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Ref Type Journal Article
PMID (40069402)
Authors 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
Title A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer.
Journal Vol Issue Date Pages Journal Short Title
NPJ precision oncology 9 1 2025 Mar 11 67 NPJ Precis Oncol
URL
Abstract Text 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).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
STK11 inact mut lung non-small cell carcinoma no benefit Vistusertib Phase II Actionable In a Phase II trial, Vistusertib (AZD2014) did not result in a clinically relevant objective response rate (OR) or durable clinical benefit (DCB) in STK11-deficient non-small cell lung cancer patients, with an OR of 9.8% (2/26, 2 partial responses) and DCB of 24.4% (6/26) in those with KRAS co-mutations, and OR of 0% (0/17) and DCB of 14.6% (2/17) in KRAS wild-type patients, and led to feedback reactivation of Akt signaling in STK11-deficient lung cancer cell lines in culture (PMID: 40069402; NCT02664935). 40069402