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

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.


Introduction
Immune Checkpoint Inhibitors (ICIs), such as anti-programmed cell death 1 (anti-PD-1), antiprogrammed cell death ligand 1 (anti-PD-L1), and anti-cytotoxic T lymphocyte antigen 4 pathways (anti-CTLA-4), represent a significant step forward in cancer treatment. ICIs have actually changed the outcomes for several metastatic cancers including, lung cancer, melanoma, renal cell carcinoma and many other tumors. However, few specific data have been published so far in the elderly population.
Several meta-analyses compared the clinical efficacy of ICIs between young and elderly patients (1)(2)(3). Although they showed no difference between the two groups, the chosen cut-off age of 65 clearly is not representative of the elderly population. Therefore, we conducted a systemic review and study-level meta-analysis of randomized controlled trials (RCTs) to compare the benefit of ICIs between patients under 75 years of age and those over 75 years of age.

Methods
Research strategy: We performed a meta-analysis according to a predefined written protocol. Eligible studies included patients more than 75 years old with advanced cancer having a treatment either with ICI (or addition of other therapies to ICI) versus "standard of care". Only randomized phase III controlled trials comparing these 2 treatment modalities were included. They compared benefits and risks of both treatment modalities concerning overall survival (OS). Publications included in this metaanalysis were identified by an electronic PubMed search updated on January 2020 using the following keywords: "RCT", "phase III", "nivolumab", "pembrolizumab", "atezolizumab", "durvalumab", "avelumab", "ipilimumab" and "tremelimumab", We tried to obtain additional references by crosschecking the available publications. We also searched for abstracts in the proceedings of American conferences. An EMBASE query did not bring additional references. We did not find a systematic review on this topic in the Cochrane database. As scheduled in a written protocol, each article was carefully read by 3 reviewers (T.L., G.D.G., and S.C.). Disagreements were resolved by discussion between all authors of this meta-analysis.
Data extraction: Data extracted from eligible studies included study characteristics (first author, year of publication, treatments arms); study population (median age, characteristics of cancers, line of treatment, number of patients under 75 years of age and number of patients over 75 years of age in each treatment arm). We also collected Hazard Ratios (HRs) for Overall Survival (OS) based on age subgroups (younger vs ≥ 75 years).
Statistical analyses: The Cochrane collaboration method for meta-analysis, using the Review Manager software (RevMan version 5.3; Oxford, UK), was applied to compute the analyses. Statistical heterogeneity was assessed with χ 2 tests and I 2 statistics, with a χ 2 test p < 0.05 indicating 4 heterogeneity and I 2 values of 30-60% corresponding to moderate heterogeneity. A fixed effect model was used to calculate the cumulative hazard ratio (HR) when heterogeneity among studies was weak and a random model was applied when that heterogeneity was marked. Subgroup analyses were run each time for the different line setting. Meta-analysis results with 95% confidence interval (CI) are reported HRs for OS. Differences in the HRs between the younger and older groups were assessed using Chi² test. All tests were two sided and p < 0.05 defined significance.

Discussion
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. 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

Conclusion
Physiological aging is associated with changes in immune system response. Our study highlights the fact that the clinical benefit of ICIs in patients over 75 years of age may be predominantly retained in the first-line treatment of metastatic diseases. Different immunotherapy combination strategies or combination of chemotherapy with immunotherapy should be considered for older patients to improve clinical efficacy in second line setting. Exploring the molecular and immune mechanisms represents a tough challenge for future study in this field of cancer treatment.

Conflicts of interest/Competing interests:
The authors declare that they have no conflicts of interest relating to this article.

Role of the funding source
This study was not funded by any sponsors.

Authorship
TL designed research, collected data, analyzed and interpreted data, and wrote the manuscript. GDG and SC contributed to collection of data and revision of the manuscript. VFD and KC participated in the elaboration of the research design and revision of the manuscript.

Funding
None.