Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification

Abstract

PURPOSE Preclinical cancer models harboring CCNE1 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 CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 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). RESULTS 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. CONCLUSION Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.

CCNE1Amplification as a Therapeutic Target

“…[10][11][12] The tumors of patients who responded to adavosertib showed an enrichment for CCNE1 amplification. These observations form the basis of the study by Fu et al, 1 the first study to our knowledge to select patients on the basis of tumor CCNE1 amplification status. Amplification of CCNE1 is prevalent in multiple cancer types, including high-grade serous ovarian (HGSOC), gastroesophageal, and uterine serous cancers (USC), and is associated with poor prognosis.…”

“…10-12 The tumors of patients who responded to adavosertib showed an enrichment for CCNE1 amplification. These observations form the basis of the study by Fu et al, 1 the first study to our knowledge to select patients on the basis of tumor CCNE1 amplification status.…”

“…Other therapeutic strategies that similarly target replication stress have also been reported to be active against CCNE1-amplified tumors, such as ATR and PKMYT1 inhibitors that are also regulators of cell cycle checkpoints. [27][28][29] Notably, these agents all indirectly target CCNE1, and the modest response rate reported by Fu et al 1 indicates that other molecular alterations may be required to sensitize cells to drugs targeting replication stress. A more direct way of targeting CCNE1amplified tumors is CDK2 inhibition.…”

“…In the companion to this article, Fu et al 1 report the results from a phase II trial of adavosertib, a WEE1 kinase inhibitor, in CCNE1 -amplified solid tumors. Of the 27 patients evaluable, the overall response rate (ORR) was 27%, with a median duration of response of 2.1 months.…”

“…In summary, it is an important time in the targeting of CCNE1 -amplified tumors, as multiple novel strategies are emerging. The study by Fu et al 1 demonstrates that it is feasible to conduct studies using this biomarker. Other trials are following, accompanied by essential translational studies to better understand the pathway and hopefully improve outcomes for patients with these difficult-to-treat cancers.…”