From Clinical Trials to Real-World Practice: Surgical Feasibility and Postoperative Outcomes After Neoadjuvant Chemoimmunotherapy for Locally Advanced NSCLC in a Single-Center Experience

Background/Objectives: Perioperative chemo-immunotherapy (CHT-IO) has emerged as a standard treatment strategy for resectable stage II–IIIB NSCLC. However, data regarding surgical feasibility, mini-invasive surgery rates, perioperative outcomes, and postoperative complications in real-world single-center experiences remain limited. Methods: A retrospective single-center analysis was performed including consecutive patients with locally advanced NSCLC treated with perioperative chemo-immunotherapy between March 2024 and March 2026. Patients received platinum-based chemotherapy combined with pembrolizumab or durvalumab, followed by surgical resection with curative intent. Surgical, pathological, and postoperative outcomes were analyzed. Results: Thirty patients received neoadjuvant CHT-IO, of which 25 (83.3%) underwent surgical resection. Reasons for failure to proceed to surgery included treatment-related toxicity or deterioration in performance status (n = 3), disease progression (n = 1), and patient refusal (n = 1). Lobectomy was the most performed procedure (64%), while a minimally invasive approach (uniportal VATS) was adopted in 44% of cases. Moderate-to-severe pleural adhesions (64%) and hilar fibrosis (60%) were observed intraoperatively. Despite these technical challenges, conversion to thoracotomy was required in only one case (4%), no intraoperative complications occurred, and complete (R0) resection was achieved in 96% of patients. Pathological complete response and major pathological response were observed in 36% and 52% of cases, respectively. Postoperative complications occurred in 56% of patients, although most were Clavien–Dindo grade I–II. The presence of comorbidities was the only factor associated with an increased risk of postoperative complications (OR 10.00, 95% CI 0.99–100.46; p = 0.05). Median length of hospital stay was 5.65 ± 2.04 days. One postoperative death due to septic complications was recorded. Conclusions: In this real-world monocentric experience, the combination of perioperative CH-ICIs and surgical resection (including mini-invasive approach) was safe and feasible in patients with locally advanced NSCLC. High rates of complete (R0) resection and encouraging pathological responses were observed, consistent with outcomes reported in randomized trials. Although surgery was overall frequently technically demanding, these changes did not appear to compromise perioperative safety or oncological radicality, even when minimally invasive approaches were adopted. Larger studies with longer follow-up are needed to better define long-term oncological outcomes.