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Publications

Journal Article Ahead of print

PubMed: 42714874 DOI: 10.1158/1078-0432.CCR-26-1365

Ceralasertib plus durvalumab in Ras mutant and Ras wild type advanced non-small cell lung cancer: Two cohorts of the phase II platform National Lung Matrix Trial.

Clin Cancer Res

Authors: Gary Middleton, Richard Buchanan, Joshua Savage, Joe De La Mata Chicharro, Manita Mehmi, Rosanna J Wilkins, Richard D W Kelly, Claire Wilson, Aditi Kanhere, Helen L Robbins, Luke Ames, Alastair Greystoke, Adam Dangoor, Judith Cave, Paul Shaw, Nicola Steele, Katy Clarke, Pooja Bhatnagar, Mary O'Brien, Sanjay Popat, Martin D Forster, James Spicer, Nicholas Coupe, Sarah Danson, David Gilligan, Dakshinamoorthy Muthukumar, Gillian Price, Yvonne Summers, Elizabeth Toy, Timothy Yap, Charles Swanton, Andrew Beggs, Heather Long, Eva Petermann, Lucinda Billingham

Affiliations

  • University of Birmingham Birmingham, West Midlands United Kingdom.
  • University of Birmingham Birmingham United Kingdom.
  • University of Birmingham United Kingdom.
  • University of Liverpool Liverpool United Kingdom.
  • Newcastle University Newcastle upon Tyne United Kingdom.
  • Bristol Haematology and Oncology Centre Bristol United Kingdom.
  • University Hospital Southampton NHS Foundation Trust Southampton United Kingdom.
  • Velindre Cancer Centre Cardiff United Kingdom.
  • Beatson West of Scotland Cancer Centre Glasgow United Kingdom.
  • St James's University Hospital Leeds United Kingdom.
  • The Royal Marsden London United Kingdom.
  • Royal Marsden NHS Foundation Trust London United Kingdom.
  • University College London London United Kingdom.
  • King's College London London United Kingdom.
  • Oxford University Hospitals NHS Trust Oxford United Kingdom.
  • University of Sheffield Sheffield United Kingdom.
  • Cambridge University Hospitals NHS Foundation Trust United Kingdom.
  • Colchester Hospital Colchester United Kingdom.
  • Aberdeen Royal Infirmary Aberdeen United Kingdom.
  • Manchester University NHS Foundation Trust Manchester United Kingdom.
  • Royal Devon University Healthcare NHS Foundation Trust Exeter United Kingdom.
  • The University of Texas MD Anderson Cancer Center Houston, TX United States.
  • The Francis Crick Institute London United Kingdom.

Abstract

PURPOSE

Pre-clinical data suggests that ceralasertib, a potent ATR inhibitor, might reverse resistance to anti-PD-(L)1 in KRAS mutant lung adenocarcinoma (LUAD). Activity of ceralasertib/durvalumab was, therefore, assessed in two prospective, parallel immune checkpoint blockade (ICB)-resistant cohorts, one harbouring KRAS mutations (J1), the other without (NAJ), within the National Lung Matrix Trial.

METHODS

Oral ceralasertib was administered (240 mg twice daily on days 15-28) with durvalumab (1500 mg IV, on day 1 of every 28-day cycle) until disease progression. Co-primary outcomes were objective response (OR) and 24-week durable clinical benefit (DCB). Biological impacts of ceralasertib were assessed in a human BJ-hTERT KRASV12ER-TAM model. Immunological impact of KRAS mutation was assessed using gene-level processed LUAD TCGA PanCancer data.

RESULTS

Between 02-Jul-2020 and 31-Oct-2021, 43 patients were registered; 19 and 18 of whom were evaluable for outcome analysis in cohorts J1 and NAJ, respectively. Cohort target recruitment (30 participants each) was not reached due to trial closure at the pre-planned end of funding. Bayesian estimates of DCB rates (95% credible intervals) were 37.7% (19.1-59.2) for J1 and 29.3% (12.6-51.2) for NAJ. Two participants demonstrated OR, both KRAS mutant, one of whom had KEAP1/STK11 co-mutation. KRAS mutation significantly increased the proportion of cells harbouring ceralasertib-induced micronuclei. Ceralasertib blunted KRAS-mediated STAT1 downregulation.

CONCLUSION

Whilst outcome measures on ceralasertib/durvalumab in anti-PD-(L)1 resistant LUAD patients are modestly higher in KRAS mutant participants, these differences are not significant, a result likely related to the modest impact of KRAS mutation alone on the immunobiology of LUAD.

MeSH

Cells, Lung, Neoplasms, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Small Cell Lung Carcinoma, Mutation