Abstract 1471: Incorporation of SKI-G-801, novel AXL inhibitor, with anti-PD-1 inhibitor plus chemotherapy improved anti-tumor activity and survival outcome via enhancing anti-tumor T cell immunity
Authors: Pyo Kyoung-Ho , Lee Wongeun , Lee Hee Kyu , Kim Dong Kwon , Jo Ha Ni , Synn Chun-Bong , Kim Jae Hwan , Byeon Yeongseon , Kim Young Seob , Ahn Beung-Chul , Hong Min Hee , Lim Sun Min , Cho Byoung Chul , Kim Hye Ryun 
Published: July 2021

Background: AXL has been identified to play multiple roles in the tumor microenvironment including the promotion of epithelial-mesenchymal transition and immune evasion. SKI-G-801, a small molecule inhibitor targeting phosphorylation of AXL, presented strong inhibition of cancer migration and invasion. Anti-PD-1(αPD-1) combined with paclitaxel(Pac)/carboplatin(Carbo) and pemetrexed(Pem)/cisplatin(Cis) are standard therapy in non-squamous and squamous lung cancer patients, respectively. Herein, we present that adding AXL inhibition with SKI-G-801 on αPD-1 plus chemotherapy suppressed tumor growth and improved overall survival and also enhanced anti-tumor T cell immunity in both non-squamous and squamous lung cancer models.

Methods: C3PQ squamous and TC-1 non-squamous lung cancer bearing mouse models were established. In C3PQ squamous model, mice were treated with 2 cycles of induction Carbo + Pac + αPD-1 and 13 cycles of maintenance with αPD-1. In TC-1 non-squamous model, mice were treated with 3 cycles of induction with Cis + Pem + αPD-1 and 14 cycles of maintenance therapy. Both models included the groups of SKI-G-801 treatment from induction therapy and/or maintenance therapy. The tumor growth and survival were monitored for 60 days in both models. The tumor infiltrated lymphocytes were analyzed by flow cytometry.

Results: In TC-1 non-squamous model, upfront addition of SKI-G-801 on αPD-1 plus Pem/Cis chemotherapy followed by αPD-1 and Pem maintenance showed the superior overall survival to the others (vs. αPD-1+ Pem/Cis and αPD-1 + Pem maintenance; p&lt;0.001, vs. αPD-1 + Pem/Cis and αPD-1 + Pem + SKI-G-801 maintenance; p&lt;0.01, vs. αPD-1 + Pem/Cis and SKI-G-801 maintenance; p&lt;0.01). In C3PQ squamous model, upfront addition of SKI-G-801 on αPD-1 plus Pac/Carbo followed by αPD-1 prolonged the overall survival compared the others (vs. αPD-1+Pac/Carbo and αPD-1 maintenance; p&lt;0.05, vs. αPD-1 + Pac/Carbo and αPD-1+ SKI-G-801 maintenance; p&lt;0.05, vs. αPD-1 + Pac/Carbo + SKI-G-801 maintenance; n.s.). In line with survival outcomes, upfront SKI-G-801 on αPD-1 combined with chemotherapy showed the strong tumor growth inhibition compared to the others. Especially, effector memory T cells (CD3+CD4+CD44+CD107-) and IFN-γ secretion level of CD8+ T cells were significantly increased in SKI-G-801 treated groups in C3PQ model (p&lt;0.05).

Conclusion: Incorporation of SKI-G-801, a novel AXL inhibitor, with αPD-1 combined with chemotherapy significantly improved overall survival and anti-tumor activity in both non-squamous and squamous lung cancer model through enhancing cytotoxicity of CD8+ T cells and memory CD4+ T cells. These findings provide mechanistic insight into the activity of SKI-G-801 combined with standard therapy and support its clinical development in metastatic NSCLC as first line therapy.

Citation Format: Kyoung-Ho Pyo, Wongeun Lee, Hee Kyu Lee, Dong Kwon Kim, Ha Ni Jo, Chun-Bong Synn, Jae Hwan Kim, Yeongseon Byeon, Young Seob Kim, Beung-Chul Ahn, Min Hee Hong, Sun Min Lim, Byoung Chul Cho, Hye Ryun Kim. Incorporation of SKI-G-801, novel AXL inhibitor, with anti-PD-1 inhibitor plus chemotherapy improved anti-tumor activity and survival outcome via enhancing anti-tumor T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1471.