Background and Importance It could be hypothesised that patients older than 65 years old may experience decreased immune function due to the natural aging process, which could lead to a more limited response to immunotherapy compared to those younger than 65 years old.

The forest-plot analysis for age-dependent overall survival from the clinical trial of cemiplimab in combination with chemotherapy in locally advanced or metastatic non-small-cell lung cancer (NSCLC), EMPOWER-Lung 3, showed a borderline interaction between the subgroups younger and older than 65 years old, with a p-interaction=0.0895 (own calculation) and HR 0.53 (0.39–0.72), HR 0.81 (0.55–1.18), respectively.

Aim and Objectives To verify the consistency of the hypothesis of an age-related effectiveness by a meta-analysis considering all approved immunotherapy combinations in first-line NSCLC.

Material and Methods A MEDLINE-PubMed literature search was conducted for phase III randomised clinical trials (RCTs) with similar population and duration of pembrolizumab, atezolizumab ± bevacizumab, nivolumab + ipilimumab, durvalumab + tremelimumab and cemiplimab, in combination with chemotherapy and nivolumab + ipilimumab. A meta-analysis was performed with the MetaSurv calculator. The primary endpoint was overall survival (OS) in patients younger and older than, or equal to, 65 years of age. Age-dependent OS data for immunotherapy combinations versus a common comparator, platinum-based chemotherapy, were compared. Interaction was considered significative if p<0.05 and doubtful if 0.05≤p<0.1.

Results A pooled HR of 0.67 (95% CI 0.58–0.76), p<0.000001 was obtained in patients younger than 65 years of age. Heterogeneity among trials estimate values were as follows: Q 14.84, p=0.03812. I2 53% (CI 95% 0–79%).

In those older than 65 years old, the combined HR obtained was 0.77 (95% CI 0.70–0.84), p<0.000001. Heterogeneity estimate values were as follows: Q for heterogeneity 0.81 p=0.99733. I2 0% (CI 95% 0–0%).

The calculated p-interaction between the combined HRs of the under-65 and over-65 groups was 0.0551, which is considered a doubtful interaction in a subgroup analysis.

Conclusion and Relevance A significant benefit for immunotherapy-chemotherapy over chemotherapy alone was shown in both age groups. There is some consistency regarding a greater effectiveness of immunotherapy in patients under 65 years of age, but more data would be needed to confirm this possible difference.

Conflict of Interest No conflict of interest.