Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Abstract 974: Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification
Ist Teil von
Cancer research (Chicago, Ill.), 2021-07, Vol.81 (13_Supplement), p.974-974
Erscheinungsjahr
2021
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Abstract
Background: Wee1 kinase, which prevents premature mitotic entry by inhibiting cyclin-dependent kinases (CDKs), may be essential when cyclin E1 is overexpressed in order to prevent DNA damage and cell death. In preclinical studies, cancer models harboring CCNE1 amplification are highly sensitive to treatment with adavosertib, a Wee1 kinase inhibitor. A multicenter phase 2 study was conducted to assess the antitumor activity of adavosertib in patients with CCNE1 amplified advanced refractory solid tumors.
Methods: Patients with advanced refractory solid tumors harboring CCNE1 amplification pre-identified in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. They had refractory disease, on standard options available, or they declined standard-of-care therapy. Eligible patients must be aged ≥ 18 years and had measurable disease per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and adequate organ functions. After informed consent, patients received adavosertib 300 mg daily on days 1 to 5 and 8 to 12 of a 21-day cycle. The primary endpoint was objective response rate (ORR). The trial employed Simon's two-stage design.
Results: Between January 22, 2019 and May 20, 2020, 29 patients with 12 tumor types were enrolled on study: ovarian = 14, breast = 3, endometrial = 2; and carcinosarcoma, cholangiocarcinoma, esophageal, gallbladder, germ cell tumor, melanoma, prostate, sarcoma, sarcomatoid and urothelial = 10 (1 each tumor). Median follow-up was 11.7 months. The median line of prior systemic therapy was 4 (range 1-8). Twenty-seven patients were evaluable for response. In these patients, 7 confirmed partial responses (PR) were observed, for an ORR of 25.9% (95% CI 15.1-47.5%). The median progression-free survival was 4.0 months and one-year overall survival was 55%. In 13 patients with measurable high-grade serous ovarian cancer, 5 achieved PR (38.5%) and 8 had stable disease ≥6 months/PR (61.5%). Other PRs were seen in 1 urothelial carcinoma and 1 melanoma. Fifteen patients experienced grade 3 or higher treatment-related adverse events: neutropenia (24%), thrombocytopenia (17%), anemia (14%), nausea (17%), diarrhea (17%) and fatigue (17%). Sixteen patients required dose duction of adavosertib to 250 mg, and 7 further to 200 mg. Biomarker analysis is ongoing to investigate potential biomarkers of response.
Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in patients with refractory solid tumors harboring CCNE1 amplification, especially in high-grade serous ovarian cancer. Further exploration of adavosertib in CCNE1 amplified high grade serous ovarian cancer is warranted.
Citation Format: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard Carvajal, Thomas J. George, Ying Yuan, Yuko Yamamura, Shannon Westin, Yan Xing, Ecaterina E. Ileana Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon, Naoko Takebe, Charles Kunos, Karen Lu, Khanda Keyomarsi, Funda Meric-Bernstam. Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 974.