In a single-institution phase II trial reported in the Journal of Clinical Oncology, Joyce F. Liu, MD, MPH, and colleagues found that the WEE1 inhibitor adavosertib produced durable responses in women with recurrent uterine serous carcinoma.
The investigators stated, “Uterine serous carcinoma is a distinct histologic subtype of endometrial cancer, with molecular characteristics suggesting frequent cell-cycle dysregulation paired with a high level of oncogene-driven replication stress. Adavosertib is a potent and selective oral inhibitor of the WEE1 kinase, a key regulator of the G2/M and S phase cell-cycle checkpoints. Because cells with impaired cell-cycle regulation and high replication stress may be vulnerable to WEE1 inhibition, we conducted this study to assess the activity of adavosertib monotherapy in women with recurrent uterine serous carcinoma.”
Joyce F. Liu, MD, MPH
Study Details
In the study, 34 women seen at Dana-Farber Cancer Institute received oral adavosertib at a starting dose of 300 mg once daily on days 1 to 5 and days 8 to 12 in 21-day cycles until disease progression or unacceptable toxicity. The co-primary endpoints were objective response rate and progression-free survival at 6 months. It was predetermined that an objective response rate of ≥ 20% and a 6-month progression-free survival rate of ≥ 30% would warrant further investigation of the agent.
Objective Response and 6-Month Progression-Free Survival
Median follow-up at the time of the primary analysis was 5.9 months (95% confidence interval [CI] = 4.0–7.2 months). Among the 34 patients, objective response was observed in 10 (29.4%, 95% CI = 15.1%–47.5%), including complete response in 1 patient. Median duration of response was 9.0 months (95% CI = 5.3 months–not reached). An additional seven patients had stable disease for ≥ 6 months, yielding a clinical benefit rate of 50%.
A total of 16 patients were progression-free at 6 months, yielding a 6-month progression-free survival rate of 47.1% (95% CI = 29.8%–64.9%). Median progression-free survival was 6.1 months (95% CI = 4.21–9.92 months).
In an exploratory biomarker analysis, molecular characterization of specimens from 32 patients using next-generation sequencing yielded no significant associations of objective response or clinical benefit with specific molecular alterations.
KEY POINTS
- Objective response was achieved in 29.4% of patients (clinical benefit in 50%), with a median response duration of 9.0 months.
- 6-month progression-free survival was 47.1%.
Adverse Events
Treatment-related hematologic adverse events were common, including anemia in 67.6% of patients (grade ≥ 3 in 23.5%), decreased platelets in 61.8% (grade ≥ 3 in 17.6%), and decreased neutrophils in 44.1% (grade ≥ 3 in 32.4%).
Treatment-related nonhematologic adverse events of any grade included diarrhea in 76.5%; fatigue in 64.7%; nausea in 61.8%; vomiting in 35.3%; anorexia in 29.4%; and increased alanine transaminase and aspartate transaminase in 29.4% and 26.5%, respectively. Most nonhematologic adverse events were grade 1 or 2; the most common grade ≥ 3 event was fatigue (23.5%).
Overall, 26 patients (76.5%) required at least one dose hold, 11 (32.4%) required one dose reduction, 9 (26.5%) required two dose reductions, and 2 (5.9%) discontinued treatment due to adverse events.
The investigators concluded, “Adavosertib monotherapy demonstrated encouraging and durable evidence of activity in women with uterine serous carcinoma, and further investigation of this agent in this cancer and biomarkers of activity are indicated.”
Dr. Liu, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.
