AstraZeneca.

Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.

By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained. We showed that distinct combinations of , and mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of mutations without co-occurring or alterations (-mut/--WT), independently of mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16-0.63, < 0.001) was observed in anti-PD-1-treated patients harboring -mut/--WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Our study reveals that different combinations of , and mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. .