INTRODUCTION: The current standard of care for fit patients with unresectable stage III NSCLC involves concurrent chemoradiation (CRT) followed by durvalumab. Disease recurrence occurs in approximately 2/3 of patients, often necessitating subsequent systemic therapy. The only available data about re-challenge immune checkpoint blockers (ICB) in this setting derives from small retrospective series. We evaluated progression free survival (PFS) and overall survival (OS) in patients receiving either ICB-based therapy versus a chemotherapy (CT)-only for disease progression after CRT and durvalumab. MATERIALS AND METHODS: Multicenter retrospective study, conducted across 10 centers in Italy, the USA, Israel, and The Netherlands. Consecutive patients with relapsed NSCLC following CRT and durvalumab were enrolled. RESULTS: A total of 197 patients met the eligibility criteria: 93 received CT ( ± anti-VEGF), and 104 received an ICB-based treatment ( ± CT). The median PFS for patients receiving an ICB-based versus a CT-only regimen was 5.9 (95 % CI 4.3-7.6) versus 4.9 months (95 % CI 3.9-5.8), respectively (p = 0.011, HR: 0.67, 95 % CI 0.49-0.91). The median OS was 14.6 months (95 % CI 9.9-19.4) versus 8.9 (95 % CI 7.4-10.4), respectively (p = 0.005, HR: 0.61, 95 % CI 0.43-0.86). Patients with PFS ≥ 12 months on durvalumab, treated with subsequent ICB or CT median OS was 22.0 (95 % CI: 12.9-31.2) 9.8 months (95 % CI: 4.3-15.2) respectively (p = 0.024). Among patients with a PFS <
12 months on durvalumab there was no significant OS difference between ICB and CT arms. CONCLUSIONS: ICB retreatment at disease progression after CRT and durvalumab might offer an OS benefit over CT in patients who do not relapse during durvalumab treatment.