Optimal Management of Patients with Advanced NSCLC Harboring High PD-L1 Expression and Driver Mutations.

Patients with stage IV or recurrent/metastatic non-small cell lung cancer (NSCLC) whose tumors harbor high PD-L1 expression and driver mutations with approved targeted treatments (EGFR, ALK, BRAFV600E, ROS1) should receive initial therapy with targeted therapy based on impressive clinical activity. PD-(L)1 inhibitors have demonstrated minimal activity in many driver mutation subsets including EGFR and ALK and appears to have more benefit in smoking-associated oncogenic drivers (KRAS, BRAF). For KRAS-driven tumors, co-mutations such as STK11/LKB1 are negative predictive markers of immunotherapy with or without chemotherapy. Therefore, driver mutations need to be evaluated before pursuing immunotherapy independent of PD-L1 expression level. Caution should be used with TKIs following or concurrent with immunotherapy owing to potentially increased toxicity. New immunotherapy combinations are needed especially for oncogene-driven tumors associated with never or light smoking history.