Tolerability Hinders Adavosertib Activity in Recurrent or Persistent Uterine Serous Carcinoma

Treatment with the oral, small-molecule Wee1 kinase inhibitor adavosertib was clinically active but not well tolerated in patients with recurrent or persistent uterine serous carcinoma who previously received platinum-based chemotherapy, according to findings from the single-arm phase 2b ADAGIO trial (NCT04590248) presented at the 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.¹

The results demonstrated that the objective response rate (ORR) was 26.0% (95% CI, 17.9%-35.5%) in evaluable patients in the full analysis set (n = 104). Most patients experienced partial response (25.0%). Stable disease and progressive disease occurred in 40.4% and 26.9% of patients, respectively, leading to a disease control rate (DCR) of 51.4% (95% CI, 41.6%-61.1%). The median duration of response (DOR) was 4.7 months (95% CI, 3.8-8.3).

“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,” lead study author Joyce F. Liu, MD, associate chief and director of clinical research in the Division of Gynecologic Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, said in a presentation of the data.

Uterine serous cancer is an aggressive subtype of endometrial cancer, with 5-year survival rates that fall between 35% and 50% for patients with stage I/II disease and 0% and 15% for those with stage III/IV disease. Moreover, the disease accounts for 40% of all endometrial cancer–associated deaths despite representing less than 10% of all cases of endometrial cancer.

Oncogenic mutations and amplifications of the disease can increase replication stress, sensitizing the tumor to inference of cell cycle regulation by Wee1 inhibition. In a prior phase 2 study (NCT03668340), adavosertib demonstrated clinical activity in this population, with an ORR of 29.4% (95% CI, 15.1%-47.5%) and a 6-month progression-free survival (PFS) rate of 47.1% (95% CI, 29.8%-64.9%).²

The phase 2b study enrolled fit women (ECOG performance status of 0 or 1) at least 18 years of age with histologically confirmed recurrent or persistent uterine cancer and evidence of measurable disease per RECIST v1.1 criteria. Prior treatment with at least 1 platinum-based chemotherapy was required, and prior exposure to checkpoint inhibitors, VEGF inhibitors, and HER2-directed therapy was permitted. Notably, local confirmation of disease was required for study entry and was followed by central confirmation.

Eligible patients received 300 mg of oral adavosertib once daily on days 1 through 5 and 8 through 12 every 21 days. Treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

The primary end point of the study was blinded independent centrally reviewed ORR per RECIST v1.1 criteria. Secondary end points included DOR, PFS, depth of response, overall survival (OS), DCR, safety and tolerability, and pharmacokinetics. 

The study enrolled 144 patients. Due to screening failure (n = 35), 109 patients received treatment, comprising the full analysis set. Nineteen patients did not meet the definition of uterine serous carcinoma, leaving 90 patients for inclusion in the centrally confirmed analysis set. At data cut off, May 23, 2022, 7 patients were still receiving treatment.

Treatment discontinuation occurred primarily because of disease progression (n = 64), followed by adverse effects ([AEs] n = 19), participant decision (n = 10), investigator decision (n = 2), death (n = 1), or other (n = 6).

Regarding baseline characteristics, the median patient age was 68.8 years (standard deviation [SD], 7.1), and most patients were White (84.4%) and had pure serous histology (77.1%). Mean body mass index was 29.6 kg/m2 (SD, 7.7) and median number of prior lines of therapy was 3 (range, 0-8). Performance status was split between 0 (46.8%) and 1 (53.2%). Regarding prior therapy, all patients had received platinum-based chemotherapy, 98.2% had taxanes, 28.4% had PD-(L)1 inhibitors, and 17.4% had other therapies.

Median PFS, which was performed at a median follow-up of 2.7 months (range, 0.0-13.2), was 2.8 months (95% CI, 2.6-3.9). The 6- and 12-month PFS rates were 18.1% (95% CI, 10.4%-27.6%) and not calculable (NC), respectively. Median OS was 9.6 months (95% CI, 8.3-NC). The 6- and 12-month OS rates were 73.0% (95% CI, 63.4%-80.5%) and 46.8% (95% CI, 34.7%-58.1%), respectively. 

An analysis by PD-(L)1 inhibitor status was also performed. In the population of patients who had previously received this treatment (n = 31), the ORR was 17.9%. Median DOR, PFS, and OS were 5.0 months (95% CI, 4.4-NC), 2.8 months (95% CI, 1.4-3.5), and 8.7 months (95% CI, 6.4-NC), respectively. Patients who had not had prior exposure to PD-(L)1 inhibitors (n = 78) achieved an ORR of 28.9%. Median DOR, PFS, and OS in this population were 4.2 months (95% CI, 3.2-NC), 3.4 months (95% CI, 2.6-4.2), and 11.4 months (95% CI, 8.3-NC), respectively.

Regarding safety, grade 3 or greater treatment-related AEs (TRAEs) occurred in 60.6% of patients. AEs leading adavosertib dose reduction, interruption, or discontinuation occurred in 55.0%, 56.9%, and 14.7% of patients, respectively.

The most common AEs leading to dose reduction were anemia (11.0%), nausea (11.0%), and fatigue (10.1%). The most common AEs leading to dose interruption were fatigue (13.8%) and asthenia (11.9%). Other reported any-grade TRAEs included diarrhea (59.6%), anemia (58.7%), constipation (11.9%), vomiting (33.0%), neutropenia (27.5%), abdominal pain (13.8%), and thrombocytopenia (22.9%).

Serious AEs were reported in 26.6% of patients, and AEs leading to death occurred in 1 patient.

“The most common treatment-related serous AEs were neutropenia [grade 2, n = 1; grade 4, n = 7] and sepsis [grade 4, n = 4; grade 5, n = 1],” Liu said. Serious TRAEs of vomiting and diarrhea were also recorded (grade 2, n = 1; grade 3, n = 3 and grade 3, n = 3, respectively).

Disclosures: Dr Liu reports being in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, and Regeneron; and receiving 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.

References

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. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28; Tampa, Florida. Abstract 219.
2. Liu JF, Xiong N, Campos SM, et al. Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous carcinoma. J Clin Oncol. 2021;39(14):1531-1539. doi:10.1200/JCO.20.03167