At a median follow-up of 55.5 months, the median PFS was 13.8 months (HR, 0.85; 95% CI, 0.65-1.12; P = .247) among patients who received durvalumab plus CRT (n = 219), whereas the median PFS among patients who received placebo plus CRT (n = 109) was 9.4 months (HR, 0.85; 95% CI, 0.65-1.12; P = .247). Notably, the lack of a statistically significant improvement in PFS for patients in the durvalumab plus CRT arm vs patients in the placebo plus CRT arm in PACIFIC-2 stands in contrast to findings from the phase 3 PACIFIC trial (NCT01693562), the primary analysis of which showed that durvalumab after definitive CRT did significantly improve PFS compared with placebo plus CRT in this patient population (HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001).2 Additionally, at a median follow-up of 34.2 months (range, 0.2-74.7), the median PFS was 16.9 months with durvalumab vs 5.6 months with placebo (stratified HR, 0.55; 95% CI, 0.45-0.68).
“Although [the] 2- and 3-year PFS rates were numerically higher with durvalumab vs placebo [in PACIFIC-2, the] Kaplan-Meier curves did not separate in the first 6 months,” lead study author Jeffrey D. Bradley, MD, FACR, FASTRO, and coauthors wrote in the paper.1
Bradley is vice chair of Proton Therapy & Technology Development and a professor of radiation oncology at the Hospital of the University of Pennsylvania and the University of Pennsylvania Perelman School of Medicine in Philadelphia.
What were the rationale and design of the PACIFIC-2 trial?
The trial investigators wanted to optimize the potential efficacy of durvalumab and CRT that was demonstrated in the PACIFIC trial, which remains the standard of care for patients with unresectable stage III NSCLC.
The PACIFIC-2 trial enrolled patients at least 18 years of age with histologically or cytologically documented NSCLC with locally advanced unresectable stage III disease. Patients also needed to have a World Health Organization (WHO) or ECOG performance status of 0 or 1 at the time of enrollment and random assignment.
In the double-blind, placebo-control, randomized, trial, patients received either durvalumab or placebo from the start of CRT after being randomly assigned 2:1 to these respective treatment arms. Patients were administered either 1500 mg of durvalumab or placebo intravenously once every 4 weeks from the start of CRT. Following investigator assessment, patients without disease progression after completing CRT received 1500 mg of consolidation durvalumab or placebo in the same 4-week intervals until various discontinuation criteria were met.
The trial’s primary end point was PFS per RECIST 1.1 criteria by blinded independent central review. Important secondary end points were overall survival (OS), 24-month OS rate, objective response rate (ORR), duration of response (DOR), and disease control rate at 24 weeks from random assignment.
Baseline characteristics of the trial showed that patients had a median age of 63 years in both the durvalumab (range, 36-84) and placebo (range, 38-84) arms. Most patients in the durvalumab arm had a WHO/ECOG performance status of 1 (n =121; 55.3%), whereas slightly fewer patients in the arm had a WHO/ECOG performance status of 0 (n = 98; 44.7%). The placebo arm was composed of patients with similar characteristics, with most patients having a WHO/ECOG performance status of 1 (n = 56; 51.4%) and fewer patients with a WHO/ECOG performance status of 0 (n =53; 48.6%). Most patients in the durvalumab arm were White (n =141; 64.4%) and male (n = 166; 75.8%).
What were the additional efficacy and safety data from the PACIFIC-2 study of durvalumab and concurrent CRT?
Additional findings from the trial indicated that there was not a statistically significant difference in OS between each arm. Patients in the durvalumab arm had a median OS of 36.4 months compared with 29.5 months for patients in the placebo arm. The 24-month OS rate was 58.4% (95% CI, 51.6%-64.7%) in the durvalumab arm vs 59.5% (95% CI, 49.6%-68.2%) in the placebo arm (HR, 1.04; 95% CI, 0.72-1.50; P = .847).
Other secondary end points like ORR also failed to reach statistically significant difference between the arms, with patients in the durvalumab arm having an ORR of 60.7% and patients in the placebo arm achieving an ORR of 60.6% (difference, 0.2%; 95 CI, –15.2% to 16.3%; P = .976). The median DOR for patients in the durvalumab arm was 30.7 months vs 18.6 months for patients in the placebo arm.
Regarding safety, the most common any-grade adverse effects (AEs) for patients in the durvalumab arm were anemia (42.0%), pneumonitis or radiation pneumonitis (28.8%), neutropenia (27.4%), and nausea (25.6%). The most common any-grade AEs for patients in the placebo arm were also anemia (38.0%), pneumonitis or radiation pneumonitis (28.7%), neutropenia (25.9%), and nausea (24.1%). Immune-mediated AEs of any grade also occurred in 34.7% of patients in the durvalumab arm but only occurred in 15.7% of patients in the placebo arm.
“The safety profile of durvalumab in PACIFIC-2 was generally consistent with durvalumab's known profile, which is notable given that patients received durvalumab both in combination with cCRT and until progression,” the authors concluded. “However, important between-arm differences were observed in fatal AEs and AEs leading to treatment discontinuation, which were more prevalent with durvalumab and affected the proportion of patients receiving consolidation treatment.”
References
- Bradley DJ, Sugawara S, Lee KH, et al. Simultaneous durvalumab and platinum-based chemoradiotherapy in unresectable stage III non–small cell lung cancer: the phase III PACIFIC-2 study. J Clin Oncol. 2025;43(33): 3610-3621. doi:10.1200/JCO-25-00036
- Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
