As reported in the Journal of Clinical Oncology by David R. Spigel, MD, of Sarah Cannon Research Institute/Tennessee Oncology, and colleagues, long-term follow-up of the phase III PACIFIC trial has shown maintained progression-free and overall survival benefits with consolidation durvalumab (a PD-L1 inhibitor) vs placebo after chemoradiotherapy in unresectable stage III non–small cell lung cancer (NSCLC). Estimated 5-year rates were 43% for overall survival and 33% for progression-free survival in the durvalumab group.¹

David R. Spigel, MD

Interim analysis of progression-free survival in the PACIFIC trial supported the February 2018 approval of durvalumab for treatment of unresectable stage III NSCLC that has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

In the double-blind trial, 713 patients irrespective of PD-L1 expression status with no disease progression after concurrent platinum-based chemotherapy and radiotherapy were randomly assigned 2:1 to receive durvalumab at 10 mg/kg every 2 weeks (n = 476; 473 received treatment) or placebo (n = 237; 236 received treatment) for 12 months. Randomization was stratified by age, sex, and smoking history.

In primary analyses, durvalumab was associated with significant improvements in overall survival (stratified hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.53–0.87, P = .00251) and progression-free survival on blinded independent central review (stratified HR = 0.52, 95% CI = 0.42–0.65, P < .0001).^2,3

Updated Survival Data

As of data cutoff (January 2021), median follow-up was 34.2 months (range = 0.2–74.7 months) among all randomly assigned patients and 61.6 months (range = 0.4–74.7 months) among censored patients (patients last known to be alive).

Median overall survival was 47.5 months (95% CI = 38.1–52.9 months) in the durvalumab group vs 29.1 months (95% CI = 22.1–35.1 months) in the placebo group (stratified HR = 0.72, 95% CI = 0.59–0.89). Estimated 5-year overall survival was 42.9% (95% CI = 38.2–47.4%) vs 33.4% (95% CI = 27.3%–39.6%). Rates at 2, 3, and 4 years were 66.3% vs 55.3%, 56.7% vs 43.6%, and 49.7% vs 36.3%, respectively.

For stratification subgroups, hazard ratios for overall survival were 0.66 (95% CI = 0.50–0.87) for age up to 65 years and 0.79 (95% CI = 0.60–1.05) for age 65 years and older; 0.75 (95% CI = 0.59–0.95) for males and 0.64 (95% CI = 0.44–0.94) for females; and 0.75 (95% CI = 0.61–0.93) for ever-smokers and 0.42 (95% CI = 0.21–0.82) for never-smokers.

Median progression-free survival was 16.9 months (95% CI = 13.0–23.9 months) in the durvalumab group vs 5.6 months (95% CI = 4.8–7.7 months) in the placebo group (stratified HR = 0.55, 95% CI = 0.45–0.68). Estimated 5-year progression-free survival was 33.1% (95% CI = 28.0%–38.2%) vs 19.0% (95% CI = 13.6%–25.2%). Rates at 2, 3, and 4 years were 45.0% vs 25.1%, 39.7% vs 20.8%, and 35.0% vs 19.9%, respectively.

For stratification subgroups, hazard ratios for progression-free survival were 0.46 (95% CI = 0.36–0.60) for age up to 65 years and 0.76 (95% CI = 0.57–1.01) for age 65 years and older; 0.61 (95% CI = 0.48–0.76) for males and 0.52 (95% CI = 0.36–0.74) for females; and 0.61 (95% CI = 0.50–0.75) for ever-smokers and 0.33 (95% CI = 0.17–0.63) for never-smokers.

Overall, 48.5% of the durvalumab group vs 58.6% of the placebo group received at least one subsequent anticancer therapy after discontinuing study treatment, most commonly chemotherapy (33.0% vs 35.9%). Subsequent immunotherapy was received by 12.6% vs 29.1% of patients.

In post hoc analyses among patients with known PD-L1 expression status, hazard ratios for overall survival were 0.61 (95% CI = 0.44–0.85) among 212 vs 91 patients with PD-L1 expression at least 1% and 1.15 (95% CI = 0.75–1.75) among 90 vs 58 with PD-L1 expression less than 1%. Hazard ratios for progression-free survival were 0.47 (95% CI = 0.35–0.64) among patients with PD-L1 expression at least 1% and 0.80 (95% CI = 0.53–1.20) among those with PD-L1 expression less than 1%.

Additional Factors Associated With Outcomes

On multivariate analyses, factors significantly associated with overall survival in addition to treatment group were age of at least 65 years vs up to 65 years (HR =1.30, 95% CI = 1.06–1.59), squamous vs nonsquamous histology (HR = 1.28, 95% CI = 1.04–1.58), Word Health Organization performance status of 1 vs 0 (HR = 1.23, 95% CI = 1.01–1.50), Asian (n = 192) vs White (n = 494) race (HR = 0.63, 95% CI = 0.49–0.81), and male vs female sex (HR = 1.27, 95% CI = 1.01–1.61). Factors significantly associated with progression-free survival in addition to treatment group were squamous vs nonsquamous histology (HR = 1.35, 95% CI = 1.10–1.65), Asian vs White race (HR = 0.73, 95% CI = 0.58–0.93), and stage IIIB vs IIIA disease (HR = 1.30, 95% CI = 1.07–1.58).

The investigators concluded: “These updated analyses demonstrate robust and sustained [overall survival] and durable [progression-free survival] benefit with durvalumab after 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.” 

DISCLOSURE: The study was funded by AstraZeneca. Dr. Spigel has served as a consultant or advisor to Genentech/Roche, Novartis, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmithKline, Takeda, Evelo Therapeutics, Bayer, EMD Serono, Molecular Templates, Amgen, Curio Science, Intellisphere, Ipsen, Jazz Pharmaceuticals, Mirati Therapeutics, Puma Biotechnology, Sanofi/Aventis, Exelixis, Novocure, Regeneron, Lilly, Janssen, and Evidera; has received institutional research funding from Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, The University of Texas Southwestern Medical Center–Simmons Cancer Center, Merck, G1 Therapeutics, Neon Therapeutics, Takeda, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Ipsen, BIND Therapeutics, Eisai, ImClone Systems, Immunogen, Janssen Oncology, MedImmune, Molecular Partners, Agios, GlaxoSmithKline, Tesaro, Cyteir, Apollomics, Novocure, Elevation Oncology, Calithera Biosciences, Arcus Biosciences, Arrys Therapeutics, Bayer, BeiGene, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Denovo Biopharma, Hutchison MediPharma, Incyte, Kronos Bio, Loxo Oncology, MacroGenics, Molecular Templates, Oncologie, Pfizer, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Tizona Therapeutics Inc, and Verastem; and has received reimbursement for travel, accommodations, or other expenses from AstraZeneca, Genentech, and Novartis.

REFERENCES

1. 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 40:1301-1311, 2022.

2. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.

3. Antonia SJ, Villegas A, Daniel D, et al: Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379:2342-2350, 2018.