Post-progression treatment strategies and immunotherapy rechallenge sensitivity following chemoradiation and consolidation durvalumab in unresectable stage III NSCLC: The POST-PACIFIC study.

8048 Background: Durvalumab consolidation after platinum-based chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). However, optimal treatment strategies after progression remain undefined, and data guiding post-durvalumab strategies, including immunotherapy rechallenge, are limited. Methods: This global retrospective multicenter study included patients with unresectable stage III NSCLC treated with concurrent or sequential CRT who progressed after ≥1 dose of durvalumab consolidation. Survival outcomes were assessed using Kaplan-Meier and Cox methods. Immunotherapy sensitivity was defined by time from durvalumab initiation to progression: refractory (< 12 months) or sensitive (≥12 months) and correlated with outcomes after immunotherapy rechallenge. Results: Among 319 patients, median age was 66.5 years; 54.2% were male, and 96.7% had ECOG PS 0-1. Concurrent CRT was delivered in 96.5% (median RT dose 60 Gy). Median follow-up was 62.2 months. Progression pattern included locoregional recurrence in 34.8% and distant relapse in 65.2%. Of 293 patients receiving a first subsequent therapy (FST), chemotherapy (CT) ± VEGF inhibition was most common (31.7%), followed by local ablative therapy (LAT, 30.7%), immunotherapy ± CT (18.4%), targeted therapy (TT, 10.9%), and durvalumab beyond progression (BP) ± LAT (6.5%). When comparing FST, immunotherapy rechallenge demonstrated superiority over CT. Compared with CT ± VEGF inhibition, immunotherapy ± CT was associated with a higher objective response rate (ORR: 40.7% vs. 16.9%, p < 0.01) and significantly improved progression-free survival (mPFS2: 8.48 vs. 4.14 months; HR 0.41, p < 0.01) and overall survival (mOS2: 23.7 vs. 12.2 months; HR 0.41, p < 0.01), findings confirmed in multivariable analyses. Patients with actionable oncogenic drivers or indolent, focal relapses achieved the most favorable outcomes with TT or durvalumab BP ± LAT, respectively, reflecting a disease biology amenable to highly effective systemic or localized interventions. Among patients who received immunotherapy rechallenge, those relapsing ≥12 months after durvalumab initiation experienced higher ORR and numerically longer PFS and OS. Additionally, upfront rechallenge was independently associated with superior survival in multivariable models (PFS aHR: 0.51, p < 0.01; OS aHR: 0.46, p < 0.01) and with higher ORR (41.5% vs. 17.6%, p = 0.04), compared with later-line rechallenge. Conclusions: Post-PACIFIC treatment approaches are heterogeneous, but immunotherapy-based strategies provide superior efficacy over CT alone. Patients with prolonged benefit from durvalumab (≥12 months) retain immune sensitivity and derive the greatest benefit from immunotherapy rechallenge, particularly as FST.