In a clinical trial in patients with recurrent uterine serous carcinoma, one-third of study participants responded to treatment with the Wee1 inhibitor adavosertib, according to data presented by Liu et al at a virtual session of the Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer (Abstract 7).
Mechanism of Action of Adavosertib
Uterine serous carcinoma accounts for about 10% of uterine cancers but up to 40% of deaths from the disease, explained the trial leaders. Adavosertib takes advantage of an inherent weakness in the relentless growth of some cancer cells, and uterine serous carcinoma is one such cancer. More than 90% of cases are marked by a mutation or other abnormality in the TP53 gene, which plays a critical role in the checkpoint between the first phase of cell growth and the DNA duplication phase. The absence of functional TP53 places strain on a checkpoint further on in the cell cycle called G2/M. Providing a final quality check, G2/M guards the entry to mitosis. Hobbling G2/M by blocking one of the proteins involved in it could burden tumor cells with so much DNA damage that they cannot survive. That is the strategy behind adavosertib, which targets a protein called Wee1 that helps regulate the G2/M checkpoint. The new trial marked the first time the drug, which has been tested in patients with other cancers (including breast and ovarian cancer), was tested in patients with uterine serous carcinoma.
Methods
The trial involved 35 patients, all of whom had previously been treated with platinum-based chemotherapy. Those with microsatellite instability–high/mismatch repair–deficient disease were required to have already received prior therapy with a programmed cell death 1/programmed cell death ligand 1 therapy or to be ineligible for such therapy. Patients received 300 mg of adavosertib daily on days 1 through 5 and 8 through 12 of a 21-day cycle.
“Adavosertib demonstrated remarkable activity as a single agent in this group of patients. It’s especially encouraging in a disease such as uterine serous carcinoma, for which current treatments are of limited effectiveness.”— Joyce Liu, MD, MPH
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Results
At a median follow-up of 3.8 months, 10 of 34 patients who could be evaluated had a confirmed response—a response rate of almost 30%. In some cases, the responses were exceptionally durable, with some patients still responding more than a year after undergoing treatment, presenters explained.
The most common adverse side effects of the treatment were anemia, diarrhea, nausea, and fatigue.
“Adavosertib demonstrated remarkable activity as a single agent in this group of patients,” said the study’s lead author, Joyce Liu, MD, MPH, of Dana-Farber Cancer Institute. “It’s especially encouraging in a disease such as uterine serous carcinoma, for which current treatments are of limited effectiveness.”
The study authors concluded, “Adavosertib monotherapy demonstrated clinical activity in women with uterine serous carcinoma, with a preliminary response rate of 30%. Further studies in this patient population are warranted.”
Disclosure: For full disclosures of the study authors, visit sgo.confex.com.
