Tailoring Therapeutic Strategies in Non-Small-Cell Lung Cancer: The Role of Genetic Mutations and Programmed Death Ligand-1 Expression in Survival Outcomes

Abstract

Background: This study aims to assess the real-world impact of advancements in first-line systemic therapies for non-small-cell lung cancer (NSCLC), focusing on the role of driver gene mutations and programmed death-ligand 1 (PD-L1) expression levels.

Methods: Conducted across eight medical facilities in Japan, this multicenter, retrospective observational research included 863 patients diagnosed with NSCLC and treated between January 2015 and December 2022. The patients were categorized based on the type of systemic therapy received: cytotoxic agents, molecular targeting agents, immune checkpoint inhibitors, and combination therapies. Comprehensive molecular and immunohistochemical analyses were conducted, and statistical evaluations were performed.

Results: The median overall survival (OS) shows significant variations among treatment groups, with targeted therapies demonstrating the longest OS. This study also revealed that high PD-L1 expression was common in the group treated with immune checkpoint inhibitors. Multivariate analysis was used to identify the type of anticancer drug and the expression of PD-L1 at diagnosis as the impactful variables affecting 5-year OS.

Conclusions: This study underscores the efficacy of targeted therapies and the critical role of comprehensive molecular diagnostics and PD-L1 expression in affecting OS in NSCLC patients, advocating for their integration into routine clinical practice.

Keywords: PD-L1 expression; driver oncogene; immune checkpoint inhibitors; molecular targeting agents; non-small-cell lung cancer; overall survival; personalized medicine; real-world evidence.

Figure 1

Screening, Exclusion, and Inclusion in the Study.

Figure 2

Kaplan–Meier survival curves for patients with NSCLC undergoing different systemic anticancer treatments. Figure 2 indicates the Kaplan–Meier survival curves for NSCLC patients who underwent various systemic anticancer treatment regimens. The treatment groups are categorized into four subgroups: I for immune checkpoint inhibitor, C for chemotherapy with cytotoxic agents, CI for combination chemotherapy with cytotoxic agents and immune checkpoint inhibitor, and M for molecular targeting agents. The median OS for group I was 21.75. For group C, the median OS was 16.29 months. Group CI had a median OS of 32.75 months, and group M had a median OS of 49.93 months. The statistical significance was assessed using the log-rank test. The p-values for comparisons between I/C, I/CI, I/M, C/CI, C/M, and CI/M were 0.404, 0.067, less than 0.00001, 0.001, less than 0.00001, and 0.0004, respectively.

Figure 3

Distribution of driver oncogene mutations in a cohort of 863 NSCLC patients. The frequency and percentage of various driver oncogene mutations. The EGFR mutation was identified in 310 patients (35.9%). 396 patients (45.9%) had no detectable driver oncogenes (“None”). ALK mutations were found in 30 patients (3.5%), KRAS in 16 (1.9%), MET and ROS1 each in 11 (1.3%), and BRAF in 3 (0.3%).

Figure 4

(A) Kaplan–Meier curves for overall survival after initiation of molecular targeting agents among patients with indicated driver oncogene mutations. The Kaplan–Meier survival curves showing OS outcomes for patients treated with molecular targeting agents, categorized based on the presence of specific driver oncogene mutations. The subgroups include ALK, BRAF, EGFR, MET, and ROS1. Notably, no statistical difference was observed in OS among the various subgroups, despite the limited number of patients in some categories. (B) Kaplan–Meier curves for overall survival after initiation of anti-cancer systemic therapy among patients without driver oncogene mutations or not evaluated for mutations. The Kaplan–Meier survival curves for two distinct patient groups: those who were not evaluated for driver oncogene mutations (“NE”) and those without any detected mutations (“No mutation”). Median survival times and 95% confidence intervals are given for each group. The figure highlights the significantly superior OS outcomes for patients who were evaluated and found to have no driver oncogene mutations, compared to those not evaluated (p = 0.021).

Figure 5

Kaplan–Meier curves for overall survival after initiation of systemic anticancer treatments among patients with indicated PD-L1 expression levels. (A) Among patients treated with any form of treatment. (B) Among patients treated with combination chemotherapy and immune checkpoint inhibitors or immune checkpoint inhibitors alone. (C) Among patients treated with molecular targeting agents. (D) Among patients treated with chemotherapy using cytotoxic agents.

Figure 5

Kaplan–Meier curves for overall survival after initiation of systemic anticancer treatments among patients with indicated PD-L1 expression levels. (A) Among patients treated with any form of treatment. (B) Among patients treated with combination chemotherapy and immune checkpoint inhibitors or immune checkpoint inhibitors alone. (C) Among patients treated with molecular targeting agents. (D) Among patients treated with chemotherapy using cytotoxic agents.