PMID- 33705205
OWN - NLM
STAT- MEDLINE
DCOM- 20211013
LR  - 20211013
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 39
IP  - 14
DP  - 2021 May 10
TI  - Phase II Study of the WEE1 Inhibitor Adavosertib in Recurrent Uterine Serous 
      Carcinoma.
PG  - 1531-1539
LID - 10.1200/JCO.20.03167 [doi]
AB  - PURPOSE: Uterine serous carcinoma (USC) is a distinct histologic subtype of 
      endometrial cancer, with molecular characteristics suggesting frequent cell-cycle 
      dysregulation paired with a high level of oncogene-driven replication stress. 
      Adavosertib is a potent and selective oral inhibitor of the WEE1 kinase, a key 
      regulator of the G2/M and S phase cell-cycle checkpoints. Because cells with 
      impaired cell-cycle regulation and high replication stress may be vulnerable to 
      WEE1 inhibition, we conducted this study to assess the activity of adavosertib 
      monotherapy in women with recurrent USC. PATIENTS AND METHODS: This was a 
      single-arm two-stage phase II study with coprimary end points of objective 
      response rate (ORR) and rate of progression-free survival at 6 months (PFS6). 
      Women with recurrent USC were treated with adavosertib monotherapy at a starting 
      dose of 300 mg orally once daily days 1 through 5 and 8 through 12 of a 21-day 
      cycle until disease progression. RESULTS: In 34 evaluable patients, 10 total 
      responses (one confirmed complete response, eight confirmed partial responses, 
      and one unconfirmed partial response) were observed with adavosertib monotherapy, 
      for an ORR of 29.4% (95% CI, 15.1 to 47.5). Sixteen patients were 
      progression-free at 6 months, for a PFS6 rate of 47.1% (95% CI, 29.8 to 64.9). 
      Median PFS was 6.1 months, and median duration of response was 9.0 months. 
      Frequent treatment-related adverse events (AEs) included diarrhea (76.5%), 
      fatigue (64.7%), nausea (61.8%), and hematologic AEs. No clear correlation of 
      clinical activity with specific molecular alterations was observed in an 
      exploratory biomarker analysis. CONCLUSION: Adavosertib monotherapy demonstrated 
      encouraging and durable evidence of activity in women with USC, and further 
      investigation of this agent in this cancer and biomarkers of activity are 
      indicated.
FAU - Liu, Joyce F
AU  - Liu JF
AUID- ORCID: 0000-0003-3888-3972
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Xiong, Niya
AU  - Xiong N
AD  - Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.
FAU - Campos, Susana M
AU  - Campos SM
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Wright, Alexi A
AU  - Wright AA
AUID- ORCID: 0000-0002-9776-7114
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Krasner, Carolyn
AU  - Krasner C
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Schumer, Susan
AU  - Schumer S
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Horowitz, Neil
AU  - Horowitz N
AD  - Department of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA.
FAU - Veneris, Jennifer
AU  - Veneris J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Tayob, Nabihah
AU  - Tayob N
AUID- ORCID: 0000-0001-6088-167X
AD  - Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.
FAU - Morrissey, Stephanie
AU  - Morrissey S
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - West, Gabriela
AU  - West G
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Quinn, Roxanne
AU  - Quinn R
AUID- ORCID: 0000-0002-4877-6188
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Matulonis, Ursula A
AU  - Matulonis UA
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Konstantinopoulos, Panagiotis A
AU  - Konstantinopoulos PA
AUID- ORCID: 0000-0002-1032-1479
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03668340
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210311
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidinones)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (WEE1 protein, human)
RN  - K2T6HJX3I3 (adavosertib)
SB  - IM
CIN - J Clin Oncol. 2021 May 10;39(14):1513-1517. PMID: 33797939
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers, Tumor
MH  - Cell Cycle Proteins/*antagonists & inhibitors
MH  - Cystadenocarcinoma, Serous/*drug therapy/genetics/mortality
MH  - Female
MH  - Genes, BRCA1
MH  - Humans
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy/genetics/mortality
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors
MH  - Pyrazoles/adverse effects/*therapeutic use
MH  - Pyrimidinones/adverse effects/*therapeutic use
MH  - Uterine Neoplasms/*drug therapy/genetics/mortality
COIS- Joyce F. LiuConsulting or Advisory Role: Tesaro, Mersana, Clovis Oncology, 
      Genentech/Roche, GlaxoSmithKline, Regeneron, AstraZenecaResearch Funding: 
      Genentech/Roche, AstraZeneca, Boston Biomedical, Atara Biotherapeutics, Acetylon 
      Pharmaceuticals, Bristol-Myers Squibb, Agenus, CytomX Therapeutics, Regeneron, 
      Tesaro, Clovis Oncology, Surface Oncology, 2X Oncology, Vigeo Therapeutics, 
      Aravive, Arch OncologyTravel, Accommodations, Expenses: AstraZeneca, 
      Merck(OPTIONAL) Uncompensated Relationships: Merck Susana M. CamposHonoraria: 
      AstraZeneca, EisaiConsulting or Advisory Role: GlaxoSmithKline, Eisai, 
      AstraZeneca Carolyn KrasnerResearch Funding: Cerulean Pharma Susan SchumerStock 
      and Other Ownership Interests: Johnson and Johnson Neil HorowitzPatents, 
      Royalties, Other Intellectual Property: Up to Date Author Jennifer 
      VenerisEmployment: Abbott Laboratories, Takeda, GlaxoSmithKlineStock and Other 
      Ownership Interests: AbbvieHonoraria: Michiana Hematology Oncology Ursula A. 
      MatulonisHonoraria: AdvaxisConsulting or Advisory Role: Merck, Novartis, 
      NextCureResearch Funding: Merck, Novartis, Tesaro, Syndax, Immunogen. Mersana, 
      Leap Therapeutics, Fujifilm, SQZ BiotechTravel, Accommodations, Expenses: 
      AstraZeneca Panagiotis A. KonstantinopoulosConsulting or Advisory Role: Merck, 
      Vertex, AstraZeneca, Pfizer/EMD Serono, Tesaro, Bayer, AlkermesResearch Funding: 
      Pfizer, Lilly, Tesaro, Merck Serono, AstraZeneca, Merck, BayerNo other potential 
      conflicts of interest were reported.
EDAT- 2021/03/12 06:00
MHDA- 2021/10/14 06:00
CRDT- 2021/03/11 17:15
PHST- 2021/03/12 06:00 [pubmed]
PHST- 2021/10/14 06:00 [medline]
PHST- 2021/03/11 17:15 [entrez]
AID - 10.1200/JCO.20.03167 [doi]
PST - ppublish
SO  - J Clin Oncol. 2021 May 10;39(14):1531-1539. doi: 10.1200/JCO.20.03167. Epub 2021 
      Mar 11.