Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring <i>CCNE1</i> Amplification.

Abstract

Preclinical cancer models harboring <i>CCNE1</i> amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with <i>CCNE1</i>-amplified, advanced refractory solid tumors. Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring <i>CCNE1</i> amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring <i>CCNE1</i> amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in <i>CCNE1</i>-amplified epithelial ovarian cancer is warranted.