Background and Objective: Immunotherapy and novel targeted therapies are revolutionizing the outcomes for patients with non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) historically had a marginal role in treating patients with “common” oncogenic drivers, however there’s still little evidence when it comes to uncommon and emerging molecular targets. The aim of this narrative review is to analyze the impact of immunotherapy in NSCLC harboring uncommon and novel driver mutations.

Methods: All searches were performed on MEDLINE/PubMed matching the keywords of NSCLC, immunotherapy, and the single mutations in order to obtain an oncogene-specific literature. We excluded from our research EGFR, ALK and ROS-1 mutations due to the already established role of target therapy in tumors bearing these driver mutations. We also excluded all those mutations with no target-specific therapy approved, for it was impossible to compare immunotherapy with other specific treatments. Non-English literature was excluded. All searches were conducted between May and September 2022.

Key Content and Findings: The immunologic environment and the smoking signature are predominant features in determining response rates and survival outcomes for patients treated with immunotherapy. Consistently with this statement, data from literature underline that among the oncogene-addicted family, patients carrying KRAS G12C or BRAF mutation gather better results with ICIs. On the contrary, patients harboring mutations such as RET, NTRK or EGFR’s Insertion of exon 20, with classical oncogene-addicted presentation (i.e., non-smoker, young females), tend to be refractory to immunotherapy. Many questions remain unsolved for other druggable mutations such as cMET, where the type of alteration seems to be related to the immune-sensitivity, or HER-2 with contrasting results from one study to another.

Conclusions: Target therapy still plays the main role in oncogene-addicted NSCLC’s treatment, although a deepened understanding of molecular profiling could probably open new perspectives for the use of immunotherapy even in this setting, given the promising results obtained with some specific mutations. New prospective studies could solve this challenging question.