Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification
Year: 2022
Type: article
Study design: Clinical Trial
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.
Source: Journal of Clinical Oncology
DOI: 10.1200/jco.22.00830
Authors: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard D. Carvajal, Thomas J. George, Ying Yuan, Lihou Yu, Shannon N. Westin, Yan Xing, Ecaterina E. Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Naoko Takebe, Karen Lu, Khandan Keyomarsi, Funda Meric-Bernstam
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Abbott Laboratories, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Cancer Prevention and Research Institute of Texas, Gilead Sciences, American Society of Clinical Oncology, Spectrum Pharmaceuticals, Celgene, Karyopharm Therapeutics, Array BioPharma, Regeneron Pharmaceuticals, Taiho Pharmaceutical, Novocure, Astex Pharmaceuticals, Gateway Foundation, Clovis Oncology, Parker Institute for Cancer Immunotherapy, Five Prime Therapeutics, Jounce Therapeutics, Mersana Therapeutics, Mirati Therapeutics, BeiGene, Incyte, Calithera Biosciences, Innovent Biologics, F-star Therapeutics, Puma Biotechnology, Silverback Therapeutics, MacroGenics, Eisai, Astellas Pharma, European Society for Medical Oncology, Ipsen, Symphogen, Plexxikon, Sumitomo Dainippon Pharma Oncology, Mereo BioPharma, National Institutes of Health, Genentech, University of Texas MD Anderson Cancer Center, Chugai Pharmaceutical, National Cancer Institute, Daiichi Sankyo Europe
Awards: Rational Combination Treatment Options to Reverse Resistance in Hormone Receptor-Positive Breast Cancer Refractory to Standard Therapy, G111615301, Cytoplasmic cyclin E is an early event for progression to invasive breast cancer, G2476449515, G3565137481, G4311554571, G4758135352, G5151509852, G5964914971, G644256362, G6703021058, G9000169148, Phase 1 and 2 Molecular and Clinical Pharmacodynamic Trials ETCTN, Cancer Center Support Grant
OpenAlex ID: W4311203085