Phase II Study of the WEE1 Inhibitor Adavosertib in Recurrent Uterine Serous Carcinoma
PURPOSEUterine 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 k...
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| Published in | Journal of clinical oncology Vol. 39; no. 14; pp. 1531 - 1539 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Wolters Kluwer Health
10.05.2021
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| Online Access | Get full text |
| ISSN | 0732-183X 1527-7755 1527-7755 |
| DOI | 10.1200/JCO.20.03167 |
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| Abstract | PURPOSEUterine 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 METHODSThis 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.RESULTSIn 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.CONCLUSIONAdavosertib 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. |
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| AbstractList | 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.
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.
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.
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. PURPOSEUterine 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 METHODSThis 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.RESULTSIn 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.CONCLUSIONAdavosertib 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. 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.PURPOSEUterine 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.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.PATIENTS AND METHODSThis 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.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.RESULTSIn 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.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.CONCLUSIONAdavosertib 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. |
| Author | Liu, Joyce F. Horowitz, Neil Xiong, Niya Schumer, Susan Campos, Susana M. Veneris, Jennifer Matulonis, Ursula A. West, Gabriela Krasner, Carolyn Konstantinopoulos, Panagiotis A. Tayob, Nabihah Wright, Alexi A. Morrissey, Stephanie Quinn, Roxanne |
| Author_xml | – sequence: 1 givenname: Joyce F. orcidid: 0000-0003-3888-3972 surname: Liu fullname: Liu, Joyce F. email: joyce_liu@dfci.harvard.edu organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 2 givenname: Niya surname: Xiong fullname: Xiong, Niya organization: Department of Data Science, Dana-Farber Cancer Institute, Boston, MA – sequence: 3 givenname: Susana M. surname: Campos fullname: Campos, Susana M. organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 4 givenname: Alexi A. orcidid: 0000-0002-9776-7114 surname: Wright fullname: Wright, Alexi A. organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 5 givenname: Carolyn surname: Krasner fullname: Krasner, Carolyn organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 6 givenname: Susan surname: Schumer fullname: Schumer, Susan organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 7 givenname: Neil surname: Horowitz fullname: Horowitz, Neil organization: Department of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA – sequence: 8 givenname: Jennifer surname: Veneris fullname: Veneris, Jennifer organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 9 givenname: Nabihah orcidid: 0000-0001-6088-167X surname: Tayob fullname: Tayob, Nabihah organization: Department of Data Science, Dana-Farber Cancer Institute, Boston, MA – sequence: 10 givenname: Stephanie surname: Morrissey fullname: Morrissey, Stephanie organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 11 givenname: Gabriela surname: West fullname: West, Gabriela organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 12 givenname: Roxanne orcidid: 0000-0002-4877-6188 surname: Quinn fullname: Quinn, Roxanne organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 13 givenname: Ursula A. surname: Matulonis fullname: Matulonis, Ursula A. organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA – sequence: 14 givenname: Panagiotis A. orcidid: 0000-0002-1032-1479 surname: Konstantinopoulos fullname: Konstantinopoulos, Panagiotis A. organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33705205$$D View this record in MEDLINE/PubMed |
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| Notes | Joyce F. Liu, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215; e-mail: joyce_liu@dfci.harvard.edu. ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
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