Durvalumab/Chemoradiotherapy Fails to Meet Efficacy, Safety in PACIFIC-2 Trial

Findings from the phase 3 PACIFIC-2 clinical trial (NCT03519971) show that durvalumab (Imfinzi)with platinum-based chemoradiotherapy (cCRT) did not improve efficacy or safety for patients with unresectable stage 3 non–small cell lung cancer (NSCLC).¹

The PACIFIC-2 trial failed to meet its primary and secondary end points of progression-free survival (PFS) and overall survival (OS). There was no statistically significant improvement in PFS for the durvalumab arm (n = 219) compared to the placebo arm (n = 108) (HR, 0.85; 95% CI, 0.65–1.12; P =.247). The median PFS was 13.8 months in the durvalumab arm vs 9.4 months in the placebo arm. The Kaplan-Meier survival curves for PFS overlapped during the first 6 months of treatment, indicating no early separation or benefit from the simultaneous approach. A sustained separation favoring durvalumab was observed only after 9 months.

There was also no statistically significant difference in OS between the study arms (HR, 1.03; 95% CI, 0.78–1.39; P =.823). The median OS was 36.4 months in the durvalumab arm vs 29.5 months in the placebo arm. The OS at 24 months was 58.4% in the durvalumab arm vs 59.5% in the placebo arm. The OS curves crossed at approximately 24 months, favoring placebo before this point and durvalumab after approximately 27 months.

The confirmed overall response rate was nearly identical between both arms; 60.7% in the durvalumab arm vs 60.6% in the placebo arm. The median duration of response was longer in the durvalumab arm at 30.7 months vs 18.6 months in the placebo arm.

Safety Findings

The safety profile of durvalumab in PACIFIC-2 was generally consistent with its established profile; however, the simultaneous regimen resulted in increased toxicity, leading to higher rates of discontinuation and fatal events compared to placebo.

Adverse events (AEs) occurred in 98.6% of patients in the durvalumab arm vs 100% of patients in the placebo arm. Grade 3 or 4 AEs occurred in 53.4% of patients in the durvalumab arm vs 59.3% of patients in the placebo arm. Serious AEs occurred in 47% vs 51.9% of patients between both arms. AEs leading to discontinuation occurred in 25.6% of patients vs 12% between both arms. Any-grade pneumonitis occurred in 28.8% of patients vs 28.7% between both arms.

A post-hoc analysis revealed that the higher rate of fatal AEs in the durvalumab arm was most pronounced within the first 4 months of treatment (6.8% vs 4.6%), a period corresponding to the cCRT administration and recovery.

Fatal bleeding events were more common in the durvalumab arm. This may be partially explained by a baseline imbalance, as the durvalumab arm had a numerically higher proportion of patients with known risk factors for pulmonary hemorrhage, such as squamous histology and large (T4) tumors invading major thoracic vessels.

Fatal infections were also more prevalent with durvalumab (6.8% vs 1.9%), particularly during the first 4 months. This may have been influenced by higher rates of grade ≥ 3 neutropenia in the durvalumab arm (13.7% vs 7.4%).

Trial Design and Methodology

The PACIFIC-2 trial was a phase 3, double-blind, randomized study with a total enrollment of 328 patients. Patients were enrolled across 87 sites in 14 countries. Patients were randomly assigned on a 2:1 basis.

In the treatment and consolidation phases, patients received 1500 mg intravenously every 4 weeks of durvalumab plus platinum-based cCRT. In the placebo arm patients received placebo intravenously every 4 weeks plus platinum-based cCRT.

The results of PACIFIC-2 definitively show that the strategy of administering immunotherapy concurrently with cCRT provides no additional benefit and introduces increased toxicity.

The trial did not support the preclinical hypothesis that simultaneous administration would create synergy and improve outcomes. Instead, the approach failed to prevent early progression and increased treatment-related risks.

The median OS in the PACIFIC-2 durvalumab arm (36.4 months) was lower than in the original PACIFIC trial (NCT02125461)² (47.5 months). This difference is attributed to study design; PACIFIC-2 enrolled a broader, "all-comer" population before cCRT, whereas PACIFIC enrolled a more select population of patients who had already completed cCRT without progression and had recovered from acute toxicities.

The findings are consistent with the recently reported results from the CheckMate-73L trial (NCT04026412),³ which also found no PFS benefit for a simultaneous immunotherapy strategy compared to the PACIFIC regimen. This consistency strengthens the conclusion that concurrent immunotherapy with cCRT is not an effective strategy.

The phase 3 PACIFIC-2 trial unequivocally demonstrates that administering durvalumab simultaneously with definitive cCRT, followed by consolidation durvalumab, does not improve progression-free or overall survival for patients with unresectable stage 3 NSCLC. Furthermore, this approach is associated with increased toxicity and a higher rate of treatment discontinuation.

“The PACIFIC regimen, comprising 12 months of consolidation durvalumab after definitive cCRT among patients without progression after cCRT, has demonstrated robust efficacy with 5 years of follow-up, with replicable safety and efficacy, and remains the [standard-of-care] in this setting,” concluded Bradley J et al, authors of the study.

REFERENCES

1.Bradley J, Sugawara S, Lee K 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 43, 3610-3621(2025). doi: 10.1200/JCO-25-00036.

2.A global study to assess the effects of MEDI4736 following concurrent chemoradiation in patients with stage III unresectable non-small cell lung cancer (PACIFIC). ClinicalTrials.gov. Updated October 10, 2023. Accessed November 24, 2025. https://www.clinicaltrials.gov/study/NCT02125461

3.A study of nivolumab and ipilmumab in untreated participants with stage 3 non-small cell lung cancer (NSCLC) that is unable or not planned to be removed by surgery (CheckMate73L). ClincalTrials.gov. Updated July 24, 2025. Accessed November 24, 2025. https://www.clinicaltrials.gov/study/NCT04026412