The Phase III AEGEAN trial has demonstrated that adding durvalumab to standard chemotherapy before and after surgery significantly improves outcomes for patients with resectable non-small cell lung cancer (NSCLC), marking a potential breakthrough in treating early-stage disease. The randomized, double-blind, placebo-controlled study showed substantial improvements in both event-free survival and pathological complete response rates compared to chemotherapy alone.
Trial Design and Patient Population
The AEGEAN study enrolled 802 patients with resectable NSCLC (stage II-IIIB [N2 node stage]) who were randomly assigned to receive either platinum-based chemotherapy plus durvalumab or placebo. Treatment consisted of four cycles administered intravenously every three weeks before surgery, followed by twelve cycles of adjuvant durvalumab or placebo given every four weeks after surgery.
The study's primary endpoints were event-free survival (EFS), defined as time to progressive disease that precluded surgery, disease recurrence, or death, and pathological complete response (pCR). A total of 740 patients were included in the efficacy analysis, with 366 receiving durvalumab and 374 receiving placebo. The median age was 65 years, with 71.6% male participants.
Significant Clinical Benefits Observed
The results demonstrated compelling efficacy across both primary endpoints. Patients receiving perioperative durvalumab achieved a pathological complete response rate of 17.2% compared to just 4.3% in the placebo group (p<0.001), representing approximately a four-fold improvement in complete tumor elimination before surgery.
Event-free survival showed equally impressive results, with durvalumab significantly extending EFS compared to placebo (HR 0.68; 95% CI: 0.53-0.88; P=0.004). At the 12-month landmark analysis, EFS rates were 73.4% versus 64.5% in the durvalumab and placebo groups, respectively. With a median follow-up of 11.7 months, the median EFS was 25.9 months in the placebo arm, while it had not yet been reached in the durvalumab arm.
Broad Efficacy Across Patient Subgroups
Notably, the benefits of durvalumab were observed consistently across predefined patient subgroups, regardless of disease stage or PD-L1 expression levels. This broad efficacy profile suggests the treatment could benefit a wide range of patients with resectable NSCLC, not just those with high PD-L1 expression.
Safety Profile Remains Manageable
The safety analysis revealed that perioperative durvalumab maintained a tolerable profile consistent with the individual agents. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients receiving durvalumab compared to 43.2% of those receiving placebo, indicating no significant increase in severe toxicity with the addition of immunotherapy.
Clinical Context and Significance
"Our goal is to increase cures for lung cancer. Throughout decades of research with adjuvant and neoadjuvant chemotherapy, we only succeeded in increasing cures by around 5%," said principal investigator John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology at MD Anderson. "This one study alone has the potential to increase that percentage significantly, and we look forward to many more improvements going forward."
The findings address a critical unmet need in NSCLC treatment, where approximately 30-55% of patients experience tumor recurrence within five years after surgery, depending on disease stage. Traditional chemotherapy in the neoadjuvant or adjuvant setting has provided only modest improvements in 5-year survival compared to surgery alone.
Implications for Treatment Standards
AEGEAN represents the first Phase III trial investigating perioperative immunotherapy in patients with resectable NSCLC to report positive outcomes. The data correspond to a 32% lower chance of patients experiencing disease recurrence, progression events, or death with the immunotherapy-based treatment compared to chemotherapy alone.
"This study shows that a combination of neoadjuvant and adjuvant durvalumab offers benefit for patients and may have the potential to change standard-of-care for patients with resectable non-small cell lung cancer," Heymach noted. The results add to growing evidence supporting the benefits of both neoadjuvant and adjuvant immunotherapy for these patients.
Future Research Directions
The trial continues to assess long-term EFS as well as disease-free survival and overall survival outcomes. Future studies will need to determine which patients receive the most benefit from neoadjuvant therapy and may avoid further treatment, as well as identify those who remain at high risk of recurrence and may require more intensive adjuvant regimens.
Durvalumab, an immune checkpoint inhibitor targeting PD-L1, has previously been approved for treating patients with biliary tract cancer, liver cancer, small cell lung cancer, and NSCLC in various settings. The AEGEAN results could potentially expand its use to the perioperative setting for resectable NSCLC, representing a significant advancement in the treatment paradigm for early-stage disease.
