Targeted Agent Demonstrates Strong Activity in Uterine Serous Carcinoma

A WEE1-targeted therapy, adavosertib (AZD1775), demonstrated durable antitumor activity in treating patients with recurrent uterine serous carcinoma (USC), according to preliminary results from a phase II trial.^1,2

“Adavosertib demonstrated promising preliminary clinical activity in [patients with] unselected uterine serous cancer,” Joyce F. Liu, MD, MPH, a medical oncologist at Dana-Farber Cancer Institute, said when presenting findings from the phase II trial in a webinar for the virtual 2020 Society of Gynecologic Oncology (SGO) Annual Meeting.

Adavosertib monotherapy was hypothesized to have clinical efficacy in USC due to the high frequency of TP53 mutations in USC tumors, the frequent loss and dysregulation of the G1/S cell cycle checkpoint, and the presence of oncogene-driven replication stress. When there is loss of the G1/S checkpoint, there is an increased dependence on the G2/M checkpoint, which is regulated by WEE1, Liu explained. If that checkpoint is blocked, it leads to the accumulation of significant DNA damage, causing the cancer cells to die off.^1,3 The single-arm, 2-stage study was initiated to assess this hypothesis.

The study design dictated that if 2 or more responses were seen in the first 16 patients, or a progression-free survival of ≥6 months (PFS6), an additional 19 patients could be enrolled. In the second stage, a minimum of 4 events were needed to reject the null hypothesis for the objective response rate (ORR) co-primary end point, and 8 for the PFS6 end point.

Eligible patients had histologically or cytologically confirmed recurrent or persistent USC, excluding carcinosarcomas. Prior treatment was allowed with at least 1 platinum-based chemotherapy for advanced or metastatic disease, and immune checkpoint inhibition in the case of mismatch repair deficiency or microsatellite instability–high disease.

Patients in the trial received 300 mg of adavosertib daily for days 1 to 5 and 8 to 12 of a 21-day cycle.

A total of 35 patients were enrolled with 34 evaluable for response after a median follow-up of 3.84 months. Participants had a median age of 70.2 years (range, 58.9-88.5) and had received a median of 3 prior lines of therapy (range, 1-8).

The ORR was 29.4%, consisting of all partial responses, and an additional 8.8% of patients had stable disease for at least 6 months.

The median duration of response was 6.21 months and the median PFS was 6.01 months, with a PFS rate of 55.6% at 6 months, although the complete PFS6 data were not yet mature. Liu noted that 1 patient was still on therapy for more than 12 months as of data cutoff.

The most common treatment-related adverse events (TRAEs) included diarrhea (76.5%), nausea (55.9%), anemia (55.9%), fatigue (55.9%), platelet count decrease (47.1%), and neutrophil count decrease (44.1%). Grade ≥3 TRAEs included neutrophil count decrease (32.4%), anemia (20.6%), fatigue (17.6%), and platelet count decrease (14.7%) most frequently. These were typically managed with dose interruption or dose reductions, Liu noted.

“[The findings are] especially encouraging in a disease such as USC, for which current treatments are of limited effectiveness,” Liu said in a statement prior to the presentation.

_References:

_{1. Liu JF. A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. SGO webinar published on April 23, 2020. https://bit.ly/2Kwn33c. Accessed April 24, 2020.}

_{2. Liu JF, Tayob N, Campos SM, et al. A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. Presented at: Society of Gynecologic Oncology Annual Meeting. Abstract 7.}

_{3. New targeted agent produces considerable responses in trial with patients with uterine serous carcinoma [news release]. Boston, MA: Dana-Farber Cancer Institute; April 23, 2020. https://bit.ly/3bCfpA6. Accessed April 24, 2020.}