Uterine Serous Carcinoma Responds to the WEE1 Inhibitor Adavosertib

Uterine serous carcinoma (USC), an aggressive form of endometrial cancer for which effective treatments are lacking, is often characterized by signs of cell-cycle dysregulation and DNA replication stress. Noting that the serine/threonine kinase WEE1 is an important regulator of the G₂–M checkpoint and is involved in the response to DNA single- or double-strand breaks, Liu and colleagues conducted a phase II single-arm clinical trial of the WEE1 inhibitor adavosertib in 35 patients with recurrent or persistent USC. Among the 34 patients whose disease was evaluable for response (one patient withdrew due to personal reasons not related to adverse events), the median progression-free survival was 6.1 months and the overall response rate was 29.4% (10 patients), with one patient (3%) having a complete response and nine patients (26%) having partial responses. Of the ten patients whose disease responded to adavosertib treatment, the median duration of response was 9.0 months; additionally, seven patients (21%) had stable disease for at least six months. As expected based on prior studies, hematologic abnormalities were common, with anemia, low platelet count, or low neutrophil count arising in 67.6%, 17.6%, or 32.4% of patients, respectively. Other than hematologic abnormalities, the most common treatment-emergent adverse events were gastrointestinal or constitutional, including diarrhea, fatigue, nausea, vomiting, and anorexia. Interestingly, although the proposed mechanism for adavosertib suggests that tumors with mutations affecting cell-cycle regulation or the DNA damage response should be more sensitive to the drug, an exploratory biomarker analysis found no statistically significant association between response and aberrations affecting the genes encoding p53, KRAS, CCNE1, MYC, PIK3CA, or HER2. In summary, the results of this trial provide support for continued investigation of adavosertib in USC; in particular, further investigation to find biomarkers of response may prove fruitful.

Liu JF, Xiong N, Campos SM, Wright AA, Krasner C, Schumer S, et al. Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous carcinoma. J Clin Oncol 2021 Mar 11 [Epub ahead of print].

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