A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer
There are no current stratified medicine options for STK11-deficient NSCLC. STK11 loss mediates mTORC activation, GLUT1 up-regulation and increased glycolysis. This metabolic reprogramming might represent a therapeutic vulnerability targetable with mTORC1/2 inhibition. In arm B2 of the National Lung Matrix Trial 54 patients with NSCLC received vistusertib, of which 49 were STK11-deficient (30 with KRAS mutation (B2D), 19 without (B2S)). Objective response (OR) and durable clinical benefit (DCB) rates with 95% credible intervals (CrI) were estimated from posterior probability distributions generated using Bayesian beta-binomial conjugate analysis. In B2D, 2 per-protocol patients obtained OR (estimated true OR rate (95%CrI) 9.8% (2.4-24.3). Estimates of true DCB rate (95%CrI): B2D 24.4% (11.1-42.3), B2S 14.6% (3.6-34.7). Overall, vistusertib cannot be recommended in this context. Longitudinal ctDNA analysis demonstrates enrichment of SMARCA4 mutations post-treatment. In vitro studies show adaptive resistance to mTORC1/2 inhibition via AKT reactivation. (NCT02664935, ISRCTN38344105, EudraCT 2014-000814-73, 10 June 2015).
Authors
- Lucinda Jane Billingham (ORCID: https://orcid.org/0000-0001-8581-4262)
- Joshua Savage (ORCID: https://orcid.org/0000-0003-0599-0245)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Alastair Greystoke (ORCID: https://orcid.org/0000-0001-9168-0387)
- DAVID M. GILLIGAN (ORCID: https://orcid.org/0000-0002-5125-0806)
- Manita Mehmi (ORCID: https://orcid.org/0000-0001-8220-9331)
- Peter Fletcher (ORCID: https://orcid.org/0000-0001-5905-831X)
- Uma Maheswari (ORCID: https://orcid.org/0000-0002-2366-2336)
- James Spicer (ORCID: https://orcid.org/0000-0003-3732-8491)
- Alexander M. Frankell (ORCID: https://orcid.org/0000-0002-0341-7878)
- H.L. Robbins
- Gary Middleton (ORCID: https://orcid.org/0000-0001-5695-3474)
- P. Nicholas Shaw (ORCID: https://orcid.org/0000-0001-7154-592X)
- Andrew D. Beggs (ORCID: https://orcid.org/0000-0003-0784-2967)
- David J. McBride (ORCID: https://orcid.org/0009-0006-5482-8040)
- Sanjay Popat (ORCID: https://orcid.org/0000-0003-2087-4963)
- Yvonne Summers
- Maya Bajracharya
- Judith Cave (ORCID: https://orcid.org/0000-0002-1497-0310)
- Pooja Jain (ORCID: https://orcid.org/0000-0002-0645-8026)
- Danielle Power
- Dean A. Fennell
- Nicola Steele
Institutions
- Guy's Hospital (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Imperial College Healthcare NHS Trust (GB)
- King's College London (GB)
- Leicester Royal Infirmary (GB)
- Beatson West of Scotland Cancer Centre (GB)
- The Francis Crick Institute (GB)
- St James's University Hospital (GB)
- Illumina (United Kingdom) (GB)
- Royal Marsden Hospital (GB)
- The Christie Hospital (GB)
- Cancer Research UK Clinical Trials Unit (GB)
- Velindre Cancer Centre (GB)
- Addenbrooke's Hospital (GB)
- University of Birmingham (GB)
- Newcastle University (GB)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1038/s41698-025-00838-4
- Citations
- 3
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42