Adavosertib promise in uterine serous carcinoma dimmed by side effects

The oral, small molecule Wee1 kinase inhibitor adavosertib exerts antitumour effects in patients with advanced recurrent or persistent uterine serous carcinoma (USC), but this benefit appears to be limited by the drug’s tolerability, as shown in the single-arm, phase IIb ADAGIO study.

The primary endpoint of blinded independent centrally reviewed objective response rate (ORR) with adavosertib was 26.0 percent (95 percent confidence interval [CI], 17.9–35.5), with a disease control rate (DCR) of 51.4 percent (95 percent CI, 41.6–61.1), according to principal investigator Dr Joyce Liu, from Dana-Farber Cancer Institute, Boston, Massachusetts, US, who presented their results at SGO 2023.

One patient achieved complete response, 26 had partial response, 42 had stable disease, 28 experienced disease progression, and seven were not evaluable. The median duration of response (DOR) was 4.7 months (95 percent CI, 3.8–8.3). [SGO 2023, abstract 219]

However, “[a]davosertib dosed at 300 mg daily was not well tolerated, despite toxicity management, in this heavily pretreated USC population,” Liu reported. “Discontinuation of adavosertib due to adverse events (AEs) occurred in 17 percent of patients,” with more than 50 percent requiring dose reductions and/or treatment interruptions during the study.

ADAGIO was a single-arm study conducted across six countries including Canada, France, Germany, Italy, Spain, and the US. The full analysis set included 109 patients (mean age 68.8 years, 84.4 percent White, mean body mass index 29.6 kg/m²) with recurrent or persistent USC treated with at least one platinum-based chemotherapy and evidence of measurable disease per RECIST v1.1 criteria. These patients were fit (ECOG performance status of 0 or 1) and had received a median of three prior lines of therapy.

All patients received oral adavosertib 300 mg once daily on days 1–5 and 8–12 of a 21-day cycle, with treatment administered until disease progression, unacceptable toxicity, or other discontinuation criteria were met, Liu said.

Of the enrolled patients, 19 did not meet the definition of USC, which left 90 patients for inclusion in the centrally confirmed analysis set. Only seven patients were still receiving treatment at data cutoff (23 May 2022).

“There were deep and sustained responses observed in some patients,” Liu noted. “Patients were able to remain on study treatment for a period of time, including some who were able to remain on study treatment for over a year.”

At a median follow-up of 2.7 months, the median progression-free survival (PFS) was 2.8 months (95 percent CI, 2.6–3.9). PFS rates at 6 and 12 months were 18.1 percent (95 percent CI, 10.4–27.6) and not calculable (NC), respectively. Meanwhile, the median overall survival (OS) was 9.6 months (95 percent CI, 8.3–NC), with respective 6- and 12-month OS rates of 73.0 percent (95 percent CI, 63.4–80.5) and 46.8 percent (95 percent CI, 34.7–58.1).

In a subgroup analysis, the activity of adavosertib slightly differed between patients who had vs had no prior exposure to PD-1 or PD-L1 inhibitor. ORR was 17.9 percent in the exposed group as opposed to 28.9 percent in the unexposed group. Median DOR was 5.0 vs 4.2 months, PFS was 2.8 vs 3.4 months, and OS was 8.7 vs 11.4 months, respectively.

Not so favourable safety profile

Liu noted that 75 patients (68.8 percent) had a grade 3 or higher AE, with AEs leading to adavosertib dose reduction in 62 (56.9 percent), dose interruption in 72 (66.1 percent), and death in four (3.7 percent).

“Diarrhoea, anaemia, and nausea were the most common AEs. This is consistent with what has been previously reported with adavosertib,” Liu said. “When we look at haematologic toxicities, there were anaemia, neutropenia, and thrombocytopenia in a number of patients, including grade 3 or higher events.”

Serious AEs were documented in 26.6 percent of patients, leading to death in one patient. Treatment-related serious AEs included neutropenia (grade 2, n=1; grade 4, n=7), sepsis (grade 4, n=4; grade 5, n=1), vomiting (grade 2, n=1; grade 3, n=3), and diarrhoea (grade 3, n=3).

“Overall, our findings indicate that while Wee1 inhibition results in antitumour activity and may remain a viable treatment target, the therapeutic window for adavosertib is narrow,” Liu said.