1UT Southwestern Medical Center, Dallas, TX, USA. 2BerGenBio ASA, Bergen Norway. 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4Merck & Co., Inc., Kenilworth, NJ, USA.

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

AbstractMutations in the tumor suppressor STK11/LKB1 are associated with negativepredictive and prognostic impact in non-small cell lung cancer patients receivingimmune checkpoint blockade in several published cohorts, although there havebeen some conflicting reports on the association of such mutations with patientoutcomes in this setting [1-9]. We found that introduction of a Stk11/Lkb1 (L)mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss(KP) resulted in a syngeneic KPL tumor model that recapitulated the responses andtumor microenvironment of human STK11/LKB1 mutant NSCLCs. Mechanistically,KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells to respond to ICB treatment.Systemic inhibition of AXL with the small molecule inhibitor bemcentinib/BGB324results in increased type I interferon secretion from dendritic cells that expandstumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1ICB for KPL tumors. This effect was observed in syngeneic immunocompetent mousemodels and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumorxenografts. Anecdotally, 3 of 3 evaluable NSCLC patients with identified STK11/LKB1mutations receiving bemcentinib and pembrolizumab demonstrated objectiveclinical response to combination therapy. We conclude that in these models AXL is acritical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

STK11 Mutated Tumors Lack TCF1 CD8 T Cells

Funding Resources / Acknowledgements This work was supported by: CPRIT training grant RP210041(to HL); RCN industrial PhD studentship 311397(to AR); BerGenBio ASA and NIH grants R01 CA243577 and U54 CA210181 (to RAB); NIH SPORE P50CA070907, U54 CA224065, and CPRIT RP160652 (to JDM); RP150072 and RP180725 (Y-XF); NIH P30CA142543 (RAB, JDM, Y-XF). We also thank the ARC, Whole Brain Microscopy Facility and Flow CytometryFacility cores at UTSW for assistance and we acknowledge NIH P01 HD087150 for cord blood collection.

Huiyu Li1, Zhida Liu1, Longchao Liu1, Hongyi Zhang1, Chuanhui Han1, Luc Girard1, Hyunsil Park1, Anli Zhang1, Chunbo Dong1, Jianfeng Ye1, Austin Rayford2, Michael Peyton1, Xiaoguang Li1, Kimberley Avila1, Xuezhi Cao1, Shuiqing Hu1, Md Maksudul Alam1, Esra Akbay1, Luisa M. Solis3, Carmen Behrens3, Sharia Hemandez-Ruiz3, Lu Wei3, Ignacio Wistuba3, John. V. Heymach3, Michael Chisamore4, David Micklem2, Hani Gabra2, Gro Gausdal2, James B. Lorens2, Bo Li1, Yang-Xin Fu1, John D. Minna1, and Rolf A. Brekken1

Conclusion / SummaryLack of TCF1-expressing CD8 T cells prevents ICB efficacy in KPL tumors. Systemic inhibition of AXL increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells and restored anti-PD-1 efficacy in STK11/LKB1 mutant tumors. Anecdotally, NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. These results show that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

Therapeutic Effects in NSCLC Xenografts & Patients

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Bemcentinib Sensitizes STK11 Mutant tumors to ICB TherapyKPL Allografts TCF1 CD8 T Cells

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References: 1Gu M, Xu T, et al. Ther Adv Med Oncol. 2021;13:17588359211006950. 2Cho BC, et al. Cancer Res. 2020;80(16 Supplement):CT084. 3Aredo JV, et al. Lung Cancer. 2019;133:144-150. 4Kwack WG, et al. Oncol Targets Ther. 2020;13:8901–8905. 5Shire NJ, et al. PLoS One. 2020;15(9):e0238358. 6Skoulidis F, et al. Cancer Discov.2018;8(7):822-835. 7Wang H, et al. 2020;84:106574. 8Kitajima S, et al. Cancer Discov. 2019;9(1):34-45. 9 Mograbi B, et al. Diagnostics (Basel). 2021;11(2):196

Table 1: NCT03184571, BerGenBio ASA and Merck & Co., Inc.Age/Gender 79 / Male 73 / Male 51 / MalePrevious therapy Carboplatin / Paclitaxel Pembrolizumab AtezolizumabSTK11 mutation Moderate LD140PY Moderate D115V High S271fsKRAS mutation Not detected Not detected Not detectedTP53 mutation High (multiple variants) Moderate R337L High R110PPD-L1 TPS 0 15 0AXL Expression Tumor and Immune weak pos. Immune strong pos. Immune pos.Target Lesions 1 Lung, 1 Adrenal 1 lymph node, 1 chest wallSum Longest Diam. 79 mm 85 mm 129 mmPFS on study 10.1 months 3.5 months 6.2 monthsOverall survival >33 months (ongoing) 10 months 10 monthsBest response Partial Response Stable Disease Stable Disease

Graphic Abstract