Efficacy without compromising resection: surgical outcomes from AEGEAN

Lung cancer remains the most commonly diagnosed cancer worldwide, with an estimated 2,480,300 new cases, and is also the leading cause of cancer-related death, accounting for an estimated 1,817,200 deaths globally and 124,990 deaths in the United States in 2026 (1,2). The 5-year survival rate for non-small cell lung cancer (NSCLC) is reported to be 26.4% among all stages, while only 17.3% in stage IIIB (3). The survival rates improved significantly after the introduction of immunotherapy for patients with advanced NSCLC compared to the pre-immunotherapy era (4). While surgery is the first-line curative intent treatment for eligible patients, yet neoadjuvant and perioperative immunotherapy have provided significantly improved event-free survival and major pathological response rates (5-10). Such an approach raises persistent practical challenges for multidisciplinary teams due to concerns of delayed surgery, increased perioperative morbidity, disease progression before curative surgery, and potential interaction with operative techniques, feasibility and safety.

Mitsudomi et al. (11) in this AEGEAN surgical analysis provide reassurance that adding durvalumab to neoadjuvant platinum-doublet chemotherapy does not compromise surgical timing, feasibility, approach, or perioperative safety, while numerically improving R0 resection correlated with radiologic response after neoadjuvant therapy and nodal downstaging. AEGEAN is a phase III, randomized, double-blind, placebo-controlled trial that enrolled patients with treatment-naïve resectable NSCLC, stage IIA–IIIB N2 nodal disease, with Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and documented tumor programmed death-ligand 1 (PD-L1) status (5). Patients with tumors classified as T4, other than size >7 cm, or confirmed presence of EGFR mutation or ALK translocation were excluded. A total of 740 patients received up to four 3-weekly cycles of platinum-doublet chemotherapy plus durvalumab (n=366) or placebo (n=374), before curative-intent resection, then received up to 12 cycles of adjuvant durvalumab or placebo every 4 weeks. Surgery was prespecified within 40 days after the last neoadjuvant dose per study protocol. The other perioperative chemoimmunotherapy trials described a comparable time frame, no definitive surgical window is universally standardized. That has enabled a clinically interpretable definition of surgical delay as more than 40 days.

This trial answered a clinical practice challenge of whether neoadjuvant therapy would limit surgical intervention. Adding durvalumab as neoadjuvant treatment allowed curative-intent surgical resection in most patients, and the median interval from last neoadjuvant dose to surgery was identical at 34 days among both the durvalumab and placebo groups. 80.6% vs. 80.7% proceeded with surgery and were deemed completed in 77.6% vs. 76.7% in both groups. Among those who proceeded with surgery, 17.3% vs. 22.2% experienced a surgical delay, where logistical reasons were the most common reason; nevertheless, treatment-related adverse effects (AEs) caused surgical delay in only 3.1% vs. 4.3% of cases in both groups. Progressive disease in 6.8% in the durvalumab group vs. 7.8% in the placebo group was the leading reason precluding surgery, among other reasons, including patients’ decision, medical unfitness or AEs prior to surgery in 1.4% vs. 1.1% in both groups, respectively.

Open and minimally invasive approaches occurred at almost equal frequencies across arms with notable geographic variations, and lobectomy remained the predominant operation in 88.1% vs. 85.4%, followed by pneumonectomy. In other words, perioperative durvalumab did not obviously force surgeons into more extensive resections. This adds credible reasoning during patient counseling and selection of therapy. Most importantly, R0 resection rates were numerically higher in the durvalumab group in 94.7% vs. 91.3% in the placebo group, even in stage III disease; 93.9% vs. 90.3%. Although concurrent chemoradiotherapy (CCRT) was the standard of care for unresectable stage III NSCLC (12,13), this analysis provides pragmatic reassurance that a surgery-first curative strategy remains feasible for selected stage III patients treated with perioperative immunotherapy. In AEGEAN, curative-intent thoracic surgery was completed in 75.4% of patients with stage III disease in the durvalumab arm, with R0 resection achieved in 93.9% compared with 90.3% in the placebo arm. In parallel, the PACIFIC trial cemented durvalumab as consolidation therapy after CCRT by significantly prolonging progression-free survival, and established the rationale for early use of immunotherapy (13).

A key finding from this study was that the exploratory analyses suggest neoadjuvant treatment provides significant nodal downstaging and radiological response correlating with a higher likelihood of postoperative pathological responses. Patients with N1 or N2 nodal status had downstaging to N0 in 53.6% vs. 46.2% and 47.3% vs. 40.2% among both groups respectively. Patients with complete or partial radiologic responses before surgery were more likely to have a pathological complete response with a positive predictive value of 27.2% in the durvalumab group vs. 8.5% in the placebo group. A result that can align with deeper biological activity with neoadjuvant therapy and predict a potential lower risk of locoregional recurrence.

Surgical safety profile remains an indispensable aim of the overall clinical management approach and patient selection for therapy. In this study, surgery was equally safe among both arms, where AEs of any grade were reported in 40.2% of the durvalumab group vs. 39.2% in the placebo group. Grade 3–4 AEs were not increased with durvalumab arm; 8.4% vs. 9.3% and surgical complication rates were equally comparable between groups; 59.1% vs. 60.1%.

This AEGEAN surgical outcomes trial (11) offers a key reassurance for multidisciplinary oncology teams that adding durvalumab does not appear to exact a surgical trade-off in timing, approach, or postoperative safety in patients with stage II–IIIB N2 node stage NSCLC without EGFR/ALK alterations. The study reported around 20% of patients who did not undergo surgery, which is consistent with other perioperative chemo-immunotherapy trials: pembrolizumab-KEYNOTE-671 (6), nivolumab-Checkmate 77T (7), toripalimab-Neotorch (9) and tislelizumab-RATIONALE-315 (10), and the neoadjuvant nivolumab-Chekmate816 trial (8) (Table 1). That correlates with surgical candidacy in 82% of patients who received neoadjuvant chemotherapy without immunotherapy in another trial (14). Limitations of this study include variability in local standards of surgical resection among international institutions and limited invasive mediastinal staging. Preoperative mediastinal staging is essential in selected patients, if fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scans revealed positive mediastinal nodes or negative mediastinum with tumors greater than 3 cm, central tumors, or clinical N1 disease, to guide accurate treatment choice and prognosis (15,16). In this trial, less than half of patients with N2 nodal status had pathological confirmation at baseline. It is possible that the clinically defined—pathologically unconfirmed—nodal status has resulted in overestimation of the efficacy results or possibly underrepresentation of the actual nodal disease at baseline. Additionally, the descriptive analysis of this report is not powered as a superiority analysis without a clear identification of perioperative endpoints for patient candidacy for resectability or the type of surgical approach.

With those reassuring positive results in favor of durvalumab use in the perioperative setting, the remaining challenge may not be only operative feasibility, however integration of other biomarkers, specific patients’ characteristics to guide appropriate patient selection and predict maximal benefit to reduce surgical attrition rates with minimal toxicities during neoadjuvant treatment. In this analysis, perioperative chemoimmunotherapy demonstrated a safe and feasible surgical approach among patients with resectable NSCLC. Such results may encourage future trials to study the potential effect of chemoimmunotherapy to allow metastasectomy in carefully selected patients with advanced unresectable NSCLC beyond the scope of AEGEAN. A similar trajectory has been observed in metastatic renal cell carcinoma, where consolidative metastasectomy, often alongside systemic immunotherapy, has offered meaningful disease control in appropriately selected patients (17,18).

In conclusion, AEGEAN’s operative dataset strengthens confidence that perioperative durvalumab can be delivered without compromising surgery, shifting the field’s focus from “can we get patients to the OR safely?” to “how do we optimize selection, sequencing, and biomarkers to ensure the right patients derive a durable cure?”

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0337/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0337/coif). A.D. reports consulting role in Sanofi, Amgen, Foundation Medicine, AstraZeneca, Janssen Oncology, Merus, Daiichi Sankyo, AbbVie, Regeneron, Bristol Myers Squibb, Bayer, Lilly, and ConcertAI; and grants from LUNGevity Foundation, Lung Cancer Research Foundation, and Robert Winn Clinical Trials Career Development Award. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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