Timing of immune checkpoint inhibitors for metastatic patients over 75 years of age: the earlier the better

Abstract

Background The impact of ageing on Immune Checkpoint Inhibitors (ICIs) effectiveness remains controversial. However, data from clinical studies do not show any difference between patients over 65 years and those under 65 years. We focused our study on patients over 75 and looked at the potential impact of timing in the use of ICIs. Methods We performed a meta-analysis of published randomized control trials (RCTs) concerning ICIs versus standard therapy in patients with advanced solid tumors. Overall Survival (OS) among the older (≥75 years) was compared with that of younger patients (< 75 years). Hazard ratios (HRs) with their 95% confidence interval (CI) were collected and pooled. Results Fifteen phase III studies evaluating anti-PD-1(nivolumab or pembrolizumab), anti-PD-L1 (atezolizumab or avelumab) or anti-CTLA-4 (ipilimumab) were included. Patients were enrolled for Non-Small-Cell-Lung-Cancer, Renal-Cell-Carcinoma, Melanoma, Head-and-Neck-Squamous-Cell-Carcinoma or Gastric Cancer. Eight studies assessed treatment in first-line setting and seven in the second line. The median age was 64 years, with 906 patients over 75 years of age and 5233 youngers. In first-line setting, HRs for death were 0.78 (95% CI: 0.61-0.99) in patients ≥75 years versus 0.84 (95% CI: 0.71-1.00) in younger. In second line setting, HRs for death were 1.02 (95% CI: 0.77-1.36) in patients ≥75 years versus 0.68 (95% CI: 0.61-0.75) in younger with a statistically significant difference observed between subgroups (p interaction = 0.009). Conclusions ICIs appears to be effective in patients over 75 years of age. However, the survival benefit is mainly observed in first-line treatment.

Efficacy of PD-1/PD-L1 inhibitors in patients with advanced gastroesophageal cancer: An updated meta-analysis based on randomized controlled trials

“…Intriguingly, subgroup analysis on age demonstrated that PD-1/PD-L1 inhibitors could considerably prolong the OS of gastroesophageal cancer patients regardless of the patient's age. In general, aging significantly impacts normal cells in the tumor microenvironment, causing frailty in older patients to limit their capacity to receive further treatment (Landre et al, 2020). However, after the variables including line of therapy, therapeutic schedules, and tumor types were merged with age for pooled analysis, significant potential curative effects with PD-1/PD-L1 inhibitors were observed in the <65 or ≥65 years subgroups.…”

“…However, after the variables including line of therapy, therapeutic schedules, and tumor types were merged with age for pooled analysis, significant potential curative effects with PD-1/PD-L1 inhibitors were observed in the <65 or ≥65 years subgroups. A previous meta-analysis targeted at age also revealed that in the first line treatment, PD-1/PD-L1 inhibitors were effective not only for patients aged <75 years, but also for patients aged >75 years (Landre et al, 2020). Thus, the upper age limit of PD-1/PD-L1 inhibitors might need to be re-assessed in the future.…”