Abstract
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.
Highlights
For patients diagnosed with early stage (Stages I-IIIA) non-small-cell lung cancer (NSCLC), surgery is the primary curative treatment in patients where resection is possible.[1]
The advantages of a neoadjuvant treatment approach include the timely treatment of subclinical micrometastatic disease, reduction in tumor bulk prior to surgery, increased tumor T-cell infiltration, improved R0 resection rate, increased knowledge of drug sensitivity, along with higher treatment compliance and drug delivery rates compared with adjuvant therapy.[6,8,9,10]
Emerging clinical data from exploratory, single-arm and randomized studies of patients with NSCLC receiving neoadjuvant treatment with immune checkpoint inhibitors (ICIs) prior to resection, have demonstrated promising anti-tumor efficacy, with major pathological response rates of 20–45%, increasing to 57–83% when combined with CT.[14,15,16,17,18]
Summary
For patients diagnosed with early stage (Stages I-IIIA) non-small-cell lung cancer (NSCLC), surgery is the primary curative treatment in patients where resection is possible.[1]. Neoadjuvant immunotherapy may have the further advantage of leveraging the tumor as an antigen source, potentially enhancing anti-tumor T-cell response, leading to anti-tumor immunity which could reduce metastatic spread[12] and further improve long-term clinical outcomes.[13] Emerging clinical data from exploratory, single-arm and randomized studies of patients with NSCLC receiving neoadjuvant treatment with immune checkpoint inhibitors (ICIs) prior to resection, have demonstrated promising anti-tumor efficacy, with major pathological response (mPR; ≤10% residual viable tumor tissue in the lung primary tumor at time of surgery) rates of 20–45%, increasing to 57–83% when combined with CT.[14,15,16,17,18] Recent data from the phase 3 CheckMate 816 trial demonstrated a statistically significant improvement in pathological complete response (pCR; absence of any viable tumor cells after complete evaluation in resected lung tissue and all sampled regional lymph nodes) in patients with early-stage, resectable NSCLC following neoadjuvant treatment with the programmed cell death-1 (PD-1) inhibitor nivolumab in combination with CT, versus CT alone.[19] These findings further support the rationale for combining ICIs targeting the PD1/programmed cell death ligand-1 (PD-L1) pathway with CT in the neoadjuvant setting. In this manuscript we describe the design and rationale of the study
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