Background
Phase 3, double-blind, placebo-controlled RCT. 713 patients with unresectable stage III NSCLC without disease progression after ≥2 cycles of platinum-based concurrent CRT. Enrolled from 235 sites in 26 countries. Patients with EGFR/ALK mutations were not excluded (~6% enrolled). Durvalumab started within 1–42 days after the last RT fraction.
Interventions and follow up
Arm A: Durvalumab 10 mg/kg IV q2wks × up to 12 months (N=476)
Arm B: Placebo q2wks × up to 12 months (N=237)
Primary endpoint: PFS and OS (co-primary)
mFollow up: 14.5 months (PFS analysis); updated OS median 25.2 month
Arm B: Placebo q2wks × up to 12 months (N=237)
Primary endpoint: PFS and OS (co-primary)
mFollow up: 14.5 months (PFS analysis); updated OS median 25.2 month
Results
PFS: 17.2 vs 5.6 months, HR 0.51 (95% CI 0.41–0.63), P<.001
OS: HR 0.68 (99.73% CI 0.47–0.997), P=.0025
24-month OS rate: 66.3% vs 55.6%
ORR: 28.4% vs 16.0%
Median duration of response: 72.8% ongoing at 18 months (durvalumab) vs 46.8% (placebo)
OS: HR 0.68 (99.73% CI 0.47–0.997), P=.0025
24-month OS rate: 66.3% vs 55.6%
ORR: 28.4% vs 16.0%
Median duration of response: 72.8% ongoing at 18 months (durvalumab) vs 46.8% (placebo)
Adverse events
Main adverse events: Grade ≥3 AEs: 30.5% vs 26.1%. Any-grade radiation pneumonitis: 33.9% vs 24.8%; grade ≥3: 3.4% vs 2.6%. Hypothyroidism any grade: 9.5% vs 3.0%. Serious AEs leading to discontinuation: 15.4% vs 9.8%. No increase in grade ≥3 pneumonitis beyond what was seen with CRT alone.
Conclusions
Durvalumab consolidation after concurrent CRT significantly improved both PFS (HR 0.51) and OS (HR 0.68) in unresectable stage III NSCLC — the first regimen to show an OS benefit in this setting. This established the PACIFIC regimen as global standard of care and transformed the management of stage III NSCLC.
Key Limitations
Key Limitations: EGFR-mutant patients (particularly those receiving EGFR-TKIs in Japan after CRT) appeared to derive no benefit or potential harm from durvalumab — a critical biomarker finding. PD-L1 status was not a stratification factor; benefit was seen regardless of PD-L1 expression, though interpretation requires caution. Optimal RT technique and dose were not mandated — varying regimens were used across sites. Randomization up to 42 days post-RT may select for healthier patients who recovered, introducing potential bias. Randomized discontinuation timing between arms (12 months vs. open-ended) may limit OS interpretation.
Clinical Context
FDA approved in 2018 for stage III NSCLC without progression after platinum-based CRT regardless of PD-L1. The PACIFIC regimen — concurrent CRT (60 Gy + platinum/taxane or etoposide) → durvalumab 12 months — is now the global standard. ESMO-MCBS score 4. Patients with sensitizing EGFR mutations are typically excluded from durvalumab per updated guidelines. Mean heart dose <20 Gy (RTOG 0617 lesson) and optimal RT are prerequisites to maximize benefit. LAURA trial (durvalumab for oligometastatic/stage IV after CRT) is extending the paradigm.
References