Clinical Characteristics and Pharmacokinetics Change of Long-Term Responders to Antiprogrammed Cell Death Protein 1 Inhibitor Among Patients With Advanced NSCLC

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) induce long-term, durable responses in patients with advanced NSCLC. Nevertheless, these responses are limited to a few patients, and most responders have disease progression. The purpose of this study was to determine the differences in clinical factors and blood drug concentrations between long-term responders (LTRs) and non-LTRs.

Methods: We retrospectively analyzed consecutive patients with advanced NSCLC who received antiprogrammed cell death protein 1 (PD-1) inhibitor monotherapy (nivolumab) from December 22, 2015, to May 31, 2017. Patients who obtained a clinical benefit for more than 6 months were referred to as "responders"; among these, individuals who had a durable response for more than 2 years were defined as "LTRs." Those with a clinical benefit for less than 2 years were defined as "non-LTRs."

Results: A total of 212 patients received anti-PD-1 inhibitor monotherapy. The responders accounted for 35% (75 of 212) of the patients. Of these, 29 (39%) were LTRs and 46 (61%) were non-LTRs. The overall response rate and median tumor shrinkage in the LTR group were significantly higher than those in the non-LTR group (76% versus 35%, p < 0.0001, and 66% versus 16%, p < 0.001, respectively). The groups had no significant difference in PD-L1 expression and serum drug concentration at 3- and 6-month post-treatment initiation.

Conclusions: Significant tumor shrinkage was associated with a long-term response to an anti-PD-1 inhibitor. Nevertheless, the PD-L1 expression level and pharmacokinetic profile of the inhibitor could not be used to predict the durable response among the responders.

Keywords: Anti–PD-1 inhibitor; Long-term response; Non–small cell lung cancer; Pharmacokinetics.

Figure 1

Flow diagram of the study. CR, complete response; Dec., December; LTR, long-term responder; PFS, progression-free survival; PR, partial response.

Figure 2

PD-L1 status in patients with advanced NSCLC. (A) Bar graph illustrating the PD-L1 status (PD-L1 ≥50%, PD-L1 1%–49%, and PD-L1 <1%) in the non-LTR (n = 28) and LTR groups (n = 18) of patients treated with anti–PD-1 inhibitors. ∗PD-L1 expression levels of greater than or equal to 50% and less than 50% were compared between the patients in the LTR and non-LTR groups. (B) Bar graph illustrating the PD-L1 status (PD-L1 ≥50%, PD-L1 1%–49%, and PD-L1 <1%) for each response period (6–11, 12–23, 24–35, and ≥36 mo) in patients treated with anti–PD-1 inhibitors. LTR, long-term responder; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival.

Figure 3

Best response and tumor shrinkage. (A) Bar graph illustrating the percentage of patients with the best response (CR, PR, and stable disease) to anti–PD-1 inhibitors in the non-LTR (n = 46) and LTR (n = 29) groups. (B) Bar graph illustrating the percentage of patients with the best response (CR, PR, and stable disease) to anti–PD-1 inhibitors at each response period (6–11, 12–23, 24–35, and ≥36 mo). (C) Waterfall plot of tumor shrinkage in the responders at each response period (6–11, 12–23, 24–35, and ≥36 mo). ∗p values were calculated by comparing the LTR and non-LTR groups. CR, complete response; LTR, long-term responder; ORR, objective response rate; PD-1, programmed cell death protein 1; PR, partial response.

Figure 4

Pharmacokinetic analysis in patients treated with nivolumab. (A) Dot plot illustrating nivolumab trough concentrations at 3M, 6M, 12M, and 24M. (B) Dot plot illustrating nivolumab trough concentrations at 3M in the non-LTR (n = 31) and LTR (n = 20) groups. (C) Dot plot illustrating nivolumab trough concentrations at 6M in the non-LTR (n = 31) and LTR (n = 22) groups. ∗p values were calculated by comparing the 3M and 6M, the 3M and 12M, and the 3M and 24M groups. ∗∗p values were calculated by comparing the LTR and non-LTR groups. 3M, 3 months after the start of treatment; 6M, 6 months after the start of treatment; 12M, 12 months after the start of treatment; 24M, 24 months after the start of treatment; LTR, long-term responder.