The oral, small-molecule Wee1 kinase inhibitor adavosertib was clinically active but not well tolerated by more than half the patients with recurrent or persistent uterine serous carcinoma in the phase IIb ADAGIO trial. The findings were reported at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer by Joyce F. Liu, MD, MPH, Associate Chief and Director of Clinical Research, Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston.¹

“Overall, our findings indicate that while Wee1 inhibition results in antitumor activity and may remain a viable treatment target, the therapeutic window for adavosertib is narrow. Adavosertib dosed at 300 mg daily was not well tolerated, despite toxicity management, in this heavily pretreated population,” Dr. Liu commented.

The objective response rate in this population of patients previously treated with platinum-based chemotherapy was 26.0% in the full analysis set of 104 evaluable patients and 28% in the centrally confirmed analysis set of 85 evaluable patients; almost all were partial responses. The disease control rates were 51.4% and 50.0%, respectively, and the median duration of response was 4.7 months in each analysis, Dr. Liu reported.

Joyce F. Liu, MD, MPH

In the discussion period, Dr. Liu said that, anecdotally, there were several patients who might have achieved a longer response but came off study, perhaps because of toxicity. She does not think we have enough information to know whether the overall short duration of response could be attributed completely to treatment resistance since a prior study reported a median duration of response to be 9 months.

“There are patients who will have deep and prolonged responses, but then there are patients who don’t seem to get that level of benefit…. I don’t think we can fully understand why based on ADAGIO alone. I think there were a lot of complicating factors…, and that’s where having biomarkers will be important,” she said.

Need for Better Treatment

Uterine serous cancer is an aggressive subtype of endometrial cancer, with 5-year survival rates of between 35% and 50% for patients with stage I/II disease and between 0% and 15% for the later stages. Although it represents just 10% of endometrial cancers, uterine serous cancer accounts for 40% of all deaths associated with endometrial cancer. Oncogenic mutations and molecular alterations leading to cell cycle dysregulation can increase replication stress, sensitizing the tumor to further interference of cell-
cycle regulation by Wee1 inhibition with drugs like adavosertib, Dr. Liu explained.

ADAGIO Details

Adavosertib was evaluated in this single-arm trial of 144 patients, of whom 109 were treated and constituted the full analysis set and 90 were included in the centrally confirmed analysis set. Many patients (77%) had pure serous histology. Median lines of therapy were three; essentially, all patients had received both a platinum compound and a taxane, 28% had received a checkpoint inhibitor, and a number of patients received additional agents.

Patients received oral adavosertib at 300 mg/d on days 1 through 5 and then 8 through 12 every 21 days, until disease progression or unacceptable toxicity. The study’s primary endpoint was objective response rate by blinded independent central review. 

At a median follow-up of 2.7 months, median progression-free survival was 2.8 months; the progression-free survival rate at 6 months was 18.1% and was not calculable at 12 months. Median overall survival was 9.6 months, with 6- and 12-month survival rates of 73.0% and 46.8%, respectively.

An analysis by prior treatment revealed responses in 17.9% of patients previously treated with immunotherapy and 28.9% in those without. Median overall survival in these subsets was 8.7 months vs 11.4 months, respectively, Dr. Liu reported.

Safety Concerns

Although adavosertib showed antitumor activity, it also presented safety concerns. Grade ≥ 3 treatment-related adverse events were observed in 60.6% of patients and led to treatment discontinuation in 14.7%. More than 50% of patients required dose reductions and/or interruptions of adavosertib.

The most common grade ≥ 3 treatment-related toxicities were neutropenia (21.1%), fatigue (13.8%), diarrhea (8.3%), anemia (8.3%), and thrombocytopenia (8.3%). Those of any grade were most commonly diarrhea (59.6%), anemia (58.7%), nausea (59.6%), asthenia (38.5%), fatigue (39.4%), and vomiting (33.0%). There were several grade 4 toxicities, including neutropenia (6.4%) and sepsis (3.7%). One death from neutropenic sepsis was possibly related to treatment.

“There was a lot of toxicity on this trial and a very narrow therapeutic window. Although the majority of patients discontinued treatment because of disease progression, close to 40% discontinued treatment for other reasons, much of which was related to toxicity and management of safety issues that arose during the course of the trial,” Dr. Liu observed. 

DISCLOSURE: Dr. Liu has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, and Regeneron; and has received research funding from 2X Oncology, Acetylon Pharmaceuticals, Agenus, Aravive, Arch Oncology, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, CytomX Therapeutics, Genentech/Roche, Impact Therapeutics, Regeneron, Surface Oncology, Vigeo Therapeutics, and Zentalis.

REFERENCE

1. Liu JF, Colombo N, Oza A, et al: ADAGIO: A phase IIb, open-label, single-arm, multicenter study assessing the efficacy and safety of adavosertib (AZD1775) as treatment for recurrent or persistent uterine serous carcinoma. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Abstract 2019. Presented March 27, 2023.