TY - JOUR
T1 - Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification
AU - Fu, Siqing
AU - Yao, Shuyang
AU - Yuan, Yuan
AU - Previs, Rebecca A.
AU - Elias, Anthony D.
AU - Carvajal, Richard D.
AU - George, Thomas J.
AU - Yuan, Ying
AU - Yu, Lihou
AU - Westin, Shannon N.
AU - Xing, Yan
AU - Dumbrava, Ecaterina E.
AU - Karp, Daniel D.
AU - Piha-Paul, Sarina A.
AU - Tsimberidou, Apostolia M.
AU - Ahnert, Jordi Rodon
AU - Takebe, Naoko
AU - Lu, Karen
AU - Keyomarsi, Khandan
AU - Meric-Bernstam, Funda
N1 - Funding Information:
Research Funding: Repare Therapeutics (Inst), Apeiron Biologics (Inst), Blueprint Medicines (Inst), Schrodinger, Inc (Inst), NIH, National Cancer Institute R01 grants CA255960 and CA223772 and CPRIT multi-investigator grant RP180712
Funding Information:
Supported by Cancer Therapy Evaluation Program National Cancer Institution (NCI CTEP). This research was supported in part through the NIH/NCI Cancer Center Support Grant P30 CA016672.
Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/3/20
Y1 - 2023/3/20
N2 - PURPOSEPreclinical 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 METHODSPatients 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).RESULTSThirty 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.CONCLUSIONAdavosertib 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.
AB - PURPOSEPreclinical 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 METHODSPatients 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).RESULTSThirty 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.CONCLUSIONAdavosertib 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.
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U2 - 10.1200/JCO.22.00830
DO - 10.1200/JCO.22.00830
M3 - Article
C2 - 36469840
AN - SCOPUS:85150338558
VL - 41
SP - 1725
EP - 1734
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 9
ER -