Purpose: We have previously reported that PD-L1-positive rate on CTCs at baseline was correlated with response to nivolumab in NSCLC patients. Here, we conducted a longitudinal follow-up investigation of PD-L1 expression on CTCs and its association with clinical outcome.
Methods: For CTC detection, 3ml of peripheral blood was collected from advanced NSCLC patients treated with nivolumab at baseline and week 4, 8, 12 and 24 or until progressive disease (PD). CTCs were enriched by microcavity array system based on the difference in size and defined as DAPI-positive, CK-positive, and CD45-negative cells and evaluated for PD-L1 expression by additional immunostaining.
Results: Forty-five patients were enrolled between January 2016 and January 2018 at Wakayama Medical University. The patient characteristics were as follows: median age 68 years (range, 49-86); male 75%; stage III/IV, 25/75%; adenocarcinoma/ squamous cell carcinoma/ other, 68/25/7%; partial response/stable disease/PD/not evaluable, 20/25/45/9%. At baseline, CTCs were evaluated in 44 patients (median, 13; range, 1-104) and PD-L1 positive CTCs were detected in 82% patients (median 29%; range, 0-100%), at week 4, evaluated in 31 patients (median, 4; range, 0-115) and detected in 58% patients (median, 13%; range, 0-100%), at week 8, evaluated in 16 patients (median, 11; range, 1-276) and detected in 56% patients (median, 7%; range, 0-60%), at week 12, evaluated in 13 patients (median, 11; range, 0-449) and detected in 62% patients (median, 15%; range, 0-88%), and at week 24, evaluated in 11 patients (median, 8; range, 0-35) and detected in 55% patients (median, 26%; range, 0-92%). Significant decrease in the ratio of PD-L1 positive CTCs between week 4 to week 8 was determined by Wilcoxon-matched-pairs signed rank test. Cutoff value of PD-L1-positivity rates in CTCs to segregate durable clinical benefit (DCB) from non-DCB was calculated to be 7% at week 8 according to ROC curve. Progression free survival was significantly longer in the patients with 7% or more of PD-L1 positivity rates (n = 8) than in those with less than 7% (n = 8) (p < 0.01) at week 8, suggesting the predictive significance of early evaluation of PD-L1 expression on CTCs after nivolumab treatment. Interestingly, CTC count in 7 out of 9 patients who had a partial response (PR) transiently increased from the one immediately prior to achieving a PR. Progression free survival was significantly longer in patients with 1.5 times or more increase of CTC count (n = 6) than in those with less than 1.5 times (n = 3) (p < 0.05), suggesting the transient tumor cell intravasation due to nivolumab treatment and its potential correlation with the duration of response depending on its magnitude.
Conclusions: Longitudinal evaluation of PD-L1-expressing CTCs may have a predictive potential in NSCLC patients treated with nivolumab.
Citation Format: Yasuhiro Koh, Mio Ikeda, Shunsuke Teraoka, Koichi Sato, Nahomi Tokudome, Atsushi Hayata, Hiroaki Akamatsu, Yuichi Ozawa, Keiichiro Akamatsu, Katsuya Endo, Masayuki Higuchi, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Longitudinal investigation of PD-L1 expression on circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) patients treated with nivolumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 775.