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Proffered Paper session - Gastrointestinal tumours, colorectal 1

382O - Inhibition of WEE1 is effective in TP53 and RAS mutant metastatic colorectal cancer (mCRC): A randomised phase II trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring


18 Sep 2021


Proffered Paper session - Gastrointestinal tumours, colorectal 1


Cytotoxic Therapy;  Clinical Research;  Cancer Biology

Tumour Site

Colon and Rectal Cancer


Jenny Seligmann


Annals of Oncology (2021) 32 (suppl_5): S530-S582. 10.1016/annonc/annonc698


J. Seligmann1, D.J. Fisher2, L.C. Brown2, R. Adams3, J. Graham4, P. Quirke5, S. Richman5, R. Butler3, E. Domingo6, A. Blake6, M. Braun7, F. Collinson1, R. Jones3, E. Brown8, E. De Winton9, T. Humphies6, R. Kaplan2, R. Wilson4, M. Seymour1, T. Maughan10

Author affiliations

  • 1 Oncology Department, St. James's University Hospital - Leeds Teaching Hospitals NHS Trust, LS9 7TF - Leeds/GB
  • 2 Mrc Clinical Trials Unit, University College London, L1 - London/GB
  • 3 Oncology, Velindre Cancer Centre, c2 - Cardiff/GB
  • 4 Medical Oncology, Beatson Cancer Centre, g2 - Glasgow/GB
  • 5 Pathology Department, St. James's University Hospital - Leeds Teaching Hospitals NHS Trust, LS9 7TF - Leeds/GB
  • 6 Mrc Oxford Institute For Radiation Oncology,, University of Oxford, o2 - Oxford/GB
  • 7 Medical Oncology, Christie Hospital, m2 - Manchester/GB
  • 8 Medical Oncology, Western General Hospital, E2 - Edinburgh/GB
  • 9 Medical Oncology, Royal United Hospital, B2 - Bath/GB
  • 10 Oncology, Oxford Institute for Radiation Oncology, OX3 7DQ - Oxford/GB


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Abstract 382O


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 hypothesised that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitise tumours to WEE1 inhibition.


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 randomised 2:1 between Adavosertib or active monitoring (AM). The primary outcome was progression-free-survival (PFS).


Between Jul 2017 and Mar 2020 718 patients were registered into FOCUS4; 247 (34%) were RAS/TP53-mutant. 69 patients were randomised from 25 UK hospitals (44 to Adavosertib; 25 to AM) and recruitment terminated early due to COVID-19 and following DMEC review of efficacy data. Adavosertib was associated with a PFS improvement over AM (median 3.61 vs 1.87 months; HR=0.35[95% CI 0.18-0.68], p=0.0022). In pre-specified subgroup analysis, Adavosertib activity was greater in left-sided tumours HR=0.24 [95% CI 0.11–0.51], versus right-sided HR=1.02 [95% CI 0.41–2.56] (interaction p=0.043). Adavosertib activity was limited to tumours with KRAS12/13 mutations, rather than mutations in extended KRAS or NRAS (interaction p=0.01). Overall survival (OS) was not improved with Adavosertib vs AM (median 14.0 vs 12.8 months; HR=0.92[95%CI 0.44-1.94], p=0.93); however in left-sided tumours, median OS was 14.1 vs 11.3 months (HR=0.37 [95%CI 0.15-0.87]) and 6.5 vs 15.5 months in right-sided (HR=2.15 [95%CI 0.72-6.43], interaction p=0.0047). Adavosertib was well tolerated; grade 3 toxicities were diarrhoea (9%), nausea (5%) and neutropenia (7%).


In this phase II randomised trial, Adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Activity was greater in patients with left-sided tumours, with potential impact on OS. Further testing is required in this sizable population of unmet need.

Clinical trial identification


Editorial acknowledgement

Legal entity responsible for the study

The authors.


MRC/NIHR, CRUK, AstraZeneca.


J. Seligmann: Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Expert Testimony: Roche Diagnostics; Financial Interests, Personal, Invited Speaker: Servier. T. Maughan: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Psioxus; Financial Interests, Institutional, Funding: Merck KGAA. All other authors have declared no conflicts of interest.

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