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Robust and Sustained Survival Benefit with Consolidation Durvalumab After Concurrent Chemoradiotherapy for Unresectable, Stage III NSCLC

Five-year survival data from the PACIFIC study
08 Feb 2022
Cancer Immunology and Immunotherapy;  Lung and other thoracic tumours

Updated survival analyses from the PACIFIC study demonstrate robust and sustained survival benefit with durvalumab in patients with unresectable, stage III non–small-cell lung cancer (NSCLC) and no disease progression after concurrent chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting. The findings are published on 2 February 2022 in the Journal of Clinical Oncology by Dr. David R. Spigel, Chief Scientific Officer at Sarah Cannon Research Institute/Tennessee Oncology in Nashville, TN, US and colleagues on behalf of the PACIFIC investigators.

The authors wrote in the background that in the phase III, placebo-controlled PACIFIC study of patients with unresectable, stage III NSCLC whose disease had not progressed after platinum-based concurrent chemoradiotherapy, administration of durvalumab for up to 12 months was associated with improvements in the primary endpoints of overall survival (OS) with stratified hazard ratio (HR) of 0.68 (95% confidence interval [CI] 0.53 to 0.87; p = 0.00251; data cut-off 22 March 2018) and progression-free survival (PFS) with stratified HR 0.52 (95% CI 0.42 to 0.65; p < 0.0001; data-cut off 13 February 2017). 

This degree of benefit with durvalumab versus placebo remained consistent at subsequent updates and durvalumab also exhibited a manageable safety profile with no detrimental effect on patient-reported outcomes compared with placebo.

It was the first study to demonstrate a survival advantage with immune checkpoint inhibitor in a curative-intent setting. So, PACIFIC represents a landmark advancement in the treatment of this population. To provide insights into long-term outcomes from PACIFIC, the study team reports updated, exploratory analyses with data cut-off of 11 January 2021, approximately 5 years after the last patient was randomly assigned, including updates to the primary analyses of OS and PFS with durvalumab versus placebo, as well as updates to key secondary endpoints. The authors also report new exploratory analyses that examined the prognostic association of baseline factors (other than assigned study treatment) with OS and PFS.

Patients with WHO performance status 0 or 1 and any tumour PD-L1 status were randomly assigned 2:1 to durvalumab administered once every 2 weeks for 12 months or placebo, stratified by age, sex, and smoking history. Time-to-event endpoint analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method.

In total, 709 of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of 11 January 2021, updated OS (stratified HR 0.72; 95% CI 0.59 to 0.89; median 47.5 versus 29.1 months) and PFS (stratified HR 0.55; 95% CI 0.45 to 0.68; median 16.9 versus 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS.

Furthermore, updates to secondary endpoints continue to demonstrate durable antitumour response and a reduced frequency of metastases with durvalumab. Safety outcomes from PACIFIC were reported with the primary analyses and were not updated for this 5-year follow-up analysis, as no patients remained on the 12-month study treatment beyond the time of the primary OS analysis.

The authors commented that further research is needed to determine the optimum duration of durvalumab treatment following concurrent chemoradiotherapy. Use of a 12-month treatment duration in PACIFIC was an empiric decision made on the basis of the regimen used in a phase I/II first-in-human study of durvalumab.

Further studies have been initiated to investigate the use of durvalumab after sequential chemoradiotherapy or radiotherapy alone for patients who are chemotherapy-ineligible, and durvalumab in combination with novel anticancer agents post-chemoradiotherapy, with the aim of extending clinical benefit to more patients in this setting. In addition, a placebo-controlled, phase III study is investigating durvalumab administered concurrently with chemoradiotherapy followed by consolidation durvalumab.

The authors concluded that updated OS and PFS remained consistent with the PACIFIC primary analyses. The findings support the use of consolidation durvalumab after chemoradiotherapy as the standard of care for patients with unresectable, stage III NSCLC.

The study was sponsored by AstraZeneca. 

Reference

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. JCO; Published online 2 February 2022. DOI: 10.1200/JCO.21.01308

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