Biomarker-Directed Use of Immune Checkpoint Inhibitors for NSCLC
Immune-checkpoint inhibitors (ICI), particularly those targeting programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), have demonstrated durable efficacy in a subset of patients with non-small cell lung cancer (NSCLC), establishing themselves as the cornerstone of first-line therapy for non-driver mutated NSCLC.1,2
Interpretation of biomarker data remains an important priority for medical oncologists managing patients with advanced NSCLC. Predictive biomarkers of ICI response currently approved by the United States FDA (shown in Figure 1) are tumor PD-L1 expression, tumor mutation burden (TMB), and microsatellite-instability (MSI).3 Current evidence-based guidelines include PD-L1 testing as part of a broader biomarker testing strategy for all patients diagnosed with NSCLC.1,2 Importantly, some oncogenic drivers (ie, EGFR exon 19 deletion or L858R point mutation; ALK, RET, or ROS1 rearrangements) are associated with less benefit from anti-PD-L1 therapy.1
Practice Tips
- Patients should be tested for these drivers prior to initiating anti-PD-L1 therapy
- Targeted therapy should take priority over immunotherapy for these patients
- Recognizing the importance of TPS of PD-L1 positivity and TMB is crucial in the selection of appropriate therapy
Existing biomarkers are imperfect; therefore, research is underway to identify predictive biomarkers beyond tumor PD-L1 expression to aid patient selection for ICI therapy (Figure 1).3-5
Immune checkpoint inhibitors approved to treat NSCLC include those that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), PD-1 or PD-L1 (Figure 2).1,2,6 These agents carry varying indications as shown in Table 2.1,2
Immune checkpoint inhibition-based therapy is the first-line standard of care for patients with metastatic NSCLC that does not harbor actionable mutations (Figure).2 Regimen selection is based on various factors including PD-L1 expression level, histology, disease symptoms and burden, and toxicity concerns.
References
- NCCN Clinical Practice Guidelines in Oncology®. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 5.2026. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
- Reuss JE, Bazhenova L, Ismaila N, et al. Therapy for stage IV non–small cell lung cancer without driver alterations: ASCO living guideline, 2026.3.0. J Clin Oncol. 2026;44:e56-e88. https://doi.org/10.1200/JCO-25-02825
- Wang SL, Chan TA. Navigating established and emerging biomarkers for immune checkpoint inhibitor therapy. Cancer Cell. 2025;43:641-664. http://doi.org/10.1016/j.ccell.2025.03.006
- 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. https://doi.org/10.1016/j.xcrm.2024.101621
- Garriazzo E, Colamartini F, Ubaldi M, Santo V, Brunetti L, Tomarelli C. Emerging predictive biomarkers of immunotherapy sensitivity in patients with non-small cell lung cancer. Immunotargets Ther. 2025;15:567238. https://doi.org/10.2147/ITT.S567238
- National Cancer Institute. Drugs Approved for Lung Cancer. Updated March 14, 2025. https://www.cancer.gov/about-cancer/treatment/drugs/lung
- 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
All URLs accessed April 13, 2026
