Pathological Response, Tumor Microenvironment Dynamics, and Survival Dissociation after Neoadjuvant Chemoimmunotherapy for Lung Cancer with Rare Histological Subtypes.

Abstract

Although perioperative chemoimmunotherapy is standard for resectable non-small cell lung cancer (NSCLC), evidence in rare histological subtypes remains scarce owing to their low incidence and limited representation in clinical trials. We retrospectively analyzed 77 patients with resectable rare-subtype lung cancer (excluding adenocarcinoma, squamous cell carcinoma and small cell lung cancer) who received neoadjuvant chemoimmunotherapy followed by surgery at Guangdong Provincial People's Hospital between January 2019 and October 2025. Pathological response, predictive biomarkers, immune microenvironment dynamics, and survival were assessed. The major pathological response (MPR) rate was 48.1% (37/77), with 22.1% achieving pathological complete response (pCR). MPR was strongly predicted by PD-L1 expression ≥ 75% and ΔSUV_max reduction ≤ - 50% (P < 0.001). Treatment increased CD3⁺ T cell infiltration from baseline (P = 0.010). Among post-treatment tumors, MPR was associated with higher CD20⁺ B cell infiltration versus non-MPR (P = 0.023). After 28.6 months median follow-up, the 2-year event-free survival (EFS) rate was 74.0% and the 3-year overall survival (OS) rate was 95.4%. Notably, a dissociation between EFS and OS was observed. EFS benefit was driven by pCR (2-year pCR 86.2%), but both pCR and MPR-non-pCR achieved 100% 3-year OS, versus 90.4% in non-MPR. Adjuvant immunotherapy did not appear to improve EFS in either subgroup (MPR but not pCR: P = 0.316; pCR: P = 0.755). Neoadjuvant chemoimmunotherapy demonstrates encouraging efficacy in rare subtypes of lung cancer, with distinct predictive biomarkers and survival patterns, warranting further prospective validation.