Abstract 4479: Immune exhaustion of tumor microenvironment mediates crizotinib resistance in ALK rearranged advanced non small cell lung cancer

Abstract

Abstract Introduction: Previous study showed the correlation between immune tumor microenvironment and the efficacy of checkpoint inhibitor in non-small cell lung cancer (NSCLC). This study evaluated whether biomarkers for immune tumor microenvironment including programmed death ligand 1 (PD-L1), cluster of differentiation 8 (CD8), Granzyme B (GZMB) and T cell receptor (TCR) could predict the treatment response to the first-line crizotinib of patients with ALK-rearranged non-small cell lung cancer (NSCLC). Methods: We retrospectively evaluated patients with advanced NSCLC who received crizotinib at Hunan Cancer Hospital between January 2016 and December 2018. The patients' baseline expression of PD-L1, CD8 and GZMB was evaluated in one slide using immunofluorescence. TCR was also evaluated with paired blood samples simultaneously. Results: All the 108 eligible patients were stratified according to their expression profile into PD-L1+/CD8+/GZMB+ (n=21), PD-L1-/CD8+/GZMB+ (n=42), PD-L1+/CD8-/GZMB- (n=23), and PD-L1-/CD8-/GZMB- (n=22) group. Patients with strong PD-L1 expression have a significantly inferior objective response rate (36.5% versus 72.2%, p = 0.002), and shorter progression-free survival (PFS) (5.6 versus 16.5 months, p < 0.001) as compared to patients with weak or negative PD-L1 expression. Among the four groups, we found patients with PD-L1-/CD8+/GZMB+ had the best response (85.7% versus 26%, p=?), while PD-L1+/CD8-/GZMB- showed primary resistance to crizotinib had the worse outcomes (4.6 versus 18 months, p < 0.001). Furthermore, for TCR analysis, the counts of TCR and Shannon index was strongly correlated with longer PFS for crizotinib treatment (20.6 versus 8.2months, p < 0.001; 19.3 versus 6.1 months, p < 0.001, respectively). However, the clonality acts as poor predictive marker with worse PFS (6.8 versus 18.2 months, p < 0.001). Finally, three patients with de novo resistance to crizotinib experienced a favorable response to anti-PD-1 therapy. Conclusions: This study revealed immune exhaustion for tumor microenvironment as a poor predictive marker in first-line crizotinib-treated ALK-rearranged non-small cell lung cancer. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1, CD8, GZMB, and TCR expression and suggest potential therapeutic sensitivity to PD-1 blockade. Citation Format: Yongchang Zhang. Immune exhaustion of tumor microenvironment mediates crizotinib resistance in ALK rearranged advanced non small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4479.