602 AXL targeting with bemcentinb restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through innate immune cell mediated expansion of TCF1+ CD8 T cells

Background Mutations in tumor suppressor STK11/LKB1 are associated with negative predictive and prognostic impact NSCLC patients receiving immune checkpoint inhibitors (CPI) several published cohorts, although there have been some conflicting reports on the association of such mutations patient outcomes this setting [1–9]. tumors characterized by a suppressive micro-environment devoid cytotoxic T cells, we hypothesized that targeting receptor tyrosine kinase AXL, known driver an innate microenvironment, would restore sensitivity to PD-1 syngeneic pre-clinical models as well harboring mutated NSCLC. Methods Stk11/Lkb1 (L) mutation was introduced CRISPR technology into murine lung adenocarcinomas driven mutant Kras Trp53 loss (KP). Sensitivity towards anti-PD-1 evaluated absence presence small molecule AXL inhibitor bemcentinib KPL model human xenograft carrying mutation. The landscape mapped following introduction therapeutic intervention anti-PD-1/pembrolizumab bemcentinib. FFPE fine-needle aspirate biopsies target lesions were acquired from at screening immediately prior enrollment BGBC008, PhII single-arm, 2-stage study (200mg/d) pembrolizumab (200 mg/q3wk) for previously-treated stage IV adenocarcinoma who CPI naïve or refractory. Patients assessed response according RECIST1.1 criteria scheduled scan intervals. Results Introduction resulted refractory tumor. Mechanistically occurred because NSCLCs lacked TCF1-expressing CD8 phenotype recapitulated NSCLCs. Systemic inhibition increased type I interferon secretion dendritic cells resulting expansion tumor-associated TCF1+PD-1+CD8 restored PD-1. This effect observed immunocompetent mouse humanized mice bearing xenografts.In ongoing clinical trial ( NCT03184571 ), 3 evaluable identified demonstrated objective response/clinical benefit combination Conclusions In these models, is critical targetable suppression contributing resistance. Our results show rescues deficit represents new strategy therapy Acknowledgements authors like thank all their caretakers participating trial. Trial Registration treated enrolled BGBC008 (BerGenBio ASA Merck & Co., Inc., Kenilworth NJ, USA, ) References Gu M, Xu T, Chang P. KRAS/LKB1 KRAS/TP53 co-mutations create divergent signatures adenocarcinomas. Ther Adv Med Oncol. 2021;13:17588359211006950. Cho BC, Lopes G, Kowalski DM. Relationship between STK11 KEAP1 mutational status efficacy KEYNOTE-042: monotherapy first-line PD-L1 positive advanced Cancer Res. 2020;80(16 Supplement):CT084. Aredo JV, Padda SK, Kunder CA. Impact KRAS subtype concurrent pathogenic non-small cell cancer outcomes. Lung Cancer. 2019;133:144–150. Kwack WG, Shin SY, Lee SH. Primary Resistance Immune Checkpoint Blockade STK11/TP53/KRAS-Mutant Adenocarcinoma High Expression. Oncol Targets Ther. 2020;13:8901–8905. Shire Klein AB, Golozar A. (LKB1) metastatic NSCLC: Prognostic value real world. PLoS One. 2020;15(9):e0238358. 6. Skoulidis F, Goldberg ME, Greenawalt Inhibitor KRAS-Mutant Adenocarcinoma. Discov. 2018;8(7):822–835. 7. Wang H, Guo J, Shang X. Less infiltration worse prognosis after immunotherapy harbored Int. Immunopharmacol. 2020;84:106574. 8. Kitajima S, Ivanova E, Gou S. Suppression STING Associated LKB1 Loss KRAS-Driven 2019;9(1):34–45. 9. Mograbi B, Heeke Hofman Importance Assessment Non-Small Cell Carcinomas. Diagnostics (Basel). 2021;11(2):196. Ethics Approval approved ethical committees: Use cord blood: UT Southwestern (UTSW) Parkland Hospital, STU 112010-047Animal studies: UTSW Medical Center, Institutional Animal Care Committee, APN 2015-100921Clinical study: London Bridge Research Committee (UK): 17/LO/0418; REC-South East (Norway): 2017/473; Drug University Hospital Clinic Barcelona (Spain): BGBC008/MK-3475_PN-531; College Wisconsin Review Board #4 (USA): PRO00029453