Association between changes in thioredoxin reductase and other peripheral blood biomarkers with response to PD-1 inhibitor-based combination immunotherapy in non-small cell lung cancer: a retrospective study

Background: Immunotherapy deeply changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC) in the past years. However, the objective response rate (ORR) after immunotherapy is about 20-30% of NSCLC patients. Therefore, identification of predictive biomarkers is crucial for selecting patients with NSCLC who would most benefit from programmed cell death receptor protein 1 (PD-1) inhibitor-based immunotherapy.

Methods: We retrospectively collected medical records and thioredoxin reductase (TrxR) data from 90 patients with a NSCLC who received PD-1 inhibitor-based combination therapy. Serum biomarkers were also measured at 6- and 12-week post-treatment and compared with their baseline values. Associations between changes in serum biomarkers, clinical characteristics and treatment efficacy were evaluated using univariate tests. The patients who were still alive were followed up remotely by phone or email to assess survival. The association between serum biomarkers and TrxR with overall survival (OS) and progression-free survival (PFS) were assessed by univariate and multivariate Cox proportional hazard regression. Nomogram prediction models were constructed using factors associated with PFS and OS, respectively.

Results: The median follow-up time among the 90 patients was 19.7 (range, 13.6 to 25.8) months. Median PFS and OS were 13.6 [95% confidence interval (CI): 13.5 to 13.7] and 19.7 (95% CI: 13.6 to 25.8) months, respectively. Patients with decreased carcinoembryonic antigen (CEA), albumin (Alb), and TrxR values at 6- and 12-week post-treatment compared to baseline had statistically significantly improved disease remission rates (P<0.05). Patients with decreased white blood cell (WBC), neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR) at week 6, and decreased Alb, CEA, and lymphocyte-to-monocyte ratio (LMR) at week 12 had statistically significantly increased ORRs (P<0.05). According to the univariate and multivariate Cox regression analyses, we included adenocarcinoma, Eastern Cooperative Oncology Group performance status (ECOG PS), and CEA change at week 6 post-treatment as predictors for PFS, and adenocarcinoma, change in absolute lymphocyte count (ALC), and TrxR at week 6 as predictors for OS in the nomogram models. Each nomogram was also validated internally using a bootstrap method with 1,000 resamples.

Conclusions: Change in TrxR at 6 weeks post-treatment in combination with other clinical and hematological biomarkers could be used as a predictor for treatment outcome and prognosis in NSCLC patients after PD-1 inhibitor-based combination immunotherapy.