Background: Anti-PD-1 antibody nivolumab has become a new standard treatment for pretreated, advanced non-small cell lung cancer (NSCLC). Although PD-L1 expression on tumor tissue has a predictive value, significance of its expression on circulating tumor cells (CTCs) is unknown. Here, we conducted a sequential evaluation of PD-1-expressing CTCs in NSCLC patients treated with nivolumab.
Methods: Advanced NSCLC patients who received nivolumab at Wakayama Medical University Hospital were enrolled in the study (UMIN000024414). Nivolumab was administered 3 mg/kg bi-weekly until progressive disease (PD) or unacceptable toxicity. Peripheral whole blood (3 mL) was collected in an EDTA collection tube (BD vacutainer) and processed within 3 hours for CTC evaluation at baseline, week 4 and week 8. CTCs were detected using automated microcavity array system (Hitachi Chemical Co.). PD-L1 expression was immunohistochemically examined on both tumor tissues and CTCs using anti-PD-L1 antibody, clone 28-8 (Abcam).
Results: Thirty-eight patients were registered in the study between January 2016 and September 2016. Clinical characteristics of the patients were as follows: median age 68 (range, 49 to 86); male 73 %; stage IV 100 %; squamous/non-squamous, 30/65 %. Regarding nivolumab treatment, overall response rate (ORR) was 22% (95% confidence interval [CI]: 10-38%), and median progression-free survival (PFS) was 62 days (95%CI: 40-235 days). At baseline, CTCs were detected in all patients (median, 15; range, 1-90) and PD-L1-expressing CTCs were detected in 87% of patients. Tumor proportion score (TPS) of PD-L1 expression on CTCs varied from 6% to 100%. Matched tumor tissues were available from 14 patients and 7 showed the PD-L1 TPS ≥50%. PD-L1 status on CTCs was not correlated with that on tumor tissues both using proportional score and H score (Spearman's correlation: r = 0.0007 and 0.08, respectively). On CTCs, patients with PD-L1 ≥50 % have significantly higher disease control rate than those with below 50% (83.3% versus 36.4%, p<0.01). Similarly, patients with PD-L1 ≥50 % on CTC had significantly longer PFS compared with those with below 50% (293 days versus 49 days, hazard ratio 2.41 (95% CI: 1.05-5.54), p = 0.03). During nivolumab treatment, number of CTCs was decreased (median number was 10 at 4 weeks, and 5 at 8 weeks). Among those with PD-L1 ≥50 % on CTC at baseline, changes in number and PD-L1 status on CTCs at 4 weeks did not correlate with PFS.
Conclusions: Sequential monitoring of PD-L1 expression on CTCs during nivolumab treatment was successfully conducted. PD-L1 expression on CTCs at baseline was a strong predictor in efficacy. Predictive significance of PD-L1-positive CTCs should be evaluated in a larger validation cohort.
Citation Format: Yasuhiro Koh, Hiroaki Akamatsu, Keita Mori, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Masayuki Higuchi, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Predictive impact of sequential evaluation of PD-L1-expressing circulating tumor cells in NSCLC 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 5595.