Abstract A115: mTOR targeting in STK11 deficient Non-Small Cell Lung Cancer (NSCLC): final results, pre-clinical rationale and biomarker analysis of a phase II trial of the mTORC1/2 inhibitor vistusertib in STK11 deficient lung adenocarcinoma (NLMT B2)
Authors: Robbins Helen L , Fletcher Peter , Savage Joshua , Mehmi Manita , Summers Yvonne , Greystoke Alastair , O’Rourke Noelle , Popat Sanjay , Jain Pooja , Spicer James , Cave Judith , Shaw Paul , Gilligan David , Power Danielle , Fennel Dean , Beggs Andrew D , Billingham Lucinda , Middleton Gary 
Published: December 2023

Abstract
Background: STK11 loss of function is common in lung adenocarcinoma (LUAD). STK11 deficient LUAD demonstrates mTOR activation, increased HIF-1a expression and GLUT1 up-regulation, resulting in increased glucose metabolism. STK11 loss often co-occurs with KRAS mutation. KRAS and STK11 co-mutations synergise to drive metabolic re-programming and heightened glucose dependency, reversible with mTORC1/mTORC2 inhibition. mTORC2 is a central node driving enhanced glycolysis independent of Raptor and HIF-1α. mTORC1/2 inhibition suppresses pS6K, p4EBP1, HIF1a and GLUT1 in STK11/KRAS double mutant NSCLC cells and suppresses growth in vivo. Vistusertib (AZD2014) is a selective mTORC1/2 inhibitor. We report the results of outcomes of LUAD patients with STK11 loss+/-KRAS mutation treated with vistusertib, the first study to investigate the impact of mTOR inhibition in STK11 deficient LUAD.
Results: 19 patients (17 per-protocol) had STK11 loss without concomitant KRAS mutation (cohort B2S). 30 patients had STK11 loss with concomitant KRAS mutation (26 per-protocol) (cohort B2D). The confirmed objective response rate (95% credible interval) was 3.8% (0.1 – 18.5) for B2S, 9.8% (2.4 – 24.3) for B2D. Durable clinical benefit ((DCB), defined as no progression at 4th 6 weekly on treatment CT assessment) rate was 14.6% (3.6 – 34.7) for B2S, 24.4% (11.1 – 42.3) for B2D. Tumour growth inhibition (median % change from baseline (range)) in those with DCB was -18.5% (-48.0, 3.0) and in those with progression &lt;3 months/death +10.5% (-6.0, 42.0). Median PFS was 2.29 months (1.47 – 3.85) for B2S, 2.77 months (1.91 – 4.22) for B2D. Median OS was 9.84 months (6.23 – 16.85) for B2S, 6.08 months (4.20 – 9.26) for B2D. Clinically achievable concentrations of vistusertib achieve dose-dependent inhibition of STK11 deficient LUAD cell line viability in vitro. In contrast, IC50 for everolimus (mTORC1-only inhibition) exceeds pharmacologically achievable doses in all tested STK11 deficient cell lines. Rebound FOXO and Akt phosphorylation is observed after 48 hours of vistusertib treatment, with parallel activation of ERK. Longitudinal ctDNA from B2S/B2D were analysed using the Illumina TSO500 ctDNA platform. Using conventional p&lt;0.05 for significance, 2 genes were enriched at progression versus baseline: SMARCA4 (3/36 pre, 11/27 post, p=0.005) and FOXP1 (0/36 pre, 4/27 post, p=0.029). TRAF2 mutations were non-significantly enriched post-treatment (1/36 pre, 5/27 post, P = 0.076).
Conclusions: Despite strong rationale for mTORC1/2 inhibition in STK11 deficient LUAD, activity of vistusertib is modest. Pre-clinical work suggests that STK11 mutant LUAD cell lines are not exempt from relief of feedback inhibition during prolonged mTORC1/2 inhibition, driving Akt and FOXO phosphorylation. Further, longitudinal ctDNA analysis suggests that vistusertib treatment may drive selection for SMARCA4 mutations, which appears to be a common mechanism of resistance to targeted therapies. HLR and PF contributed equally. LB and GM contributed equally.
Citation Format: Helen L Robbins, Peter Fletcher, Joshua Savage, Manita Mehmi, Yvonne Summers, Alastair Greystoke, Noelle O’Rourke, Sanjay Popat, Pooja Jain, James Spicer, Judith Cave, Paul Shaw, David Gilligan, Danielle Power, Dean Fennel, Andrew D Beggs, Lucinda Billingham, Gary Middleton. mTOR targeting in STK11 deficient Non-Small Cell Lung Cancer (NSCLC): final results, pre-clinical rationale and biomarker analysis of a phase II trial of the mTORC1/2 inhibitor vistusertib in STK11 deficient lung adenocarcinoma (NLMT B2) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A115.