ICIs provide interesting response rates in many tumors and maintain a better quality of life than other anticancer therapies. As older patients are more fragile than younger because of frequent comorbidities and organic failures, the therapeutic option of immunotherapy is particularly attractive in this population. However, no randomized study has been reported so far in the elderly population. Therefore, meta-analyses are an interesting approach to identify trends and generate working hypotheses. In the meta-analysis by Nishijima et al., 5 RCTs with anti-PD-1 agents and 4 with anti-CTLA-4 agents were retained, with a cut-off of 65 years (1). OS and PFS benefit were shown without difference between age-group. The meta-analysis by Elias et al. focused on 9 RCTs with anti-PD-1 and anti-PDL-1 agents, with a cut-off of 65 years of age (2). Conclusions were similar to those of Nishijima et al. More recently,
Ninomiya et al. published a meta-analysis including of 24 studies for anti-CTLA-4 and anti-PD(L)-1, with a cut-off at 65 years of age. A lower efficacy of anti-CTLA-4 in the elderly was reported without any difference in OS depending on the location of the primary or the line of treatment (3). Finally, the meta-analysis by Li et al. had several cut-offs of age (under 65, over 65, over 75). For patients over 75 years, 8 studies were retained, and no OS benefit was observed (21). Overall the impact of ageing on ICIs effectiveness therefore remains controversial.
To the best in our knowledge, we report the first meta-analysis assessing efficacy of ICIs in patients over the age of 75. A benefit on OS was observed for both younger and older patients. However, the overall benefit (HR = 0.86) observed in the elderly is of borderline significance (p = 0.08). This is likely due to the small numbers of patients over the age of 75 included in each study. Second, the meta-analysis showed differences depending on the timing of ICIs. In first-line setting, the benefit was statistically significant (p = 0.04) for the elderly and similar in younger patients (heterogeneity P = 0.58). In second-line setting, there was no benefit in elderly patients (p = 0.88) while the benefit remained significant in younger patients (heterogeneity P = 0,009). From a biological point of view, ageing is known to dramatically affect the normal cells of the tumor microenvironment. Age-induced immunosenescence occurs in effector T cells and other immune cell types crucial for tumour immunity. These changes are supposed to induce a shift towards the activation and infiltration of more immunosuppressive cell populations in the elderly, such as M2-like immunosuppressive macrophages.(22). As chemotherapy has also been shown to further accelerate this process, it could be assumed that using first-line treatment before immunotherapy could decrease the likelihood of checkpoint inhibitor efficacy.
Our study has several limits. First, it concerns different types of cancers. As the efficacy of ICIs appears very different depending on the tumor type, the impact of ICIs and their timing could be different. Second, the population of elderly patients who are included in RCT is obviously selected and is not representative of patients managed in daily practice. The question whether our observations could be applied to more frail patients remains to be answered. Third, our study concerns different drugs or different drug combinations. Finally, it should be noted that for some studies, patients were selected on tumor/immune cells expression levels of PD-L1 that could interfere for treatment decisions in older patients.
What could be the consequences for the daily management of elderly patients according to primary tumors? For melanoma patients, Checkmate 066 study and additional cohort studies of patients aged over 80 have confirmed the benefit of ICIs (23, 24). The only issue is to consider or not the addition of an anti-CTLA-4 agent according to the geriatric assessment. In patients with non-oncogenic driven NSCLC, the standard of care is a combination of chemotherapy and anti-PD-1 agent. In frail patients, immunotherapy alone could be the optimal option considering the side effects of chemotherapy and tumor/immune cells expression levels of PDL-1. In renal cell cancer, current standard first-line treatments for intermediate-risk and poor-risk are based on combinations with either anti-CTLA-4 and anti-PD-1 agents or anti-PD-1 and anti-VEGF-R agents. Such combinations may be unsuitable because of frailty. The question whether an anti-PD-1 agent alone could be used remains to be validated.