Adavosertib Is Safe and Efficacious in CCNE1-Amplified Solid Tumors

Cyclin E (encoded for by the CCNE1 gene) overexpression promotes genomic instability, with the kinase WEE1 preventing apoptosis in cyclin E–overexpressing cells. Use of adavosertib, a WEE1 inhibitor, reverses this phenotype and promotes cell death through mitotic catastrophe and unrepaired DNA damage. Cyclin E has been demonstrated to be predictive of response to adavosertib, supporting its use as a potential biomarker. Additionally, frequent amplification of CCNE1 is observed in many tumor types, and preclinical studies have indicated that cells with CCNE1 amplification were more sensitive to adavosertib treatment. In order to assess if adavosertib has antitumor activity in tumors harboring CCNE1 amplification, Fu and colleagues conducted a multicenter, phase II clinical trial in 30 patients with advanced refractory solid tumors that had histologically confirmed CCNE1 amplification. The primary objective of the study was objective response rate (ORR). Partial responses (PR) were seen in eight patients, with three patients having stable disease (SD). No complete responses were observed. The ORR was determined as 27%, with the overall median progression-free survival (PFS) being 4.1 months and the median overall survival (OS) being 9.9 months. In the 14 patients with ovarian cancer, the ORR was 36%, with five patients experiencing PRs and three having SD lasting at least 6 months. Moreover, patients with ovarian cancer had a median PFS of 6.3 months and a median OS of 14.9 months. Evaluation of toxicity showed 18 patients (60%) had grade 3 or higher treatment-related adverse events, including anemia, decreased neutrophil count, diarrhea, reduced platelet count, nausea, and fatigue. Biomarker exploration indicated concurrent TP53 gene aberrations in responders. In conclusion, the results of this study indicate that adavosertib is safe, with antitumor efficacy in CCNE1-amplified tumors, especially ovarian tumors, and suggest future trials involving this drug both alone and in combination with other therapeutic agents.

Fu S, Yao S, Yuan Y, Previs RA, Elias AD, Carvajal RD, et al. Multicenter phase II trial of the WEE1 inhibitor adavosertib in refractory solid tumors harboring CCNE1 amplification. J Clin Oncol 2022 Dec 5 [Epub ahead of print].

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