A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer
Abstract
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.
Author
Middleton, Gary
Robbins, Helen L
Fletcher, Peter
Savage, Joshua
Mehmi, Manita
Summers, Yvonne
Greystoke, Alastair
Steele, Nicola
Popat, Sanjay
Jain, Pooja
Spicer, James
Cave, Judith
Shaw, Paul
Gilligan, David
Power, Danielle
Fennell, Dean
Bajracharya, Maya
McBride, David J
Maheswari, Uma
Frankell, Alexander M
Swanton, Charles
Beggs, Andrew D
Billingham, Lucinda
Robbins, Helen L
Fletcher, Peter
Savage, Joshua
Mehmi, Manita
Summers, Yvonne
Greystoke, Alastair
Steele, Nicola
Popat, Sanjay
Jain, Pooja
Spicer, James
Cave, Judith
Shaw, Paul
Gilligan, David
Power, Danielle
Fennell, Dean
Bajracharya, Maya
McBride, David J
Maheswari, Uma
Frankell, Alexander M
Swanton, Charles
Beggs, Andrew D
Billingham, Lucinda
Date
2025-03-11
Type
Journal Article
Subject
Carcinoma, non-small-cell lung
Collections
Citation
Middleton G, Robbins HL, Fletcher P, Savage J, Mehmi M, Summers Y, Greystoke A, Steele N, Popat S, Jain P, Spicer J, Cave J, Shaw P, Gilligan D, Power D, Fennell D, Bajracharya M, McBride DJ, Maheswari U, Frankell AM, Swanton C, Beggs AD, Billingham L. A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer. NPJ Precis Oncol. 2025 Mar 11;9(1):67. doi: 10.1038/s41698-025-00838-4
Journal / Source Title
NPJ precision oncology
DOI
10.1038/s41698-025-00838-4
PMID
40069402
Publisher
Springer Nature