Phase 2 study of Wee1 inhibitor adavosertib in recurrent uterine carcinosarcoma

Uterine carcinosarcoma (UCS) is a rare but aggressive tumor with high rates of recurrence and poor prognosis, and novel therapies are urgently needed. P53 mutations are identified in over 90% of cases, and other cell cycle alterations are commonly found indicating potential vulnerability to Wee1 kinase inhibition. The purpose of this study was to determine the activity and safety of adavosertib, a Wee1 inhibitor, in recurrent or persistent UCS.

This was a phase II single-institution study of patients with persistent or recurrent UCS. Eligible patients had a confirmed TP53 alteration, RECIST measurable disease, and prior treatment with platinum based systemic therapy. Patients were treated with adavosertib at a starting dose of 300 mg orally once daily days 1-5 and 8-12 of a 21 day cycle until progression. The co-primary endpoints were objective response rate (ORR) and rate of progression-free survival (PFS) at 6 months. Molecular alterations were identified by targeted next generation sequencing where available.

9 patients enrolled prior to drug discontinuation by the sponsor. ORR was 22.2 % (95 % CI 2.8-60 %) with 2 partial responses. 3 patients (33.3 %) had stable disease. Median PFS was 2.7 months (95 % CI 0.9 - not reached). Treatment-related adverse events (all grades) occurred in 8 patients (88.9 %), most commonly diarrhea (77.8 %) and fatigue (66.7 %).

In this phase II trial of 9 patients with TP53-mutated UCS, adavosertib demonstrated limited activity. However, future studies of molecular alterations and combinatorial strategies continue to be of interest in UCS with limited treatment options.