Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

FOCUS4 Trial Investigators; Jenny F. Seligmann; David J. Fisher; Louise C. Brown; Richard A. Adams; Janet Graham; Philip Quirke; Susan D. Richman; Rachel Butler; Enric Domingo; Andrew Blake; Emma Yates; Michael Braun; Fiona Collinson; Rob Jones; Ewan Brown; Emma de Winton; Timothy C. Humphrey; Mahesh Parmar; Richard Kaplan; Richard H. Wilson; Matthew Seymour; Timothy S. Maughan

doi:10.1200/JCO.21.01435

Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

FOCUS4 Trial Investigators, Jenny F. Seligmann, David J. Fisher, Louise C. Brown, Richard A. Adams, Janet Graham, Philip Quirke, Susan D. Richman, Rachel Butler, Enric Domingo, Andrew Blake, Emma Yates, Michael Braun, Fiona Collinson, Rob Jones, Ewan Brown, Emma de Winton, Timothy C. Humphrey, Mahesh Parmar, Richard KaplanRichard H. Wilson, Matthew Seymour, Timothy S. Maughan

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Abstract

PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition.

METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level.

RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%).

CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.

Original language	English
Pages (from-to)	3705-3715
Number of pages	11
Journal	Journal of Clinical Oncology
Volume	39
Issue number	33
Early online date	18 Sept 2021
DOIs	https://doi.org/10.1200/JCO.21.01435
Publication status	Published - Nov 2021

Bibliographical note

Funding Information:
FOCUS4-C was cofunded by the MRC/NIHR Efficacy and Mechanism Evaluation (EME) program and CRUK with funding commencing in April 2013. Drug supply and distribution of adavosertib and an educational grant were provided by AstraZeneca Ltd. The MRC Clinical Trials Unit at UCL receives core funding from the Medical Research Council within UKRI (Budget: MC_UU_12023/20).

Publisher Copyright:
© 2021 by American Society of Clinical Oncology

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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FOCUS4 Trial Investigators, Seligmann, J. F., Fisher, D. J., Brown, L. C., Adams, R. A., Graham, J., Quirke, P., Richman, S. D., Butler, R., Domingo, E., Blake, A., Yates, E., Braun, M., Collinson, F., Jones, R., Brown, E., de Winton, E., Humphrey, T. C., Parmar, M., ... Maughan, T. S. (2021). Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring. Journal of Clinical Oncology, 39(33), 3705-3715. https://doi.org/10.1200/JCO.21.01435

@article{10d4013ec81b4709b6ada33c86056924,

title = "Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring",

abstract = "PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.",

author = "{FOCUS4 Trial Investigators} and Seligmann, {Jenny F.} and Fisher, {David J.} and Brown, {Louise C.} and Adams, {Richard A.} and Janet Graham and Philip Quirke and Richman, {Susan D.} and Rachel Butler and Enric Domingo and Andrew Blake and Emma Yates and Michael Braun and Fiona Collinson and Rob Jones and Ewan Brown and {de Winton}, Emma and Humphrey, {Timothy C.} and Mahesh Parmar and Richard Kaplan and Wilson, {Richard H.} and Matthew Seymour and Maughan, {Timothy S.} and G. Middleton and A. Russell",

note = "Funding Information: FOCUS4-C was cofunded by the MRC/NIHR Efficacy and Mechanism Evaluation (EME) program and CRUK with funding commencing in April 2013. Drug supply and distribution of adavosertib and an educational grant were provided by AstraZeneca Ltd. The MRC Clinical Trials Unit at UCL receives core funding from the Medical Research Council within UKRI (Budget: MC_UU_12023/20). Publisher Copyright: {\textcopyright} 2021 by American Society of Clinical Oncology",

year = "2021",

month = nov,

doi = "10.1200/JCO.21.01435",

language = "English",

volume = "39",

pages = "3705--3715",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "33",

}

FOCUS4 Trial Investigators, Seligmann, JF, Fisher, DJ, Brown, LC, Adams, RA, Graham, J, Quirke, P, Richman, SD, Butler, R, Domingo, E, Blake, A, Yates, E, Braun, M, Collinson, F, Jones, R, Brown, E, de Winton, E, Humphrey, TC, Parmar, M, Kaplan, R, Wilson, RH, Seymour, M & Maughan, TS 2021, 'Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring', Journal of Clinical Oncology, vol. 39, no. 33, pp. 3705-3715. https://doi.org/10.1200/JCO.21.01435

Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring. / FOCUS4 Trial Investigators; Seligmann, Jenny F.; Fisher, David J. et al.
In: Journal of Clinical Oncology, Vol. 39, No. 33, 11.2021, p. 3705-3715.

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

TY - JOUR

T1 - Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer

T2 - A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

AU - FOCUS4 Trial Investigators

AU - Seligmann, Jenny F.

AU - Fisher, David J.

AU - Brown, Louise C.

AU - Adams, Richard A.

AU - Graham, Janet

AU - Quirke, Philip

AU - Richman, Susan D.

AU - Butler, Rachel

AU - Domingo, Enric

AU - Blake, Andrew

AU - Yates, Emma

AU - Braun, Michael

AU - Collinson, Fiona

AU - Jones, Rob

AU - Brown, Ewan

AU - de Winton, Emma

AU - Humphrey, Timothy C.

AU - Parmar, Mahesh

AU - Kaplan, Richard

AU - Wilson, Richard H.

AU - Seymour, Matthew

AU - Maughan, Timothy S.

AU - Middleton, G.

AU - Russell, A.

N1 - Funding Information: FOCUS4-C was cofunded by the MRC/NIHR Efficacy and Mechanism Evaluation (EME) program and CRUK with funding commencing in April 2013. Drug supply and distribution of adavosertib and an educational grant were provided by AstraZeneca Ltd. The MRC Clinical Trials Unit at UCL receives core funding from the Medical Research Council within UKRI (Budget: MC_UU_12023/20). Publisher Copyright: © 2021 by American Society of Clinical Oncology

PY - 2021/11

Y1 - 2021/11

N2 - PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.

AB - PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.

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DO - 10.1200/JCO.21.01435

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SN - 0732-183X

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Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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