Wee KINASE INHIBITOR FOR SEROUS CARCINOMA?

The experimental agent adavosertib showed hints of efficacy against recurrent uterine serous carcinoma in early data from a phase 2 trial.

The overall response rate among 21 patients with advanced uterine serous carcinoma treated with adavosertib monotherapy was 30%, and an additional patient had an unconfirmed response at the time of data cutoff, reported Joyce F. Liu, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.

"These results were noteworthy for the preliminary response rate of 30% that was observed in the first cohort of patients on this study, especially as, on average, patients on this study had received three prior treatments for their cancer. For us, this was an exciting signal of activity, especially for a targeted therapy used by itself in this type of cancer," Dr. Liu said in an interview.

Preliminary results of the phase 2 trial were published in an abstract that had been slated for presentation at the Society of Gynecologic Oncology's Annual Meeting on Women's Cancer. The meeting was canceled because of the COVID-19 pandemic.

Adavosertib is a small molecule that inhibits the Wee1 kinase, a “gatekeeper” of the G2-M cell cycle checkpoint that is highly expressed and active in several types of cancer.

"Molecular characterization of these cancers has demonstrated that they have frequent p53 mutations as well as significant alterations in oncogenes," Dr. Liu said. "These characteristics mean that these are cancers that may both have significant dysregulation of their cell cycle combined with high levels of replication stress. We hypothesized that these cancers could therefore be particularly vulnerable to further dysregulation of the cell cycle, which can be mediated by a drug such as adavosertib, which interrupts regulation of the G2-M cell cycle checkpoint by inhibiting the protein Wee1."

Study details

The study enrolled women with recurrent uterine serous carcinoma. Patients were eligible if any disease component was considered to be serous, except for carcinosarcomas. The patients had a minimum of one prior platinum-based chemotherapy regimen (median 3, range 1-7), with no upper limit on prior lines of therapy required for eligibility.

Patients with microsatellite high/deficient mismatch repair disease had to have received prior therapy with programmed death-1/ligand-1 inhibitor, or to have been deemed ineligible for immunotherapy with a checkpoint inhibitor.

The patients received adavosertib at 300 mg daily on days 1 through 5 and days 8 through 12 of each 21-day cycle.

The trial would be considered successful if at least of 4 of 35 patients planned for accrual had a confirmed response or if 8 patients were progression free at 6 months. The coprimary endpoints are overall response rate of 20% or more, or a progression-free survival rate at 6 months of 30% or more.

Results and next steps

As of Aug. 20, 2019, the investigators had enrolled 27 patients, of whom 21 were evaluable for response.

The overall response rate was 30%, consisting of six confirmed partial responses. One additional patient had an unconfirmed response. Eleven of the 21 patients had stable disease, and 3 had disease progression.

Eleven patients remained on treatment with adavosertib at the time of data cutoff. Progression-free survival data were not mature.

The most frequent adverse events included anemia and diarrhea in 67% of patients each, nausea in 58%, and fatigue in 50%.

Frequent grade 3 or higher adverse effects included anemia, neutropenia, and syncope, all occurring in 21% of patients.

Dr. Liu said the investigators plan to present updated data from the study at a future meeting.

"We are planning additional cohorts in this study that will allow us to more deeply investigate why certain uterine serous cancer patients had very good responses to adavosertib and to identify potential biomarkers of response," she said.

"Additionally, we plan to investigate whether adavosertib has similar activity in another type of uterine cancer, uterine carcinosarcoma, that shares many similar molecular characteristics with uterine serous carcinoma, including p53 mutations and oncogenic alterations, that might make it similarly vulnerable to targeting Wee1," she said.

Dr. Liu disclosed ties with AstraZeneca, which supported the trial, as well as Merck and other companies.

SOURCE: Liu JF et al. SGO 2020, Abstract 7.