Biomarker-Directed Use of Immune Checkpoint Inhibitors for NSCLC
The treatment landscape of driver-negative NSCLC is rapidly evolving.1 Immune-checkpoint inhibitors, specifically those targeting PD-1 or PD-L1, have demonstrated durable efficacy in a subset of patients with NSCLC, becoming the cornerstone of first-line therapy.2 Research is underway to identify biomarkers that might predict which patients respond best to the immune checkpoint inhibition beyond the tumor PD-L1 expression.3
Examples of predictive biomarkers for immune checkpoint inhibition include antigen presentation, lymphocytes (ie, tumor-infiltrated or peripheral), the gut microbiome, and DNA damage signaling pathways (Figure 1, Table 1).
Immune checkpoint inhibitors that are currently available to treat non-small cell lung cancer include those that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1) (Figure 2).2,5
A number of checkpoint inhibitors currently have approved indications in the treatment of patients with NSCLC, as monotherapy and in combination regimens (Table 2).2,5,6
Interpretation of biomarker data remains an important priority for medical oncologists managing patients with advanced NSCLC. Current evidence-based guidelines include PD-L1 testing as part of a broader biomarker testing strategy for all patients diagnosed with NSCLC. Importantly, some oncogenic drivers (eg, some oncogenic drivers [ie, EGFR exon 19 deletion or L858R; ALK, RET, or ROS1 rearrangements] have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors) are associated with less benefit from anti-PD-L1 therapy.2 All patients should be tested for these drivers prior to initiating anti-PD-L1 therapy. Targeted therapy should take priority over immunotherapy for these patients.2 Recognizing the importance of TPS of PD-L1 positivity and TMB is crucial in the selection of appropriate therapy.
References
- Grant MJ, Herbst RS, Goldberg SB. Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol. 2021;18:625-644. https://doi.org/10.1038/s41571-021-00520-1
- NCCN Clinical Practice Guidelines. Non-Small Cell Lung Cancer. Version 3.2025. January 14, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
- Yamaguchi H, Hsu JM, Sun L, Wang SC, Hung MC. Advances and prospects of biomarkers for immune checkpoint inhibitors. Cell Rep Med. 2024;5:101621. doi:10.1016/j.xcrm.2024.101621
- Bai R, Lv Z, Xu D, Cui J. Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark Res. 2020;8:34. https://doi.org/10.1186/s40364-020-00209-0
- Suraya R, Tachihara M, Nagano T, Nishimura Y, Kobayashi K. Immunotherapy in advanced non-small cell lung cancers: Current status and updates. Cancer Manag Res. 2022;14:2079-2090. https://doi.org/10.2147/CMAR.S366738
- National Cancer Institute. Drugs Approved for Lung Cancer. Updated March 14, 2025. Accessed April 4, 2025. https://www.cancer.gov/about-cancer/treatment/drugs/lung.
