The small molecule inhibitor of tyrosine kinase WEE1 adavosertib demonstrated promising clinical activity in a single-arm, phase 2 study of patients with unselected uterine serous cancer (USC), with an objective response rate of 29.4%, said Joyce F. Liu, MD, MPH, Director of Clinical Research, Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, at the ASCO 2020 virtual annual meeting. The responses were durable, with a median duration of response of 9.03 months.
The median progression-free survival (PFS) of 34 evaluable patients who received treatment with adavosertib monotherapy was 6.14 months.
USC is a distinct histologic subtype of uterine cancer that comprises approximately 10% of endometrial cancer diagnoses but up to 40% of deaths associated with this cancer. The treatment options for USC are limited.
“We were specifically interested in the activity of adavosertib in USCs based upon the molecular characteristics of these tumors, which suggests that these cancers may have particular sensitivity to WEE1 inhibition,” said Dr Liu. “USCs display features suggesting the frequent presence of oncogene-driven replication stress, with Myc amplification in approximately 20% of tumors, as well as mutations and amplifications in KRAS, NRAS, and ERBB2.”
USC is also characterized by frequent loss and dysregulation of the G1/S checkpoint, with frequent p53 mutations in >90% of cases, as well as CCNE1 amplification approximately 25% of the time.
Adavosertib selectively inhibits WEE1 and may be most active in patients with p53 mutation. WEE1 is a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDK1) to inactivate the CDC2/cyclin B complex. Inhibiting the activity of WEE1 prevents the phosphorylation of CDC2 and impairs the G2/M checkpoint.
“P53-mutated cells hypothetically could be more sensitive to the loss of the G2/M checkpoint via WEE1 inhibition,” Dr Liu said.
Patients with histologically confirmed USC were enrolled in the investigator-initiated study and received treatment with adavosertib monotherapy in a dosing regimen of 30 mg daily on days 1 to 8 and 8 to 12 of a 21-day cycle. Imaging was conducted every 2 cycles for the first 6 cycles; thereafter, the interval could be extended to every 3 cycles per the investigator’s discretion. Eligibility criteria included having measurable disease and having received ≥1 previous lines of platinum-based chemotherapy for advanced or metastatic USC.
The first stage of the study enrolled 16 patients. If ≥2 responses were observed, an additional 19 patients were to be enrolled, for a total accrual of 35 patients. The patients received treatment until disease progression or discontinuation of therapy for other reasons.
Of the 35 women enrolled, 34 were evaluable. The patients’ median age was 70.2 years, and they had a median of 3 previous lines of therapy. The median follow-up was 5.9 months.
Of the 10 responses, 1 was a complete response and 9 partial responses. The clinical benefit rate, which includes stable disease for ≥6 months, was 50%.
The 6-month PFS rate with adavosertib treatment was 59.6%.
“The observed clinical activity was durable in many patients. Half of the patients remained on treatment for at least 6 months, with 2 patients still on treatment >12 months after starting study therapy,” Dr Liu noted.
There was no clear correlation between single-gene alterations and clinical outcomes, “and a biomarker to identify likely responders to adavosertib monotherapy is needed,” she said.
The most common adverse events associated with the use of adavosertib were diarrhea (85.3%), nausea (61.8%), anemia (64.7%), fatigue (64.7%), and decreases in platelet (55.9%) and neutrophil counts (44.1%). Most adverse events were grade 1 or 2, but adverse events frequently related to grade ≥3 included neutropenia (32.3%), anemia (23.5%), and fatigue (23.5%). Most adverse events reported by patients in the trial were managed with dose interruptions and dose reductions.
In all, 32.4% of patients required 1 dose reduction and 26.5% required 2 dose reductions. A total of 2 patients discontinued the study because of adverse events.