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

• Tác giả: Maya Bajracharya, Andrew D Beggs, Lucinda Billingham, Judith Cave, Dean Fennell, Peter Fletcher, Alexander M Frankell, David Gilligan, Alastair Greystoke, Pooja Jain, Uma Maheswari, David J McBride, Manita Mehmi, Gary Middleton, Sanjay Popat, Danielle Power, Helen L Robbins, Joshua Savage, Paul Shaw, James Spicer, Nicola Steele, Yvonne Summers, Charles Swanton
• Ngôn ngữ: eng
• Ký hiệu phân loại: 152.1 Sensory perception
• Thông tin xuất bản: England : NPJ precision oncology , 2025
• Bộ sưu tập: NCBI
• ID: 696491

Tóm tắt

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).