Abstract A052: Detection of serum protein levels for predicting clinical benefit in advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors
Authors: Oyanagi Jun , Koh Yasuhiro , Akamatsu Hiroaki , Sato Koichi , Teraoka Shunsuke , Kanai Kuninobu , Hayata Atsushi , Tokudome Nahomi , Ozawa Yuichi , Akamatsu Keiichiro , Nakanishi Masanori , Ueda Hiroki , Yamamoto Nobuyuki 
Published: March 2020

Abstract
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-1 treatment, additional biomarkers are critically needed. While immune related adverse events (irAEs) have been reported to be associated with efficacy, there are no established biomarkers to predict irAEs onset. Here, we measured multiple serum proteins in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and explored the potential of predicting clinical response and irAE onset. Patients and Methods: Advanced NSCLC patients received nivolumab, pembrolizumab or atezolizumab until progressive disease (PD) or unacceptable toxicity. Serum samples were collected at baseline and after the treatment (at week 4 or week 6). Durable clinical benefit (DCB) was defined as patients whose response was lasting over 6 months. Using Luminex 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. 14.0). Cut-off value of serum protein levels were estimated with receiver operating characteristic curve. Results: Ninety-eight patients were registered in the study between January 2016 and May 2019 at Wakayama Medical University Hospital and 97 were included in the final analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 91); male 78%; stage III/IV 31/69%; squamous/non-squamous/unknown 29/69/2%; previous treatment: 0/≥1 22/78%; ICI: nivolumab/pembrolizumab/atezolizumab 46/41/13%. Objective response rate was 24.7% (24/97), and disease control rate was 46.4% (45/97). Among 41 serum proteins measured serially, IL-8 levels at baseline were significantly lower in DCB patients than non-DCB patients in entire cohort (p &lt; 0.05). Among those, Kaplan-Meier analysis revealed lower levels of IL-8 were significantly associated with longer PFS (cut-off, 11.9217 pg/ml; median PFS, 293 vs 59 days; p &lt; 0.01). In second or later line subset, GRO-α, IL-8, IP-10, PLGF and VEGF-D were significantly lower in DCB patients than non-DCB-patients at baseline (p &lt; 0.05). Lower levels of those proteins except for VEGF-D were significantly associated with longer PFS ((cut-off, 1.073 ng/ml, 11.9217 pg/ml, 480.8 pg/ml, and 14.83 pg/ml; median PFS, 183 vs 49, 293 vs 49, 133 vs 42 , and 153 vs 49 days; 95% CI, 56-322 days, 69 days-not reached, 58-211 days and 52-293 days; p &lt; 0.05, 0.01, 0.05, 0.01). Follistatin which we previously reported to be associated with DCB upon nivolumab treatment, also showed significant association with longer PFS both in entire cohort (cut-off, 572.5; median PFS, 160 vs 59 days; 95% CI, 68-322 days, p &lt; 0.05) and 2nd or later line subset (cut-off, 572.5; median PFS, 100 vs 49 days; 95% CI, 39-322 days, p &lt; 0.05), though it was not significantly different between DCB and non-DCB. Regarding irAEs, GRO-α levels were significantly increased between baseline and the second sampling point in patients who acquired irAEs both in entire cohort and 2nd or later line subset (p &lt; 0.01). Conclusions: We identified potential serum protein markers associated with clinical benefit and irAEs in advanced NSCLC treated with ICIs by multiplex protein-based assay.
Citation Format: Jun Oyanagi, Yasuhiro Koh, Hiroaki Akamatsu, Koichi Sato, Shunsuke Teraoka, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Yuichi Ozawa, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Detection of serum protein levels for predicting clinical benefit in advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A052. doi:10.1158/1535-7163.TARG-19-A052