Monotherapy with the experimental WEE1 inhibitor adavosertib has shown activity in patients with advanced recurrent or metastatic uterine serous carcinoma,1 according to data presented during the 2020 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer Webinar Series. The initial results of the phase II trial showed an overall response rate of 29.4% with adavosertib, despite patients having received a median of three prior treatments. Study authors called this signal of activity “especially noteworthy.”
“Uterine serous carcinoma is a disease that has limited treatment options, so I am excited about these trial results,” said Joyce Liu, MD, MPH, Assistant Professor of Medicine at Harvard Medical School and a medical oncologist at the Dana-Farber Cancer Institute, Boston. “Seeing patients with recurrent uterine serous cancer, which is a difficult-to-treat cancer, benefit from adavosertib monotherapy is gratifying.”
“Seeing patients with recurrent uterine serous cancer, which is a difficult-to-treat cancer, benefit from adavosertib monotherapy is gratifying.”— Joyce Liu, MD, MPH
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Uterine serous carcinoma is an aggressive subtype of endometrial carcinoma characterized by frequent TP53 mutations and significant alterations in oncogenes. Although uterine serous cancers represent approximately 10% of diagnoses in the United States, said Dr. Liu, they comprise up to 40% of deaths from uterine cancer. Moreover, available therapies for uterine cancer as a whole are relatively limited.
“We use carboplatin and paclitaxel with or without trastuzumab in the front-line setting, and the combination of pembrolizumab and lenvatinib was approved by the U.S. Food and Drug Administration this past year, but the remaining agents on the NCCN Compendium® have relatively limited activity,” stated Dr. Liu. She also noted that studies of doxorubicin and liposomal doxorubicin have shown response rates in the range of 10% to 15%.
Adavosertib is an experimental agent that inhibits the WEE1 kinase, a “gatekeeper” of the G2-M cell-cycle checkpoint. Dr. Liu and colleagues hypothesized that uterine serous carcinomas, which have significant dysregulation of their cell cycle, combined with high levels of replication stress, would be particularly vulnerable to inhibition of WEE1, which would promote further dysregulation of the cell cycle and increase in replication stress.
For this two-stage, single-arm, phase II study, investigators enrolled women with recurrent uterine serous carcinoma. Cancers with any component assessed as serous (with the exception of carcinosarcomas) were considered eligible for the study, and patients were required to have at least one prior platinum-based chemotherapy regimen. Patients received adavosertib at 300 mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle.
Clinical Activity and Safety Information
During the SGO webinar, Dr. Liu reported that 35 patients were enrolled on this study, with 34 evaluable for response. The median follow-up was 3.8 months, and the median number of prior lines was three. Of those evaluated, seven patients had confirmed responses, with three additional patients having an unconfirmed response.
“There was a 29% response rate, which was durable,” said Dr. Liu, who reported a duration of response of 6.2 months. “Our results showed that 38% of patients received clinical benefit, which was defined as progression-free survival of more than 6 months.”
Despite the promising activity, however, Dr. Liu noted that adavosertib monotherapy was associated with adverse events. The most frequently observed adverse events included diarrhea (82%), anemia (62%), nausea (62%), and fatigue (56%). Frequently observed grade 3 or higher adverse effects included neutropenia (32%), anemia (24%), and fatigue (18%).
“Adavosertib therapy definitely has toxicities, but they were mostly manageable with dose holds and dose reductions,” said Dr. Liu, who noted that just one patient discontinued treatment for adverse events. “We think it can still be combined with other therapies if dosing adjustments are made.”
Future Trials and Appropriate Sequencing
Before developing combinatorial strategies with adavosertib, however, Dr. Liu and colleagues are searching for biomarkers associated with some of the “profound and durable responses” observed with this monotherapy. The researchers are planning to open up additional cohorts on this trial, including one with carcinosarcomas and a translational biopsy trial.
“We’d like to understand the mechanism of action and activity of adavosertib as monotherapy in these cancers and hopefully identify which patients have tumors that will be particularly sensitive to the drug,” explained Dr. Liu. “We’d also like to study this agent in a broader population of patients with uterine serous carcinoma, including those who have had prior treatment with pembrolizumab and lenvatinib or with other immunotherapies.”
Dr. Liu noted that enrollment for the adavosertib trial occurred prior to approval of pembrolizumab and lenvatinib, which she would “definitely consider in the second-line setting for advanced mismatch repair–proficient uterine cancer.” Beyond that combination, however, there’s not a clearly defined option.
“We need to determine how active adavosertib will be in a population of patients who have received prior immune checkpoint therapy,” she concluded. “From a mechanistic perspective, however, there’s no clear reason to think that someone who has experienced disease progression through immunotherapy would develop resistance to adavosertib.”
DISCLOSURE: Dr. Liu has served as a consultant or advisor to Clovis Oncology, Genentech/Roche, GlaxoSmithKline, Mersana, Tesaro, and Regeneron; has received institutional research funding from 2X Oncology, Acetylon, Agenus, Aravive, Arch Oncology, AstraZeneca, Atara Biotherapeutics, Boston Biomedical, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, Genentech/Roche, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics; and has been reimbursed for travel, accommodations, or expenses by AstraZeneca and Merck.
1. Liu JF, Tayob N, Campos SN, et al: A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. 2020 SGO Annual Meeting on Women’s Cancer. Abstract 7. Presented March 28, 2020.
Discussant of the abstract on the WEE1 inhibitor adavosertib, Shannon N. Westin, MD, MPH, FACOG, Associate Professor and clinical investigator at The University of Texas MD Anderson Cancer Center, called the interaction between P53 and WEE1 an “opportunity for synthetic lethality.” She continued:...