A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)

Edward Maldonado; W. Kimryn Rathmell; Geoffrey I. Shapiro; Naoko Takebe; Jordi Rodon; Devalingam Mahalingam; Nikolaos A. Trikalinos; Arash R. Kalebasty; Mamta Parikh; Scott A. Boerner; Celene Balido; Gregor Krings; Timothy F. Burns; Emily K. Bergsland; Pamela N. Munster; Alan Ashworth; Patricia LoRusso; Rahul R. Aggarwal

doi:10.1158/2767-9764.CRC-24-0213

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)

Edward Maldonado^*, W. Kimryn Rathmell, Geoffrey I. Shapiro, Naoko Takebe, Jordi Rodon, Devalingam Mahalingam, Nikolaos A. Trikalinos, Arash R. Kalebasty, Mamta Parikh, Scott A. Boerner, Celene Balido, Gregor Krings, Timothy F. Burns, Emily K. Bergsland, Pamela N. Munster, Alan Ashworth, Patricia LoRusso, Rahul R. Aggarwal^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

Abstract

We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.

Original language	English (US)
Pages (from-to)	1793-1801
Number of pages	9
Journal	Cancer Research Communications
Volume	4
Issue number	7
DOIs	https://doi.org/10.1158/2767-9764.CRC-24-0213
State	Published - Jul 2024

Funding

We would like to thank the patients and their families/caregivers for their participation. This study was sponsored by the National Cancer Institute, UM1 grant# 1UM1CA186689 (P. LoRusso) and UM1CA186709 (G.I. Shapiro). This study was partly funded by AstraZeneca (AZ) but was not sponsored by AZ. We would like to thank the patients and their families/caregivers for their participation. This study was sponsored by the National Cancer Institute, UM1 grant# 1UM1CA186689 (P. LoRusso) and UM1CA186709 (G.I. Sha-piro). This study was partly funded by AstraZeneca (AZ) but was not sponsored by AZ.

ASJC Scopus subject areas

Oncology
Cancer Research
General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2767-9764.CRC-24-0213

Cite this

Maldonado, E., Rathmell, W. K., Shapiro, G. I., Takebe, N., Rodon, J., Mahalingam, D., Trikalinos, N. A., Kalebasty, A. R., Parikh, M., Boerner, S. A., Balido, C., Krings, G., Burns, T. F., Bergsland, E. K., Munster, P. N., Ashworth, A., LoRusso, P., & Aggarwal, R. R. (2024). A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170). Cancer Research Communications, 4(7), 1793-1801. https://doi.org/10.1158/2767-9764.CRC-24-0213

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title = "A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)",

abstract = "We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.",

author = "Edward Maldonado and Rathmell, {W. Kimryn} and Shapiro, {Geoffrey I.} and Naoko Takebe and Jordi Rodon and Devalingam Mahalingam and Trikalinos, {Nikolaos A.} and Kalebasty, {Arash R.} and Mamta Parikh and Boerner, {Scott A.} and Celene Balido and Gregor Krings and Burns, {Timothy F.} and Bergsland, {Emily K.} and Munster, {Pamela N.} and Alan Ashworth and Patricia LoRusso and Aggarwal, {Rahul R.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors.",

year = "2024",

month = jul,

doi = "10.1158/2767-9764.CRC-24-0213",

language = "English (US)",

volume = "4",

pages = "1793--1801",

journal = "Cancer Research Communications",

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Maldonado, E, Rathmell, WK, Shapiro, GI, Takebe, N, Rodon, J, Mahalingam, D, Trikalinos, NA, Kalebasty, AR, Parikh, M, Boerner, SA, Balido, C, Krings, G, Burns, TF, Bergsland, EK, Munster, PN, Ashworth, A, LoRusso, P & Aggarwal, RR 2024, 'A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)', Cancer Research Communications, vol. 4, no. 7, pp. 1793-1801. https://doi.org/10.1158/2767-9764.CRC-24-0213

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T1 - A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)

AU - Maldonado, Edward

AU - Rathmell, W. Kimryn

AU - Shapiro, Geoffrey I.

AU - Takebe, Naoko

AU - Rodon, Jordi

AU - Mahalingam, Devalingam

AU - Trikalinos, Nikolaos A.

AU - Kalebasty, Arash R.

AU - Parikh, Mamta

AU - Boerner, Scott A.

AU - Balido, Celene

AU - Krings, Gregor

AU - Burns, Timothy F.

AU - Bergsland, Emily K.

AU - Munster, Pamela N.

AU - Ashworth, Alan

AU - LoRusso, Patricia

AU - Aggarwal, Rahul R.

PY - 2024/7

Y1 - 2024/7

N2 - We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.

AB - We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.

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A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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