Efficacy of Anti-PD-1/PD-L1 Monotherapy or Combinational Therapy in Patients Aged 75 Years or Older: A Study-Level Meta-Analysis

Abstract

Recent trials have shown a promising anti-tumor activity for advanced cancer patients treated with PD-1/PD-L1 inhibitors; however, little is known on the use of PD-1/PD-L1 inhibitors in adults over 75 years of age. Here, we performed a study-level meta-analysis to compare the efficacy of anti-PD-1/PD-L1 agents between elderly (≥ 75 years) and non-elderly (< 75 years) patients. In the present study, we systematically reviewed phase 2/3 trials of PD-1/PD-L1 inhibitors of advanced solid tumors that reported treatment effect (hazard ratio [HR]) in patients based on age (≥ 75 years vs. < 75 years) and set anti-PD-1/PD-L1 monotherapy or combinational therapy as experimental arm. The HRs of OS and progression-free survival (PFS) are based on random-effect models. Overall, a total of eight qualifying trials comprising 5,393 subjects were included for meta-analysis, and 472 patients (8.8%) were aged 75 years or older. The overall estimated HR for OS was 0.70 (0.62–0.79) in patients < 75 years vs. 0.94 (0.67–1.30) in patients ≥ 75 years. Anti-PD-1/PD-L1 agents improved OS of melanoma patients in both elderly (HR 0.25 [0.10-0.60]) and non-elderly (HR 0.49 [0.33–0.71]) group. The OS difference in the efficacy of PD-1/PD-L1 inhibitors between elderly and non-elderly patients was significant (P = 0.043 for interaction). The overall estimated HR for PFS was 0.77 (0.60–1.00) in patients < 75 years vs. 0.97 (0.60–1.58) in patients ≥ 75 years. Therefore, with the exception of melanoma, elderly patients (≥ 75 years) could not benefit from the anti-PD-1/PD-L1 agents in survival, and toxicity profile of anti-PD-1/PD-L1 drugs should be explored in this population.

Immune checkpoint expression and relationships to anti‐PD‐L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice

“…Clinical data on ICI efficacy in elderly individuals with cancer are encouraging but inconclusive, with retrospective meta-analyses showing similar or improved efficacy in aged (> 60 years) versus young (< 60 years) melanoma patients treated with ICI agents, [14][15][16][17][18] while another study showed no significant progression free survival (PFS) improvement in cancer patients ≥ 75 years of age treated with ICI versus control groups, while younger patients (< 75 years) had significant PFS improvement. 19 Despite contradictory data, age-related differences likely occur, but clinical studies could be underpowered due to low enrollment of elderly adults into clinical trials 20 or age effects on ICI in humans do not manifest until ages greater than those thus far studied.…”

The efficacy of immune checkpoint inhibitors in elderly patients: a meta-analysis and meta-regression

“…was based on eight trials involving patients treated with anti-PD-1/PD-L1. 60 The study showed that except for melanoma, anti-PD-1 and PD-L1 did not benefit elderly patients aged ≥75 years in terms of PFS and OS. Another meta-analysis of 34 studies by Huang et al.…”

“…Recently, two meta-analyses addressed the efficacy of ICIs between age <75 and ≥75 years. 60 , 61 The meta-analysis by Nie et al. was based on eight trials involving patients treated with anti-PD-1/PD-L1.…”

Efficacy and toxicity of Ipilimumab-Nivolumab combination therapy in elderly metastatic melanoma patients

“…It is worth mentioning that in most studies the cut off age is 65 with only a small number of studies addressing the older population -75 and over (17-20), though the results for this age group seem to be comparable if not superior to those of patients younger than 75. This seems to be the case mainly in Melanoma as a meta-analysis published by Nie et al (21) has shown lower response rate for patients over 75 in comparison to younger patients with other types of solid tumors. The authors hypothesis for the difference between Melanoma and other tumor types is based on a study published by Samstein et al in 2019 which showed that Melanoma patients over 75 have a higher tumor mutational burden (TMB) when compared to other tumor types of the same age group (22).…”

“…This seems to be the case mainly in Melanoma as a meta-analysis published by Nie et al. ( 21 ) has shown lower response rate for patients over 75 in comparison to younger patients with other types of solid tumors. The authors hypothesis for the difference between Melanoma and other tumor types is based on a study published by Samstein et al.…”