In patients with resectable non-small cell lung cancer (NSCLC), perioperative durvalumab plus neoadjuvant chemotherapy, as compared with neoadjuvant chemotherapy alone, was associated with significantly better results with regard to the two primary endpoints of event-free survival (EFS) and pathological complete response (pCR), with a safety profile that was consistent with the individual agents, and had no detrimental effect on the completion of neoadjuvant chemotherapy or surgery.
The findings from the primary analyses of EFS and pCR from the phase III, international, double-blind, placebo-controlled AEGEAN study are published by Dr. John V. Heymach of the Department of Thoracic–Head and Neck Medical Oncology, M.D. Anderson Cancer Center in Houston, TX, US, and colleagues on 2 November 2023 in The New England Journal of Medicine.
The authors wrote in the background that chemotherapy administered in the neoadjuvant or adjuvant period offers only a modest 5% improvement in 5-year NSCLC survival as compared with surgery alone. After positive results from phase III studies, PD1 and PD-L1 inhibitors have received approval for use as a component of either neoadjuvant treatment in combination with platinum-based chemotherapy or adjuvant treatment following resection and platinum-based chemotherapy for patients with resectable NSCLC.
Perioperative regimens that combine the benefits of neoadjuvant and adjuvant immunotherapy could further improve long-term outcomes by priming antitumour immunity while the primary tumour and lymph nodes are present and eradicating residual micrometastases both before and after surgery.
In the phase III, international, double-blind, placebo-controlled AEGEAN study, the investigators 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.
Randomisation was stratified according to disease stage (II or III) and PD-L1 expression (≥1% or <1%). Primary endpoints were EFS 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 pCR evaluated centrally.
A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of EFS 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, EFS was 73.4% in patients who received durvalumab (95% CI 67.9 to 78.1), as compared with 64.5% in patients who received placebo (95% CI 58.8 to 69.6).
The incidence of pCR was significantly greater with durvalumab than with placebo (17.2% versus 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).
Improvements in EFS and pCR with durvalumab were broadly observed across subgroups, including in patients with PD-L1 expression of less than 1%, although the magnitude of benefit was greater in patients with PD-L1 expression of at least 50%. Although benefit was seen across all smoking-status subgroups, the greatest benefit was in current and former smokers, a finding consistent with the results of other immunotherapy studies.
Although improvements in EFS and pCR were greater among patients who received durvalumab, the magnitude of benefit varied, with patients with stage II disease having a relatively larger benefit about pCR and patients with stage IIIA disease (the largest subgroup) having a relatively larger benefit regarding EFS.
Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo.
The study was designed and began enrolment before approval of adjuvant osimertinib for patients with EGFR-mutated resectable NSCLC. The results of the phase III ADAURA study were published during the period in which AEGEAN was enroling patients and established a new treatment standard for patients with EGFR-mutated disease. Considering this new standard as well as emerging data from external studies that suggest patients with EGFR or ALK alterations have a limited response to immunotherapy, the AEGEAN protocol was amended to exclude these patients from further enrolment. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population.
Findings from the AEGEAN and other recent studies (CheckMate-816, IMpower010, KEYNOTE-091, Neotorch, and KEYNOTE-671) have confirmed the benefits of immunotherapy given as neoadjuvant treatment in combination with chemotherapy, as adjuvant treatment, or both in resectable NSCLC. However, differences in study design and patient populations confound cross-study comparisons.
Results from the AEGEAN study and other studies reinforce the importance of perioperative treatment approaches that combine the benefits of neoadjuvant and adjuvant immunotherapy, priming anti-tumour immunity while the primary tumour and lymph nodes are present, and eradicating residual micrometastases before and after surgery.
Although the relative contributions of the neoadjuvant and adjuvant immunotherapy components cannot be directly determined from the current study, cross-study comparisons in all-comer PD-L1 populations suggest that regimens that included a neoadjuvant immunotherapy component (both neoadjuvant-only and perioperative immunotherapy) appear to confer benefit that is at least like, if not greater than, that with adjuvant immunotherapy alone. Future studies may focus on comparing and tailoring these different approaches (neoadjuvant versus adjuvant versus perioperative immunotherapy).
The authors concluded that findings from the AEGEAN study show a clear clinical benefit with perioperative immunotherapy in patients with resectable NSCLC. Based on the current findings, perioperative durvalumab plus neoadjuvant chemotherapy should be considered as a potential new treatment option for patients with resectable NSCLC.
The study was funded by AstraZeneca.
Reference
Heymach JV, Harpole D, Mitsudomi T, et al., for the AEGEAN Investigators. Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-1684.
