Neoadjuvant immunotherapy plus chemotherapy in locally advanced stage III NSCLC patients undergoing definitive...

The optimal integration of immunotherapy with definitive chemoradiotherapy (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) remains an area of active investigation. While consolidation immunotherapy is standard, the efficacy and safety of a neoadjuvant approach are not yet established by phase III trials. This real-world study compares outcomes between neoadjuvant immuno-chemotherapy followed by CRT (NEO) and CRT followed by adjuvant immunotherapy (ADJ, the PACIFIC regimen).

In this multicenter retrospective analysis, we reviewed data from patients with stage III NSCLC who received radical thoracic radiotherapy and peri-radiotherapy immunotherapy between January 2020 and December 2023. Patients were classified into NEO (n = 321) or ADJ (n = 142) groups. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included treatment patterns, recurrence modes, and incidence of pneumonitis. Propensity score matching (PSM) and robust statistical analyses were used to minimize confounding.

The median PFS was significantly longer in the NEO group than in the ADJ group (25.0 months vs. 16.3 months; HR = 0.57, 95 % CI: 0.43-0.74; p < 0.001). Median OS was not reached (NR) in the NEO group compared to 41.1 months in the ADJ group (HR = 0.54, 95 % CI: 0.37-0.78; p = 0.001). The survival benefit for the NEO group remained consistent after PSM and multivariable adjustment. The objective response rate to neoadjuvant therapy was 68.4 %. Patterns of recurrence were similar between groups, with distant metastasis being the most common site of first progression. The incidence of grade ≥2 radiation pneumonitis was comparable (31.8 % NEO vs. 30.8 % ADJ, p = 0.925), though a non-significant trend towards higher grade ≥3 radiation pneumonitis was observed in the NEO group (14.0 % vs. 7.5 %, p = 0.071). Rates of checkpoint inhibitor pneumonitis were low and similar between groups.

In this large real-world cohort, a treatment sequence incorporating neoadjuvant immuno-chemotherapy prior to definitive CRT was associated with significantly improved PFS and OS compared to the standard adjuvant immunotherapy approach, without a definitive increase in severe pneumonitis. These findings support the further investigation of neoadjuvant immunotherapy strategies in phase III randomized trials for stage III NSCLC.