Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS: A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial.

For patients with resectable, early-stage non-small-cell lung cancer (NSCLC), surgery is the primary treatment; however, 5-year survival rates remain poor. Postoperative adjuvant platinum-doublet chemotherapy is associated with a statistically significant but modest improvement in survival of ∼5% at 5 years and is widely accepted as standard of care in patients with resectable, Stage II-III NSCLC. Neoadjuvant chemotherapy has been associated with similar improvements in overall survival to adjuvant therapy in this setting. Durvalumab, a high-affinity PD-L1 inhibitor, has become the standard of care for patients with unresectable, Stage III NSCLC following chemoradiotherapy based on improved progression-free and overall survival in the phase III PACIFIC trial. AEGEAN is a phase III, double-blind, placebo-controlled, international study that will assess pathological and clinical outcomes of durvalumab plus chemotherapy prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, Stage II-III NSCLC. Approximately 800 patients will be randomized (1:1) to receive durvalumab or placebo every 3 weeks (q3w) alongside platinum-based chemotherapy (≤4 cycles) prior to surgery, followed by durvalumab or placebo monotherapy q4w, for an additional 12 cycles post surgery, stratified by disease stage (IASLC 8th Edition, Stage II vs. Stage III) and PD-L1 tumor cell expression levels (<1% vs. ≥1%). Primary endpoints include pathological complete response and event-free survival for patients with wild-type EGFR and ALK. Key secondary efficacy endpoints include major pathologic response, disease-free survival and overall survival.