Impact of time-of-day and timing interval of neoadjuvant immunotherapy and chemotherapy infusions among patients with operable NSCLC using the inverse probability of treatment weighting method: a dual-center, retrospective study.

BACKGROUND: Although multiple studies have confirmed that adjusting the time-of-day (ToDA) of immunotherapy and timing interval (TI) of chemoimmunotherapy can improve long-term outcomes in patients with advanced non-small cell lung cancer (NSCLC), whether this model similarly improves survival among patients with operable NSCLC has not been reported. PATIENTS AND METHODS: This dual-center, retrospective study included adult patients who received neoadjuvant chemoimmunotherapy (neoCIT) for clinical stage T1-4N0-3M0 NSCLC between January 2019 and December 2024. The impact of the ToDA of neoadjuvant immunotherapy (neoIO) on the efficacy and safety were analyzed. In addition, the inverse probability of treatment weighting (IPTW)-weighted Cox regression model was used to compare disease-free survival (DFS) and overall survival (OS) between patients who received either ≥75% (≥75% group) or <75% (<75% group) of the neoIO administrations before 14:00 h. RESULTS: A total of 168 consecutive patients with a median follow-up of 30.3 months were included, of whom 123 patients (73.2%) were in the ≥75% group. Neoadjuvant treatment-related adverse events (neoTRAEs) occurred in 47.6% of the patients, including 63 (51.2%) and 17 (37.8%) patients in the ≥75% and <75% groups, respectively (P = 0.122). Pathologic complete response occurred in 31.7% of the patients in the ≥75% group and in 20.0% of those in the <75% group (P = 0.177); major pathologic response occurred in 59.3% and 48.9%, respectively (P = 0.300). According to the results of the IPTW-weighted univariate Cox analysis, patients in the <75% group had worse 3-year rates of DFS (77.1% vs. 77.9%; P = 0.065) and OS (68.3% vs. 89.1%; P = 0.033). These findings remained robust to multivariate Cox regression models (DFS: hazard ratio [HR]ffoo, 2.858; 95% confidence intervals [CIs]: 1.239-6.692; P = 0.014; and OS: HR, 7.625; 95% CIs: 1.112-52.272; P = 0.039). Additionally, a shorter mean TI of patients who received neoCIT infusions (<23.5 vs. ≥23.5 hours) emerged as an independent factor associated with better OS (HR, 0.143; 95% CIs, 0.024-0.875; P = 0.035). CONCLUSIONS: Although early infusions of most neoIO drugs did not affect safety or efficacy, it showed a potential trend toward improving long-term survival. The corresponding immune microenvironment and molecular mechanisms need further exploration to guide the design of future prospective clinical studies.