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While first line targeted therapies are the current standard of care treatment for non-small cell lung cancer (NSCLC) with actionable mutations, the cancer cells inevitably acquire resistance to these agents over time. Immune check-point inhibitors (ICIs) have improved the outcomes of metastatic NSCLC, however, its efficacy in those with targetable drivers is largely unknown. In this manuscript, we reviewed the published data on ICI therapies in NSCLC with  ALK ,  ROS1 ,  BRAF ,  c-MET ,  RET ,  NTRK ,  KRAS , and  HER2 (ERBB2)  alterations. We found that the objective response rates (ORRs) associated with ICI treatments in lung cancers harboring the  BRAF  (0–54%),  c-MET  (12–49%), and  KRAS  (18.7-66.7%) alterations were comparable to non-mutant NSCLC, whereas the ORRs in  RET  fusion NSCLC (less than10% in all studies but one) and  ALK  fusion NSCLC (0%) were relatively low. The ORRs reported in small numbers of patients and studies of  ROS1  fusion,  NTRK  fusion, and  HER 2  mutant NSCLC were 0–17%, 50% and 7–23%, respectively, making the efficacy of ICIs in these groups of patients less clear. In most studies, no significant correlation between treatment outcome and PD-L1 expression or tumor mutation burden (TMB) was identified, and how to select patients with NSCLC harboring actionable mutations who will likely benefit from ICI treatment remains unknown.

Immunotherapy in Non-Small Cell Lung Cancer With Actionable Mutations Other Than EGFR