Perioperative immune checkpoint inhibitors with or without chemotherapy versus placebo with or without chemotherapy in elderly people with localised non-small cell lung cancer.

rationaleLung cancer is typically a cancer of the elderly, with a median age at diagnosis of 71, and more than one third of the people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of cancers, including lung cancer. ICIs targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, administered in the neoadjuvant setting, the adjuvant setting, or both, are currently the standard of care for resectable non-small-cell lung cancer (NSCLC) worldwide. These ICIs are commonly used in combination with platinum-based chemotherapy and have shown superior efficacy in patients eligible for curative surgery. The concept of immunosenescence, which refers to age-related changes in the immune system - particularly a decline in the efficiency of T-cell mediated responses - raises concerns about the benefits of ICIs in the elderly population.

objectivesTo assess the benefits and harms of ICI with or without chemotherapy compared to no treatment or placebo with or without chemotherapy given before surgery, after, or both in older adults diagnosed with NSCLC at the early resectable stage. SEARCH

methodsWe searched for all eligible randomised controlled trials (RCTs) in electronic databases (CENTRAL, MEDLINE, and Embase), trial registries (clinicaltrials.gov and the World Health Organization ICTRP), references of eligible studies, meeting abstracts of the main world conferences, and the Food and Drug Administration (FDA) and European Medicines Agency (EMA) websites. The search was up to 3 July 2025. ELIGIBILITY CRITERIA: We included parallel designed RCTs comparing ICI with or without chemotherapy versus no treatment or placebo with or without chemotherapy administered before surgery, after, or both for early-stage resectable NSCLC. We excluded studies comparing differential sequencing of ICIs or combinations of ICIs with alternate interventions (e.g. radiotherapy). OUTCOMES: Our critical outcomes were overall survival and grade ≥ 3 treatment-related adverse events. Our important outcomes were disease-free survival, event-free survival, pathological complete response rate, major pathological response rate, and health-related quality of life. RISK OF BIAS: Two review authors independently used version 2 of the Cochrane risk of bias tool for randomised trials (RoB 2) to assess bias in the included studies. SYNTHESIS

methodsWe synthesised results for each outcome and pooled data where possible (using a random-effects model with DerSimonian and Laird methods for all outcomes; and the Mantel-Haenszel method for dichotomous outcomes). Where this was not possible due to the nature or the amount of data, we narratively summarised the results. Three authors independently assessed the certainty of the evidence, using the five GRADE considerations for each outcome. INCLUDED STUDIES: We included a total of 11 studies with 6788 participants, of whom 3152 were ≥ 65 years old (46.4% of all participants). We were also interested in those aged ≥ 75 years old but could not obtain the exact number of such participants in nine studies. The inclusion criteria were similar across studies: adults presenting with a resectable NSCLC (stages II to IIIB according to the eighth edition of the Tumor, Node, Metastasis (TNM) classification), with an Eastern Cooperative Oncology Group performance status score of 0 or 1. One study excluded people ≥ 70 years old. Six studies excluded NSCLC with known alterations in epidermal growth factor receptor and anaplastic lymphoma kinase genes. SYNTHESIS OF

resultsThe following results relate to people ≥ 65 years old only. The term perioperative is used to label studies evaluating the administration of treatment before (neoadjuvant) and after (adjuvant) surgery. Overall survival at any time point (in all studies) Aggregated data from three studies (590 participants) showed that perioperative ICI probably results in little to no difference in overall survival compared to placebo or no treatment, with a hazard ratio (HR) of 0.88 (95% confidence interval (CI) 0.61 to 1.26) and moderate-certainty evidence (downgraded for risk of bias). Treatment-related adverse events ≥ grade 3 at any time point One study (39 participants) provided data indicating that perioperative ICI combined with neoadjuvant chemotherapy may result in little to no difference in treatment-related adverse events ≥ grade 3 compared to neoadjuvant chemotherapy alone, with a risk ratio (RR) of 2.75 (95% CI 0.38 to 19.83) and low-certainty evidence (downgraded for indirectness and imprecision). Disease-free survival at any time point Aggregated data from three studies (1403 participants) showed that adjuvant ICI probably slightly increases disease-free survival compared to placebo or no treatment (HR 0.85, 95% CI 0.73 to 0.99) with moderate-certainty evidence (downgraded for risk of bias). Event-free survival at any time point Aggregated data from seven studies (1531 participants) showed that neoadjuvant or perioperative ICI likely increases event-free survival compared to placebo or no treatment (HR 0.61, 95% CI 0.52 to 0.71) with moderate-certainty evidence (downgraded for risk of bias). Pathological complete response Aggregated data from six studies (1068 participants) showed that neoadjuvant or perioperative ICI may result in a large increase in pathological complete response rates compared to placebo or no treatment (RR 5.07, 95% CI 3.40 to 7.54) with low-certainty evidence (downgraded for risk of bias and imprecision). Major pathological response Aggregated data from six studies (1068 participants) showed that neoadjuvant or perioperative ICI probably results in a large increase in major pathological response rates compared to placebo or no treatment (RR 2.94, 95% CI 2.32 to 3.72) with moderate-certainty evidence (downgraded for risk of bias). AUTHORS'

conclusionsIn people aged ≥ 65 years old, the addition of ICIs probably results in little to no improvement in overall survival. Based on one study, treatment-related adverse events showed a similar profile, with low-certainty evidence. However, ICIs probably increase disease-free survival, event-free survival, and major pathological response rates by a clinically meaningful margin. ICI may also increase complete pathological response rates. No study reported health-related quality of life assessments in older adults. Data were also insufficient to evaluate outcomes precisely in participants aged 65 to 75 years, those ≥ 75 years, or in PD-L1 stratified subgroups. We classified 12 studies as ongoing, as no results are yet available for elderly participants.

fundingThis Cochrane review had no dedicated funding. REGISTRATION: Protocol available via DOI: 10.1002/14651858.CD014907.