Comparative Survival of First‐Line Immunotherapy Plus Chemotherapy Versus Immunotherapy Monotherapy in Older Adults With Metastatic Non‐Small Cell Lung Cancer: An Emulated Target Trial Approach

ABSTRACT Purpose The optimal use of first‐line immune checkpoint inhibitors (ICIs) with chemotherapy (ICI‐Chemotherapy) for metastatic non–small cell lung cancer (mNSCLC) in older adults remains unclear. Our study aimed to compare overall survival (OS) between first‐line ICI‐Chemotherapy and ICI monotherapy (ICI‐Monotherapy) and to evaluate the association of chemotherapy duration with OS. Methods We emulated two target trials (CITATION‐1, CITATION‐2) using SEER–Medicare (2014–2020) data on patients aged ≥ 66 years diagnosed with mNSCLC who initiated first‐line ICIs. CITATION‐1 compared initiation of ICI‐Chemotherapy versus ICI‐Monotherapy. CITATION‐2 included patients who completed four cycles of ICI‐Chemotherapy and compared two additional cycles of ICI‐Chemotherapy versus discontinuing chemotherapy while maintaining ICI. OS at 24, 48, and 144 weeks was compared between treatment arms and reported as risk differences. Results CITATION‐1 emulation ( n = 3741) showed, in per‐protocol analyses, that ICI‐Chemotherapy reduced early risk of death compared with ICI‐Monotherapy (48‐week risk difference, −10.0%; 95% CI, −13.5% to −6.0%). By 144 weeks, the risk difference was smaller and not statistically significant (−1.8%; 95% CI, −4.5% to 1.5%), with modified intention‐to‐treat analyses showing a similar pattern. CITATION‐2 emulation ( n = 602) did not show a statistically significant difference in OS between chemotherapy continuation and discontinuation strategies as risk difference confidence intervals included the null in all modified intention‐to‐treat and per‐protocol analyses. Conclusions In older adults with mNSCLC, first‐line ICI‐Chemotherapy provides a short‐term survival advantage over ICI‐Monotherapy, whereas long‐term OS is similar between strategies. Continuing chemotherapy beyond four cycles did not show a clear mortality benefit; adequately powered studies are needed to confirm exploratory findings.