Adavosertib monotherapy active in recurrent uterine serous carcinoma
Adavosertib demonstrated clinical activity among women with recurrent uterine serous carcinoma, according to results of a phase 2 study published in Journal of Clinical Oncology.
“Uterine serous carcinoma is a distinct histologic subtype of endometrial cancer that accounts for up to 40% of endometrial cancer deaths and for which effective therapies are limited,” Joyce F. Liu, MD, MPH, researcher in the department of medical oncology at Dana-Farber Cancer Institute, and colleagues wrote. “Molecular characterization of uterine serous carcinoma suggests the presence of concomitant cell-cycle dysregulation and high replication stress that might predict for increased sensitivity to Wee1 inhibition.”
The single-arm, two-stage study included 34 women (median age, 70.2 years; 85.3% white) with recurrent uterine serous carcinoma and a median three (range, 1-8) prior lines of therapy who received the oral Wee1 inhibitor adavosertib (AZD1775, AstraZeneca) at an initial dose of 300 mg once daily on the first 5 days and days 8 to 12 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity.
Objective response rate and 6-month PFS rate served as co-primary endpoints.
Median follow-up was 5.9 months (95% CI, 4-7.2).
Results showed 10 responses to treatment, including one confirmed complete response, eight confirmed partial responses and one unconfirmed partial response. This translated to an ORR of 29.4% (95% CI, 15.1-47.5).
Responses appeared durable, according to researchers, who reported a median duration of response of 9 months.
Sixteen women remained progression-free at 6 months, which corresponded to a PFS rate of 47.1% (95% CI, 29.8-64.9). Median PFS was 6.1 months (95% CI, 4.2-9.9).
More than half (61.8%) of women in the study experienced grade 3 or higher treatment-related adverse events.
Hematologic adverse events associated with adavosertib appeared common and included anemia (67.6%; grade 3, 23.5%), platelet count decrease (61.8%; grade 3, 17.6%) and neutrophil count decrease (44.1%; grade 3, 32.4%). Other common nonhematologic adverse events included diarrhea (76.5%), fatigue (64.7%) and nausea (61.8%).
Next-generation sequencing revealed that tumors of all 32 women with available archival specimens had a TP53 mutation, with 31% having evidence of amplification or gain in CCNE1. Moreover, 19% of tumors had alterations in KRAS and 41% in PIK3CA.
“This is the first report of clinical activity of a cell cycle or replication stress targeting agent in uterine serous carcinoma,” Liu and colleagues wrote. “These results warrant further exploration and validation; if confirmed, adavosertib monotherapy could represent a novel therapeutic option for women with uterine serous carcinoma.”
In an editorial accompanying the study, Ainhoa Madariaga, MD, and Amit M. Oza, MD, both researchers at Princess Margaret Cancer Center in Toronto, noted the challenges of fully mastering adavosertib, which builds on tumor-based drivers such as TP53 and inherent replication stress to cause mitotic catastrophe. They noted that the drug previously showed efficacy among women with ovarian cancer in single-arm and randomized trials.
“The current more subtle and elegant approach at improving therapy in uterine serous carcinoma by redefining chronic single-agent dosing strategies suggests a major therapeutic breakthrough and, if confirmed, will hopefully continue to navigate through a narrow therapeutic window with great effect,” Madariaga and Oza wrote. “There is much more to do, and racial differences and disparities that indicate poorer survival and higher rates of nonendometrioid endometrial cancer subtypes within Black women need to be addressed. Efforts should continue to include underrepresented populations in clinical trials striving for clinically meaningful, cost-effective and well-tolerated therapies.”