Abstract 3245: AXL as a therapeutic target in STK11 mutant NSCLC
Authors: Blø Magnus , Rayford Austin , Madeleine Noëlly , Gärtner Fabian , Bohan Dana , Ruggio Natalie , Li Huiyu , Girard Luc , Brekken Rolf , Minna John , Ånerud Marianne , Maury Wendy , Gorcea-Carson Claudia , Gausdal Gro , Micklem David R. , McCracken Nigel 
Published: April 2023

Abstract
STK11 (LKB1) is a tumor suppressor, and loss-of-function mutations contribute to tumorigenesis. Mutations in the STK11 gene (STK11m) are present in ~ 20% of NSCLCs and are associated with poor response to chemotherapy and immune checkpoint inhibition (ICI) resulting in inferior survival outcomes. STK11m tumors are characterized by high oxidative stress/ROS, EMT, enhanced replication stress tolerance, resistance to DNA damage and a highly immunosuppressive tumor microenvironment with limited activation and expansion of anti-tumor CD8 T-cells. AXL, a member of the TAM family of receptor tyrosine kinases, is activated in response to cellular stress such as ROS and hypoxia. AXL expression and activation is associated with EMT and drug resistance, tumor tolerance towards oxidative stress and apoptosis, as well as an immunosuppressed tumor microenvironment.
We have previously shown that selective AXL inhibition by bemcentinib potentiated ICI in STK11m NSCLC preclinical models and led to objective clinical response in individuals with STK11m NSCLC receiving bemcentinib and pembrolizumab (NCT03184571). Data from this clinical study, an independent real-world cohort of patients studied at the Haukeland Hospital in Bergen, Norway (REC 45562) and published results1, suggest AXL is expressed in ~ 80% of NSCLCs harboring a STK11m, indicating AXL expression is a characteristic of STK11m NSCLC and confirming that AXL is an attractive target in STK11m NSCLC.
Inhibition of AXL in dendritic cells has been shown to increase ICI responses in preclinical models of STK11m NSCLC1. The relative contribution of targeting AXL in STK11m tumor cells vs the tumor microenvironment, and the impact on tumor cells after tumor cell targeting needs further exploration. Transcriptional analysis of STK11m and STK11wt sequences from public datasets, NCT03184571 patients and NSCLC cell lines identified transcriptional signatures consistent with the known roles of STK11 in DNA damage response and immunosuppression. Treatment of STK11m NSCLC cell lines with the AXL inhibitor bemcentinib led to a reduction in the STK11-associated DDR signature and increase in inflammatory signatures demonstrating the impact of AXL targeting on tumor cells.
Due to the high unmet medical need in individuals harboring a STK11 mutation, the encouraging efficacy in the NCT03184571 clinical trial and the high incidence of AXL protein expression in STK11m tumors, a global, open-label Phase 1b/2a trial to determine the safety, tolerability and anti-tumor activity of bemcentinib with SOC (pembrolizumab, pemetrexed and carboplatin) in 1L advanced/metastatic non-squamous NSCLC patients with STK11 mutations and no actionable mutations is currently enrolling. The Phase 1b part of the study will evaluate the safety and tolerability of bemcentinib regardless of STK11 status, whereas the Phase 2a part will assess the efficacy in NSCLC patients with STK11 mutations.
1 Li et al., 2022; Cell Rep Med., PMID: 35492873
Citation Format: Magnus Blø, Austin Rayford, Noëlly Madeleine, Fabian Gärtner, Dana Bohan, Natalie Ruggio, Huiyu Li, Luc Girard, Rolf Brekken, John Minna, Marianne Ånerud, Wendy Maury, Claudia Gorcea-Carson, Gro Gausdal, David R. Micklem, Nigel McCracken. AXL as a therapeutic target in STK11 mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3245.