Definitive Radiotherapy With or Without Chemotherapy After Planned Neoadjuvant Chemoimmunotherapy in Stages II to III NSCLC: An International Multicenter Retrospective Study

Introduction Approximately 15% to 20% of patients with resectable NSCLC receiving neoadjuvant chemoimmunotherapy on clinical trials cannot proceed to surgery due to disease progression, toxicity, or medical contraindications. The safety and efficacy of definitive radiotherapy (RT) in this population are uncertain. Methods We performed an international multicenter (13 institutions) retrospective study of patients with stages II to III NSCLC who received more than or equal to 2 cycles of neoadjuvant platinum-based chemoimmunotherapy followed by definitive RT instead of planned surgery. The primary end point was pneumonitis incidence; secondary end points included progression-free survival (PFS), overall survival (OS), and treatment-related adverse events. Results We identified 57 patients, 54 (90%) of whom had stage III NSCLC. The most common reasons for definitive RT were surgical resectability (n = 38, 67%), followed by new-onset medical contraindications (n = 15, 26%), patient preference (n=3, 5%), and complete radiographic response (n = 1, 2%). Pneumonitis occurred in 10 patients (18%), including six grade 3 to 4 events (10.5%) and one grade 5 event (2%), with no differences based on concurrent chemotherapy or consolidation systemic therapy. Most patients (n = 36, 63%) achieved partial radiographic response to neoadjuvant therapy. With median follow-up of 17 months, median PFS was 16.1 months (95% confidence interval [CI] 12.2–not reached [NR]) and median OS was not reached (interquartile range 20.5–NR). One-year OS rate was 81% (95% CI 70%–94%). PFS was longer in patients undergoing RT for medical contraindications versus surgical resectability (30.3 [95% CI 16.1–NR] versus 12.2 [95% CI 7.6–NR] mo; p = 0.037). No significant differences in PFS were observed with concurrent chemotherapy ( p = 0.64) or consolidation therapy ( p = 0.12). Among 27 patients experiencing progression after definitive RT, the most common site was the lungs (n = 19, 70.4%), followed by lymph nodes (n = 8, 29.6%) and bone (n = 5, 18.5%). Conclusion Definitive RT after neoadjuvant chemoimmunotherapy demonstrates promising effectiveness and safety in patients unable to undergo planned surgery. Prospective studies should focus on adaptive RT approaches and biomarker development to improve outcomes in this challenging population.