Background In NSCLC, mutations in LKB1/STK11, KEAP1, SMARCA4, and KRAS are associated with unfavorable treatment outcomes, regardless of treatment modality.1–4 These mutations shape tumor survival, mediate enhanced tolerance to oxidative and metabolic stress and sustain an immune suppressed tumor microenvironment (TME) resulting in reduced therapeutic efficacy.5–8 The receptor tyrosine kinase AXL is a poor prognostic biomarker in NSCLC. Activated in response to cellular stress, AXL drives drug resistance, metastasis and an immune-suppressive and tumor-promoting TME.9–12 Bemcentinib (BEM), a highly selective oral AXL inhibitor, enhances anti-tumor effects of immune-check-point inhibition (ICI) in pre-clinical NSCLC models harboring mutations in STK11, KEAP1, SMARCA4 and KRAS.9 In the BGBC008 ph2 open-label, single-arm study of BEM + pembrolizumab (PEM) in 2L NSCLC following platinum-based chemotherapy and/or ICI, the BEM+PEM combination was well tolerated and efficacious compared to historical controls.14 We present here sub-mutational analyses of patients from BGBC008, specifically those with STK11, KEAP1, SMARCA4, and KRAS mutations and those characterized by functional STK11 loss as determined by a transcriptional signature (STK11LOSS).15
Methods Exploratory analyses assessed AXL and PD-L1 expression by immunohistochemistry (IHC), mutations by whole exome sequencing (WES) and STK11LOSS by RNA sequencing. Association between mutational status and median overall survival (mOS), median progression-free survival (mPFS) and PD-L1 status were included. PD-L1 negativity (PD-L1-ve) was defined as IHC tumor proportion score (TPS)<1. AXL expression was scored in tumor (H-score) and immune cells (percent AXL+ve immune cells/tumor area). Longitudinal single-cell proteomic analysis of peripheral blood mononuclear cells (PBMCs) by mass cytometry is ongoing.
Results Of the 90 evaluable patients in the BGBC008 study, 56 pts were subjected to WES. The correlation between mutational status and clinical efficacy, as well as PD-L1 status are reported in table 1. Data indicate that AXL is present on the immune and/or tumor cells in 87–100 % of patients harboring mutations associated with poorer outcome in NSCLC. BEM+ PEM induces similar or better survival outcome in pts harboring mutations compared to wild-type (WT). Encouragingly, better mPFS in KRASmut pts compared to KRASWT regardless of the type of KRASmut or co-mutational status. A higher incidence of -PD-L1-ve status was seen in patients harbouring STK11mut and KEAP1mut as well as STK11LOSScompared to WT.
Conclusions In 2L, BEM+PEM demonstrated survival benefit in patients harboring mutations associated with poorer response to 1L platinum-based chemotherapy and/or ICI supporting the benefit of targeting AXL in patients with an immune/suppressed TME.
Acknowledgements Thank you to all the patients and their families, investigators and study coordinators who participated in and supported this study. The study was performed in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Trial Registration BGBC008 trial (NCT03184571)
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Ethics Approval This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and consistent with Good Clinical Practices (GCP) and applicable regulatory requirements. The protocol, the patient information and consent form and other relevant study documentation were approved by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) for each study center before initiation of the study.
Consent Patients provided their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment prior to commencing the study Screening procedures.
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