Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

Abstract

Purpose: Immunotherapy targeting PD-L1 improves outcomes in patients with unresectable stage III non-small cell lung cancer (NSCLC) and no progression after definitive, concurrent chemoradiotherapy (cCRT). Earlier administration of immunotherapy, simultaneously with cCRT, may improve outcomes further.

Methods: Eligible patients were randomly assigned (2:1) to receive either durvalumab or placebo administered from the start of cCRT. Patients without progression after completing cCRT received consolidation durvalumab or placebo (per initial random assignment) until progression. The primary end point was progression-free survival (PFS) by blinded independent central review. Key secondary end points included objective response rate (ORR), overall survival (OS), the proportion of patients alive at 24 months (OS24), and safety.

Results: In total, 328 patients were randomly assigned to receive durvalumab (n = 219) or placebo (n = 109). There was no statistically significant difference with durvalumab versus placebo in PFS (hazard ratio [HR], 0.85 [95% CI, 0.65 to 1.12]; P = .247) or OS (HR, 1.03 [95% CI, 0.78 to 1.39]; P = .823); OS24 was 58.4% versus 59.5%, respectively. Confirmed ORR was 60.7% with durvalumab versus 60.6% with placebo (difference, 0.2% [95% CI, -15.2 to 16.3%]; P = .976). With durvalumab versus placebo, respectively, maximum grade 3 or 4 adverse events (AEs) occurred in 53.4% versus 59.3% of patients, pneumonitis or radiation pneumonitis (group term) in 28.8% (grade ≥3: 4.6%) versus 28.7% (grade ≥3: 5.6%), AEs leading to discontinuation of durvalumab or placebo in 25.6% versus 12.0%, and fatal AEs in 13.7% versus 10.2%.

Conclusion: Among patients with unresectable stage III NSCLC, durvalumab administered from the start of cCRT failed to demonstrate additional benefit compared with cCRT plus placebo. Consolidation durvalumab following definitive cCRT remains the standard of care in this setting.

FIG 1.

Patient disposition. ^aThe safety analysis set includes all patients who underwent random assignment and received at least one dose of trial treatment or placebo; one patient assigned to the placebo group erroneously received a single cycle of durvalumab and was included in the durvalumab group for the safety analysis set. CRT, chemoradiotherapy; ITT, intention-to-treat.

FIG 2.

Kaplan-Meier analysis of (A) PFS by BICR and (B) OS (ITT population). Tick marks on the curves indicate censored observations. PFS per RECIST v1.1. PFS and OS were analyzed using a stratified log-rank test adjusting for age and disease stage, with HRs and 95% CIs estimated using a Cox proportional hazards model. Kaplan-Meier methodology was used to calculate medians for time-to-event end points. Data cutoff date, September 7, 2023. ^aBased on the Lan and DeMets approach that approximates the O'Brien Fleming spending functions; the two-sided P value boundary for declaring statistical significance for PFS is .0416 for an overall 5% alpha. ^bThe two-sided P value boundary for declaring statistical significance for OS is .045 or .05 depending on the previous levels of the multiple testing procedure. BICR, blinded independent central review; CRT, chemoradiotherapy; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival.

FIG 3.

Forest plots of (A) PFS by BICR and (B) OS in prespecified patient subgroups (ITT population). PFS per RECIST v1.1. An HR of <1 favors durvalumab and is associated with a longer PFS/OS than placebo. The size of circle is proportional to the number of events. The gray band represents the 95% CI for the main PFS/OS HR. For all patients, the analysis is based on the main stratified analysis, whereas for the subgroups, the HR and CI were calculated using an unstratified Cox proportional hazards model, with treatment as the only covariate and ties handled by Efron approach. Data cutoff date, September 7, 2023. ^aHRs and 95% CIs were not calculated if a subgroup had fewer than five events in either treatment arm. ^bAt screening. ^cAccording to version 8 of the IASLC Staging Manual in Thoracic Oncology. ^dPer IVRS. BICR, blinded independent central review; EGFR, epidermal growth factor receptor; HR, hazard ratio; IASLC, International Association for the Study of Lung Cancer; ITT, intention-to-treat; IVRS, interactive voice response system; NC, not calculable; OS, overall survival; PFS, progression-free survival.