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<p>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 <i>KRAS</i> 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 <i>SMARCA4</i> 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)</p>

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A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月11日

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  • Gary Middleton,
  • Helen L. Robbins,
  • Peter Fletcher,
  • Joshua Savage,
  • Manita Mehmi,
  • Yvonne Summers,
  • Alastair Greystoke,
  • Nicola Steele,
  • Sanjay Popat,
  • Pooja Jain,
  • James Spicer,
  • Judith Cave,
  • Paul Shaw,
  • David Gilligan,
  • Danielle Power,
  • Dean Fennell,
  • Maya Bajracharya,
  • David J. McBride,
  • Uma Maheswari,
  • Alexander M. Frankell,
  • Charles Swanton,
  • Andrew D. Beggs,
  • Lucinda Billingham

摘要

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)