Scott J. Antonia, MD, PhD
AS REPORTED in The New England Journal of Medicine by Scott J. Antonia, MD, PhD, of H. Lee Moffitt Cancer Center and Research Institute, and colleagues, the phase III PACIFIC trial has shown significantly improved overall survival, a coprimary endpoint, with the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab (Imfinzi) vs placebo after chemoradiotherapy in unresectable, stage III non–small cell lung cancer (NSCLC).1 An earlier report from the trial supported the approval of durvalumab in this setting in February 2018 on the basis of improved progression-free survival.2
IN THE DOUBLE-BLIND trial, 709 patients from 235 sites in 26 countries (in Asia, Australia, Europe, North America, South America, and Southern Africa) were randomly assigned 2:1 between May 2014 and April 2016 to receive intravenous (IV) durvalumab at 10 mg/kg (n = 473) or IV placebo every 2 weeks (n = 236) for up to 12 months as consolidation in patients with unresectable, stage III NSCLC without disease progression after at least 2 cycles of definitive platinum-based chemoradiation. Randomization was performed at 1 to 42 days after receipt of chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary endpoints were progression-free survival assessed by blinded independent central review and overall survival. After the discontinuation or completion of the trial regimen, patients could receive their assigned trial regimen again if disease control had persisted for 12 months and if disease progression was observed during follow-up.
Among all patients, the median age was 64 years; 70% were male; 69% were white, and 27% were Asian. The disease stage was IIIA in 53% and IIIB in 45%; a total of 12 patients had other disease stages, ranging from IA to IV. The World Health Organization performance status was 0 in 49% and 1 in 51%; histology was squamous in 46% and nonsquamous in 54%; the smoking status was current, former, and never for 16%, 75%, and 9%; 92% had received radiotherapy at ≥ 54 to ≤ 66 Gy and 7% at > 66 to ≤ 74 Gy; 27% had received induction chemotherapy (99.7% received chemotherapy concurrent with radiotherapy); and best response to chemoradiotherapy was complete in 2%, partial in 48%, and stable disease in 47%.
AS OF DATA cutoff in March 2018, the median follow-up was 25.2 months. Overall survival at 24 months was 66.3% in the durvalumab group vs 55.6% in the placebo group (P = .005). The median overall survival was not reached (95% confidence interval [CI] = 34.7 months to not reached) vs 28.7 months (95% CI = 22.9 months to not reached). The stratified hazard ratio (HR) for overall survival for durvalumab vs placebo was 0.68 (P = .0025). Hazard ratios favored durvalumab across prespecified subgroups. Hazard ratios were 0.62 (95% CI = 0.44–0.86) among patients aged < 65 years and 0.76 (95% CI = 0.55–1.06) among those aged ≥ 65 years; 0.78 (95% CI = 0.59–1.03) among men and 0.46 (95% CI = 0.30–0.73) among women; and 0.72 (95% CI = 0.56–0.92) among those with a smoking history and 0.35 (95% CI = 0.16–0.76) among never-smokers. In an exploratory post hoc analysis among patients with known PD-L1 expression status, hazard ratios were 0.46 (95% CI = 0.27–0.78) among 115 vs 44 patients with expression ≥ 25% and 0.92 (95% CI = 0.63–1.34) among 187 vs 105 with expression < 25%.
As of data cutoff in February 2017 for the primary analysis of progression-free survival, the median follow-up was 14.5 months, and the median progression-free survival was 16.8 months in the durvalumab group vs 5.6 months in the placebo group (HR = 0.52, P < .001). An updated analysis in the current report showed median progression-free survival of 17.2 vs 5.6 months (stratified HR = 0.51, 95% CI = 0.41–0.63). After discontinuation of study treatment, 41.0% of the durvalumab group vs 54.0% of the placebo group received additional anticancer therapy, including cytotoxic chemotherapy in 26.9% vs 30.0%, immunotherapy in 8.0% vs 22.4%, and nonimmunotherapy-based targeted treatment in 9.9% vs 13.1%; 17.2% vs 23.6% received subsequent radiotherapy.
In the current report, the median time to death or distant metastasis was 28.3 months in the durvalumab group vs 16.2 months in the placebo group (stratified HR = 0.53, 95% CI = 0.41–0.68). New brain metastases were found in 6.3% vs 11.8% of patients. The investigator-assessed median time to second disease progression or death was 28.3 months vs 17.1 months (stratified HR = 0.58, 95% CI = 0.46–0.73).
SAFETY PROFILES were similar to those previously reported. Grade 3 or 4 adverse events occurred in 30.5% of the durvalumab group vs 26.1% of the placebo group. Adverse events led to treatment discontinuation in 15.4% vs 9.8% of the patients, with the most common cause being pneumonitis in both groups (4.8% vs 2.6%). Potentially immune-related adverse events occurred in 66.7% vs 49.1% (grade 1 or 2 in 56.8% vs 43.6%); as reported in the prior publication, the most common of any grade were diarrhea (18.3% vs 18.8%), pneumonitis (12.6% vs 7.7%), rash (12.2% vs 7.3%), and pruritus (12.2% vs 4.7%). Serious adverse events occurred in 29.1% vs 23.1%. Adverse events led to death in 4.4% vs 6.4% of patients.
The investigators concluded: “[This] trial showed a survival advantage with durvalumab therapy after concurrent chemoradiation therapy in patients with stage III, unresectable NSCLC…. No new safety signals were identified.” ■
DISCLOSURE: The study was funded by AstraZeneca. For full disclosures of the study authors, visit www.nejm.org.
1. Antonia SJ, Villegas A, Daniel D, et al: Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. September 25, 2018 (early release online).
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.