Background: We have previously reported that serum IL-8 and G-CSF were correlated with clinical benefit and immune-related adverse events (irAE), respectively in non-small-cell lung cancer (NSCLC) patients treated with nivolumab. Here, we measured multiple serum proteins serially in NSCLC patients treated with pembrolizumab and explored the potential of predicting clinical response or irAE onset. This study was registered at UMIN (ID: 000024414).
Patients and Methods: Advanced NSCLC patients received pembrolizumab monotherapy (200 mg/body, q3W) until progressive disease (PD) or unacceptable toxicity. Serum samples were collected at baseline and at week 6. 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 41 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 were performed accordingly. A p value <0.05 was considered as significant.
Results: Thirty-seven patients were registered in the study between March 2017 and October 2018 at Wakayama Medical University Hospital and 32 were included in the final analysis. Demographics of the patients were as follows: median age 70 (range, 50 to 91); male 75%; smoker 88%; stage III/IV, 22/78%; squamous/non-squamous, 31/69%, previous treatment; 0/1≤, 47/53%. Objective response rate was 28% and disease control rate was 56% in the entire cohort and 40% and 67%, respectively in the first-line subset. Among 41 serum proteins measured, no serum protein at baseline was associated with efficacy or irAE onset in the entire cohort. Levels of serum VEGF-C and sCD40L at baseline, however, in the first-line subset were found significantly lower in the patient who had PR and SD than those who did not. RANTES was also found significantly lower in patients who had PR in the 2nd or later line subset. With regard to irAE prediction, changes of HB-EGF levels between baseline and week 6 were significantly smaller in irAE patients in the entire cohort and changes of MCP-1 levels were significantly smaller in irAE patients in second or later line subset. The serum proteins identified in the current study were not overlapped with those identified in advanced NSCLC patients treated with nivolumab in the previous study.
Conclusions: We identified potential serum protein markers associated with clinical benefit and irAE from pembrolizumab treatment in advanced NSCLC by multi-analyte protein-based assay. Our results suggest that serum proteins associated with efficacy and irAE may vary among different anti-PD-1 antibodies and also between in the first-line setting and later one.
Citation Format: Jun Oyanagi, Yasuhiro Koh, Shunsuke Teraoka, Kuninobu Kanai, Atsuhsi Hayata, Nahomi Tokudome, Hiroaki Akamatsu, Yuichi Ozawa, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Predictive significance of serum protein levels in advanced non-small-cell lung cancer patients treated with pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 416.