy regimen. Patients were allowed to have received previous immune checkpoint inhibitors, vascular endothelial growth factor inhibitors, and human epidermal growth factor receptor 2-targeted therapies, and those with microsatellite instability-high or mismatch repair-deficient tumors were not eligible unless previously treated with a PD-1/PD-L1 immune checkpoint inhibitor. Patients were required to have an ECOG performance status of 0 or 1, adequate organ function, and normal bone marrow function.
Adavosertib was administered at a dose of 300 mg once daily on days 1 to 5 and 8 to 12 of a 21-day cycle. The study’s primary end point was ORR, and secondary end points included DOR, depth of response, PFS, overall survival, disease control rate, safety, and tolerability.
Exploratory biomarker studies conducted as part of the ADAGIO trial sought to identify factors that might predict response to adavosertib. Although 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 a better response to Wee1 inhibition in USC. This finding warrants further investigation in future studies.
While adavosertib demonstrates antitumor activity, its limited tolerability necessitates further research to optimize its use. Future studies could explore combination therapies or alternative dosing schedules to improve the balance between efficacy and safety, ultimately leading to better outcomes for patients with this aggressive cancer.
