Immune-related gene expression profiling and alectinib efficacy for patients with ALK-Rearranged non-small cell lung cancer: exploratory analysis of a prospective observational study.

The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC). We performed immune-related gene expression profiling (irGEP) for ALK-rearranged NSCLC to assess the characteristics of the tumor microenvironment and explore potential therapeutic avenues. This study analyzed tumor samples from the ALCURE trial, a prospective observational study examining the efficacy of and mechanisms of resistance to alectinib in patients with ALK-rearranged NSCLC. The irGEP analysis was performed with a panel encompassing 750 immune-related genes. Tumor samples from 52 of the 249 ALCURE trial patients were analyzed. Tumors with high CD8A expression showed upregulation of SNAI1 and downregulation of CDH1, with these genes encoding an epithelial-mesenchymal transition (EMT)-related transcription factor and E-cadherin, respectively, suggestive of EMT progression in these tumors. Tumors with high CD8A expression also manifested downregulation of genes related to tumor angiogenesis, including ANGPT2 (angiopoietin-2) and FLT1 (VEGF receptor 1), suggestive of a quiescent angiogenic state that may facilitate the recruitment of CD8+ T cells. Progression-free survival on alectinib appeared longer in patients with high than in those with low CD8A expression; however, this difference was not statistically conclusive (HR, 0.49 [95% CI, 0.18-1.35]). CD8+ T cell infiltration may be associated with the alectinib efficacy in ALK-rearranged NSCLC. Anti-angiogenic therapies may enhance antitumor immunity and thereby augment the efficacy of alectinib as well as that of ICIs for such tumors.