Biomarkers for Immunotherapy in Driver-Gene-Negative Advanced NSCLC

Abstract

Outcome improvement in patients with driver-gene-negative advanced non-small cell lung cancer (NSCLC) has been significantly enhanced through targeting the immune system, specifically the PD-L1/PD-1 axis. Nevertheless, only a subset of patients with advanced NSCLC may derive benefits from immuno-monotherapy or immunotherapy combined with chemotherapy. Hence, in order to identify patients who will gain the maximum advantage from immunotherapy, it is crucial to investigate predictive biomarkers. This review provides a summary of the currently identified biomarkers associated with the extent of benefit from immuno-monotherapy or immunotherapy combined with chemotherapy in patients with advanced NSCLC. These biomarkers can be categorized into three groups: tumor-related, tumor-microenvironment-related, and host-factor-related.Tumor-related factors include PD-L1 expression, tumor mutational burden and specific genetic mutations, while tumor-microenvironment-related factors include extracellular vesicles and T-cell receptors, and host-related factors include systemic inflammation, circulating fatty acid profile, and the microbiome.

Vitiligo-like Lesions as a Predictor of Response to Immunotherapy in Non-Small Cell Lung Cancer: Comprehensive Review and Case Series from a University Center

“…In the rapidly evolving landscape of cancer treatment, ICIs have emerged as a transformative approach, particularly in NSCLC [1,52,53,[59][60][61][62][63][64]. Nevertheless, the success of ICI treatment is closely intertwined with the identification of predictive biomarkers [65,66]. These biomarkers play a pivotal role in stratifying patients, guiding treatment decisions, and optimizing therapeutic outcomes.…”

“…Among the main identified predictive markers, PD-L1 expression, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), neutrophil/lymphocyte ratio (NLR), and specific genetic mutations emerged as established or potential tools to tailor ICIbased strategies for NSCLC patients [65,66]. The prognostic value of these biomarkers is summarized in Table 3.…”

“…Despite its inaccurate and insufficient value, PD-L1 expression is still consensually referred to as the most current clinically impactful biomarker predictive of ICI response in NSCLC [65,66]. Trials like IMpower010, PACIFIC, KEYNOTE-024, KEYNOTE-042, IMpower110, CheckMate-026 and EMPOWER-Lung 1 are some of the most relevant studies that allowed understanding of that, for different defined cut-offs, with different drugs in different settings, higher values of PD-L1 expression tend to translate into greater benefit from ICI use or, eventually, differentiate from those without any clinical outcome advantage from ICI use [1,52,53,[59][60][61][62][63][64].…”

Development of Ex Vivo Analysis for Examining Cell Composition, Immunological Landscape, Tumor and Immune Related Markers in Non-small Cell Lung Cancer

“…Nevertheless, some NSCLC patients with high levels of tumor PD-L1 have poor responses and, vice versa, patients with low or even negative PD-L1 expression exhibit good and durable responses to checkpoint inhibitors [17][18][19]. Such discrepancy in the risk-benefit assessments of immunotherapy in NSCLC may be caused by multiple factors, including, on the one hand, a significantly heterogeneous, plastic, and dynamic expression of this marker in tumors [20][21][22][23][24][25][26][27], the availability of multiple clones of anti-PD-L1 antibodies [28][29][30], a variability between pathologists' interpretation (especially for low PD-L1 TPS) [31,32], and sample quality issues [33] in diagnostic testing; and, on the other hand, the intrinsic and as-yet undiscovered biological complexity underpinning tumor-immunity interplay [34][35][36].…”

“…NSCLC and other solid tumors are composed not only of cancer cells, but also of heterogeneous subsets of non-transformed stromal cells, mainly cancer-associated fibroblasts and tumor-infiltrating immune cells from the myeloid and lymphoid lineage, establishing a complex tumor microenvironment (TME) with peculiar structural, biophysical, and secretory characteristics which shape tumor progression and might play a key role in the responses to therapies [34][35][36][37]. At the tumor-stroma interface, the immune activation response in cancer cells is believed to be likely to lead to the preferential expression of PD-L1 in this region [34].…”