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.

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

Type

Journal Article