Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis

Abstract

An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.

Keywords: age; immune checkpoint blockade; immunosenescence; immunotherapy; inflammatory markers; metastatic non-small-cell lung cancer; real-world evidence study.

Figure 1

Kaplan–Meyer curves. (a) Overall survival (OS) and (b) progression-free survival (PFS) of metastatic non-small-cell lung cancer (mNSCLC) patients under treatment with nivolumab or atezolizumab divided into two age-related groups: age < 75 years (blue) and age > 75 years (green). In our series, we did not find any correlation with age for both overall survival (OS, patients ≤ 74 years median OS 11.4 months, 95% CI 7.2–15.7 months vs. patients ≤ 74 years median OS 8.5 months, 95% CI 0–20.5 months, p-value: 0.88) and progression-free survival (PFS, patients ≤ 74 years median PFS 5.1 months, 95% CI 3.8–6.4 months vs. patients ≥ 75 years median OS 6.2 months, 95% CI 3.8–8.6 months, p-value: 0.88).

Figure 2

Overall survival considering the inflammation status parameters among the two cohorts of patients. The analysis showed that in the younger patient cohort (age ≤ 74 years), the parameters that were statistically significant were: (A,B) the neutrophile to lymphocyte ratio (NLR) (NLR < median value median OS of 24 months vs. NLR > median value median OS of 18 months, p-value 0.038); (C,D) erythrocyte sedimentation rate (ESR) (ESR < median value median OS of 49.5 months vs. ESR > median value of 24 months, p-value 0.012); and (E,F) procalcitonin (PCT) (PCT < median value of 49 months vs. PCT > median value of 24 months, p-value 0.031). In the older patient cohort (age ≥ 75 years), these parameters were not significantly correlated.

Figure 3

Overall survival considering the inflammation status parameters among the two cohorts of patients. The analysis showed that in the younger patient cohort (age ≤ 74 years), the C-reactive protein (CRP) parameter (A,B) was statistically significant (CRP < median value of 44 months vs. CRP > median value of 24 months, p-value 0.045). In the older patient cohort (age ≥ 75 years), the only parameter that significantly correlated with a greater survival was the decrease of neutrophils (C,D) (∆Neutrophils < 0 median OS of 48.2 months vs. ∆Neutrophils ≥ 0 median OS of 20.5 months, p-value 0.008).