Background: Though PD-ligand 1 (PD-L1) expression on tumor tissue has been established as companion diagnostics in non-small-cell lung cancer (NSCLC) for anti-PD-L1 treatment, additional biomarkers to enrich the patients likely to benefit from the therapy are critically needed. Here, we conducted a serial evaluation of multiple serum proteins relevant to the modulation of immune system in NSCLC patients treated with nivolumab.
Patients and Methods: Advanced NSCLC patients after failure of at least one prior chemotherapy regimen received nivolumab monotherapy (3mg/kg, q2W) until progressive disease (PD) or unacceptable toxicity. Serum samples were collected at baseline and at week 4. Best response was classified into partial response (PR), stable disease (SD), or progressive disease (PD) according to RECIST v1.1. Using LuminexTM xMapTM technology, serum levels of 54 proteins consisting of cytokines, chemokines, growth factors, and angiogenesis factors were measured. All statistical analyses were carried out using JMP Pro software (ver. 13.0) and Mann-Whitney U test and Spearman's test were performed accordingly. A p value <0.05 was considered as significant.
Results: Thirty-eight patients were registered in the study between January 2016 and March 2017 at Wakayama Medical University Hospital and 34 were included in the final analysis. Demographics of the patients were as follows: median age 68 (range, 49 to 86); male 73 %; stage IV, 100 %; squamous/non-squamous, 30/70 %. Overall response rate was 22% (7/34), and disease control rate was 53% (18/34). Among 54 serum proteins measured serially, the level of serum TNF-α was significantly lower at baseline in non-PD patients than PD patients (p < 0.05). The level of TNF-α was also correlated with longer progression free survival (PFS) (r= -0.5693). Serum IL-8 level at week 4 in PR patients were significantly lower than those in non-PR patients (p <0.01) though no difference was observed at baseline between the two, supporting the relevance of serum IL-8 level to the efficacy of nivolumab. Correlation between IL-8 levels at week 4 and longer PFS turned out to be more significant (r=-0.6864). In addition, serum levels of VEGF-A, TGF-β1 and PDGF-AB/BB were significantly lower in PR patients than those in non-PR patients at week 4 (p <0.05). However, these protein levels were not correlated with PFS.
Conclusions: We identified that the serum levels of IL-8, TNF-α, VEGF-A, TGF-β1 and PDGF-AB/BB as potential biomarkers to predict clinical benefit from nivolumab treatment in advanced NSCLC by multi-analyte protein-based assay. Incorporating additional serum protein levels may have potential to improve the patient enrichment besides previously reported potential biomarkers such as IL-8 and VEGF levels. Further evaluation is warranted in a larger cohort to validate the findings.
Citation Format: Jun Oyanagi, Yasuhiro Koh, Hiroaki Akamatsu, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Keiichiro Akamatsu, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Predictive values of serum protein levels in advanced non-small cell lung cancer patients treated with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2608.