Efficacy of immune checkpoint inhibitors in rare oncogene-driven non-small cell lung cancer: a narrative review of BRAF, MET, HER2, RET, NTRK, and EGFR exon 20 insertions

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC) in patients without clinically relevant EGFR , ALK , or ROS1 alterations. However, their efficacy in rare oncogene-driven NSCLC and their optimal integration with targeted therapies remain incompletely defined. This narrative review summarizes the current evidence regarding ICI-based therapies in NSCLC harboring BRAF , MET exon 14 ( MET ex14) skipping, HER2 ( ERBB2 ), RET , NTRK , and EGFR exon 20 insertion ( EGFR ex10ins) alterations. Available data demonstrate substantial heterogeneity in immunotherapy responsiveness across these molecular subgroups. BRAF -mutated NSCLC appears to derive the greatest benefit from ICIs, particularly among patients with smoking-associated tumors, high PD-L1 expression, and TP53 co-mutations. In contrast, ICI monotherapy generally demonstrates modest activity in MET ex14, HER2 -mutated, and EGFR ex20ins-positive NSCLC, whereas chemoimmunotherapy produces more favorable outcomes. In addition, RET -rearranged tumors consistently demonstrate poor responses and evidence regarding NTRK fusion-positive NSCLC remains limited. Across several molecular subgroups, chemoimmunotherapy appears to provide greater clinical benefit than ICI monotherapy, although targeted therapies remain the preferred treatment strategy owing to their superior efficacy. Overall, the activity of ICIs in rare oncogene-driven NSCLC is strongly influenced by tumor biology and the immune microenvironment. Future prospective studies should focus on identifying predictive biomarkers beyond PD-L1 and defining the optimal sequencing and integration of immunotherapy with targeted therapies in molecularly selected patients.