Durvalumab After Chemoradiotherapy: Insights from the PACIFIC-5 Trial in Unresectable Stage III NSCLC

The PACIFIC-5 trial shows that consolidation durvalumab meaningfully prolongs progression-free survival (PFS) for adults with unresectable stage III non–small-cell lung cancer who have no progression after definitive chemoradiotherapy. In the modified intent-to-treat population, median PFS was 14.0 versus 6.5 months (HR 0.75), supporting broader consideration of consolidation immunotherapy in routine post‑CRT planning.

PACIFIC-5 randomized 407 patients (2:1 durvalumab:placebo) after completion of definitive concurrent or sequential platinum-based CRT, with eligibility limited to unresectable stage III disease, documented nonprogression, and WHO/ECOG performance status 0–1. Randomization was stratified by tumor PD‑L1 expression (<1% vs ≥1%) and prior CRT type. The mITT analysis excluded patients with confirmed EGFR or ALK sensitizing alterations, and PFS was assessed at prespecified imaging intervals with blinded independent central review. Broad geographic enrollment and inclusion of sequential-CRT recipients enhance applicability to heterogeneous clinical populations.

Durvalumab improved median PFS to 14.0 versus 6.5 months (stratified HR 0.75; 95% CI 0.58–0.99; p=0.038), demonstrating a statistically significant consolidation benefit in the mITT population. Overall survival data are immature at first interim analysis but trend favorably (median OS 38.3 vs 32.5 months; HR 0.87; 95% CI 0.66–1.17; p=0.346). Predefined subgroup analyses showed consistent hazard ratios after concurrent CRT (HR 0.76) and sequential CRT (HR 0.75), while benefit signals were attenuated for patients with PD‑L1 tumor‑cell expression <1% (HR 0.97) and in non‑squamous histology (HR 1.07). These results confirm a broad PFS advantage with durvalumab but suggest PD‑L1 status and histology may help refine patient selection pending mature OS and biomarker validation.

Safety was notable for pneumonitis or radiation pneumonitis, reported in 39.5% of durvalumab-treated patients (predominantly grade 1–2) and accounting for 3.7% grade ≥3 events. Treatment-emergent adverse events occurred in 94.8% versus 83.6% with placebo; grade 3–4 events occurred in 26.9% versus 23.9%. Treatment discontinuation due to adverse events was 14.4% versus 8.2%, and treatment-related deaths occurred in 1.5% of the durvalumab arm. Pragmatic monitoring—early triage for new or worsening cough or dyspnea, a low threshold for chest imaging with multidisciplinary review to distinguish radiation change from immune-mediated pneumonitis, and routine thyroid-function checks—is reasonable to mitigate risk. The PFS benefit must be weighed against a measurable increase in immune-related toxicity and higher discontinuation rates.