The landscape of perioperative immunotherapy in non-small cell lung cancer: what have we learned from the AEGEAN trial?

Curative-intent surgery is the standard of care for resectable non-small cell lung cancer (NSCLC) (1). However, an estimated 30–55% of patients develop recurrent lung cancer after surgery (2). For patients with tumor size ≥4 cm or positive lymph nodes, neoadjuvant or adjuvant chemotherapy is recommended and can improve 5-year overall survival (OS) by 5% (3,4). The advent of targeted therapy with adjuvant osimertinib for EGFR mutant NSCLC has significant improved disease-free survival (DFS) and OS in this patient subset, and promising data now exists for ALK-positive NSCLC with adjuvant alectinib (5,6). As discussed below, in NSCLC patients without these targeted alterations, anti-PD-1/PD-L1 therapies can significantly improve outcomes in the early-stage setting.

The IMpower010 trial investigated the addition of 1 year of atezolizumab after adjuvant chemotherapy (7). In the stage II–IIIA [American Joint Committee on Cancer (AJCC) 7^th edition] subgroup, median DFS was 42.3 months with atezolizumab vs. 35.3 months with best supportive care [hazard ratio (HR), 0.79; 95% confidence interval (CI): 0.64–0.96] (Table 1). OS favored atezolizumab in the PD-L1 tumor proportion score (TPS) ≥1% (HR, 0.71; 95% CI: 0.49–1.03) and PD-L1 TPS ≥50% (HR, 0.43; 95% CI: 0.24–0.78) populations, but not in the overall stage II-IIIA patients (HR, 0.95; 95% CI: 0.74–1.24) (8). Similarly, the PEARLS/KEYNOTE-091 trial found that a year of adjuvant pembrolizumab improved DFS in stage IB (≥4 cm) to IIIA (AJCC 7^th edition) NSCLC (9) (Table 1). Median DFS was 53.6 vs. 42 months in the pembrolizumab vs. placebo arms (HR, 0.76; 95% CI: 0.63–0.91). OS data is still immature for PEARLS/KEYNOTE-091. Adjuvant atezolizumab and pembrolizumab were both well tolerated overall, yielding grade 3 or higher adverse events (AEs) in 24% and 35% of patients, respectively. There was a less than 1% incidence of fatal immune-related AEs (one case each of grade 5 pneumonitis and myocarditis with atezolizumab, two cases of grade 5 myocarditis with pembrolizumab) (7,9). Based on these studies, adjuvant atezolizumab was approved by the US Food and Drug Administration (FDA) for stage II–IIIA NSCLC with PD-L1 TPS ≥1%, and adjuvant pembrolizumab was approved for stage IB (≥4 cm) to IIIA NSCLC.

PD-1 blockade has also been studied in the neoadjuvant setting. The CheckMate 816 trial showed that three cycles of neoadjuvant nivolumab combined with chemotherapy improved pathological complete response (pCR) rate compared with chemotherapy alone in stage IB (≥4 cm) to IIIA (AJCC 7^th edition) NSCLC (24.0% vs. 2.2%, P<0.001) (10) (Table 2). Median event-free survival (EFS) was 31.6 months with nivolumab plus chemotherapy vs. 20.8 months with chemotherapy alone (HR, 0.63; 95% CI: 0.43–0.91). The HR for death was 0.57 (95% CI: 0.30–1.07) and was not significant at the first interim analysis as the data is still maturing. Grade 3 and higher AEs were similar in both arms and occurred at a rate of 33.5% vs. 36.9%. There were three treatment-related deaths in the chemotherapy arm, and none in the nivolumab plus chemotherapy group. This study has led to FDA approval for neoadjuvant nivolumab in combination with chemotherapy for resectable stage IB (≥4 cm) to IIIA NSCLC.

Building on the findings from the above trials, there has been growing interest in administering anti-PD-1 therapy in both the pre- and post-operative settings to improve patient outcomes. The AEGEAN trial investigated whether the addition of perioperative durvalumab would improve EFS and pCR rate in patients with resectable stage II–IIIB (N2 nodal stage) (AJCC 8^th edition) NSCLC, compared with neoadjuvant chemotherapy alone (11). 802 patients were randomized to receive four cycles of neoadjuvant platinum-based chemotherapy combined with either durvalumab or placebo, followed by surgery and 12 additional cycles of durvalumab or placebo. The trial was amended to exclude patients with EGFR or ALK alterations, leaving a total of 740 patients in the modified intention-to-treat (ITT) population. The majority of patients received carboplatin-based chemotherapy (72.7%). In total, 77.6% of patients in the durvalumab group and 76.7% of patients in the placebo group completed curative-intent surgery, among which 94.7% vs. 91.3% had an R0 resection. However, only 65.8% vs. 63.4% went on to receive adjuvant durvalumab or placebo. At the first interim analysis, AEGEAN met its primary endpoint, with median EFS not reached in the durvalumab arm vs. 25.9 months in the placebo arm (HR, 0.68; 95% CI: 0.53–0.88) (Table 2). pCR rate was 17.2% with durvalumab and 4.3% with placebo (P<0.001). Durvalumab outperformed placebo across key subgroups, including in both squamous and nonsquamous histologies and in tumors with PD-L1 TPS <1%. However, the benefit of durvalumab in females appeared to be marginal (although they made up a minority of the population, 28%) (HR, 0.95; 95% CI: 0.58–1.56). The EGFR-mutant population (n=51), which was excluded from the modified ITT analysis, also did not benefit (HR, 0.86; 95% CI: 0.35–2.19). OS has not yet been reported. Grade 3 and higher AEs were similar with durvalumab or placebo (32.4% and 32.9%, respectively). Fatal AEs possibly related to trial treatment occurred at a frequency of 1.7% in the durvalumab arm vs. 0.5% in the placebo arm. In the durvalumab arm, these events were interstitial lung disease in two patients and immune-mediated lung disease, pneumonitis, hemoptysis, myocarditis, and decreased appetite in one patient each.

AEGEAN is one of several large phase III trials published in the past year (including KEYNOTE-671, CheckMate 77T, and Neotorch) that studied the efficacy of perioperative PD-(L)1 blockade in resectable, stage II–IIIB (N2 nodal stage) (AJCC 8^th edition) NSCLC (Table 2) (12-14). The positive results of these trials and the neoadjuvant trial CheckMate 816, all of which met their primary endpoints of improved EFS compared with chemotherapy alone, suggest that patients with early-stage NSCLC may benefit from immunotherapy given prior to surgery. These data further suggest that the benefit may be greater than what is observed with adjuvant immunotherapy. Neoadjuvant systemic therapy has several potential advantages, such as debulking/downstaging of cancer for a less extensive surgery, early treatment of micrometastatic disease, prevention of futile surgery on patients with rapid metastatic dissemination, and the ability to utilize pathological response as a prognostic factor. In the context of immunotherapy, a growing body of literature suggests that initiating therapy while the primary tumor is in place (vs. after surgical removal) is beneficial (15). The hypothesis is that higher tumor antigen burden and presence of resident tumor-specific tumor-infiltrating lymphocytes enhances T-cell priming and anti-tumor immunity. In two murine models of spontaneously metastatic breast cancer, neoadjuvant administration of anti-PD-1 and anti-CD137 antibodies resulted in 40–50% long-term survival, compared with no survivors when administered adjuvantly (16). Although total CD8⁺ T cells did not differ between the two groups, tumor-specific CD8⁺ T cells strongly increased in both the peripheral blood and metastatic organs after treatment with neoadjuvant immunotherapy, and presence of these cells correlated with survival. Paralleling these preclinical findings, the SWOG 1801 phase II trial showed that in patients with resectable stage III–IV melanoma, neoadjuvant-adjuvant administration of pembrolizumab improved 2-year EFS by 23% compared to adjuvant only (17).

In NSCLC, adjuvant atezolizumab did not benefit the PD-L1 negative subgroup (DFS: HR, 0.97; 95% CI: 0.72–1.31) (IMpower010) and adjuvant pembrolizumab did not benefit patients with squamous cell carcinoma (DFS: HR, 1.04; 95% CI: 0.75–1.45) and had marginal benefit in patients with PD-L1 expression ≥50% (DFS: HR, 0.82; 95% CI: 0.57–1.18) (PEARLS/KEYNOTE-091). In contrast, published trials of neoadjuvant/perioperative PD-1 blockade consistently demonstrate improved EFS in all PD-L1 and squamous subgroups. Additionally, the HRs for median EFS and OS are numerically lower in the neoadjuvant/perioperative trials (EFS: HRs range 0.40–0.68; OS: HRs range 0.57–0.73) compared with DFS and OS in the adjuvant trials (DFS: HRs range 0.76–0.79; OS: HRs range 0.87–0.95), although a possible confounding factor is that the neoadjuvant/perioperative trials enrolled a higher proportion of patients with N2 disease, which if discovered prior to surgery traditionally necessitates preoperative systemic therapy (1) (Tables 1,2). A similar trial to SWOG 1801, which directly compared a neoadjuvant vs. adjuvant approach, has not yet been conducted in lung cancer, and would be of great interest to determine whether neoadjuvant is superior to adjuvant PD-(L)1 blockade.

Another unanswered question is whether the addition of adjuvant PD-(L)1 blockade, as prescribed in the AEGEAN, KEYNOTE-671, Neotorch, and CheckMate 77T trials, provides benefit beyond neoadjuvant therapy alone. In mice with spontaneous metastatic breast cancer, adding adjuvant immunotherapy after neoadjuvant immunotherapy and surgery did not improve long-term survival (18). As T cell priming is thought to occur most readily in the presence of tumor antigen and tumor-infiltrating lymphocytes, further immunotherapy after surgical resection may not be beneficial, and has the potential to increase incidence of immune-related AEs, which can be lifelong and in rare cases fatal. Reassuringly, the perioperative PD-(L)1 trials in NSCLC, excepting perhaps the Neotorch trial, have not reported an excess of grade 3+ immune-related AEs compared to CheckMate 816 trial (Table 2). It should be noted that the addition of 9–10 months of immunotherapy after surgery also increases health care costs and burden of travel for patients, which may disproportionately affect vulnerable populations.

The KEYNOTE-671 investigators noted that in the subgroup of trial patients who did not achieve a pCR, perioperative pembrolizumab improved EFS with HR of 0.69 (95% CI: 0.55–0.85); in contrast, patients without a pCR in the CheckMate 816 trial did not benefit as much from neoadjuvant nivolumab alone, with a higher HR of 0.84 (95% CI: 0.61–1.17) (10,13). Similar to KEYNOTE-671, the Neotorch trial reported that perioperative toripalimab improved EFS in patients who did not achieve a pCR (HR, 0.53; 95% CI: 0.38–0.74) (12). These data are provocative, but it is difficult to draw conclusions from cross-trial comparisons. Additionally, the bulk of the EFS benefit still appears to be driven by patients who achieve a pCR (HR, 0.33 in KEYNOTE-671). Although perioperative PD-1 blockade seems to provide some benefit to the non-pCR population, there remains a need to improve outcomes for the non-pCR patient beyond what can be achieved with continued PD-1 monotherapy. circulating tumor DNA (ctDNA) minimal residual disease (MRD) assays have gained attention in recent years as a sensitive and specific indicator of disease relapse (19,20). In the CheckMate 816 trial, ctDNA clearance after two cycles of therapy was more common in the nivolumab arm (56% vs. 35%) and was associated with pCR and longer EFS (10). Similarly, data from the AEGEAN trial show higher rates of ctDNA clearance pre-surgery in the durvalumab arm compared to placebo (66% vs. 41%), and clearance after cycle 2 correlated with pCR rates (durvalumab arm: 50.0% vs. 15.1%; placebo arm: 14.3% vs. 3.1%) (21). One could envision a future in which prognostic indicators, such as pCR status or biomarkers like ctDNA, are used to make decisions regarding the necessity of adjuvant immunotherapy or other novel therapies, thus sparing toxicity for those who have low likelihood of relapse.

In an exploratory analysis, the IMpower010 investigators demonstrated that adjuvant atezolizumab improves OS in patients with PD-L1 TPS ≥1%, with the benefit driven by those in the PD-L1 TPS ≥50% group (8). From KEYNOTE-671, an OS benefit has now been reported for perioperative pembrolizumab regardless of PD-L1 status (HR, 0.72; 95% CI: 0.56–0.93) (22). This is concordant with the phase 2 NADIM II trial of perioperative nivolumab in resectable stage III NSCLC, which also demonstrated a survival benefit over chemotherapy alone (23). CheckMate 816 has yet to report mature OS data for the neoadjuvant anti-PD-1 alone approach.

The AEGEAN trial found that perioperative durvalumab combined with chemotherapy improved pCR rate and EFS in resectable NSCLC. Similar findings were reported with pembrolizumab, nivolumab, and toripalimab in the KEYNOTE-671, CheckMate 77T, and Neotorch trials (Table 2). Together, these trials offer a new paradigm for the treatment of early-stage, resectable NSCLC. At this point in time, there is no clear indication to favor any one agent over the others. All trials enrolled NSCLC patients with resectable stage II–IIIB (N2 nodal stage) (AJCC 8^th edition) NSCLC, were placebo-controlled, and included four cycles of chemoimmunotherapy followed by surgery and 12–13 cycles of immunotherapy in the experimental arm (except Neotorch, which had three cycles of pre-operative and one cycle of post-operative chemoimmunotherapy). EGFR- and ALK-mutated patients were excluded in CheckMate 77T and Neotorch and included in small numbers in AEGEAN and KEYNOTE-671. Despite these small differences in design, the results are remarkably consistent across trials, with significant pCR and EFS benefit in all (Table 2). This is in keeping with the fact that all utilized anti-PD-1 or anti-PD-L1 monoclonal antibodies, which possess similar mechanisms of action, efficacy, and safety profiles. The frequency of severe irAEs was around 5% for each agent, except for toripalimab, which was reported at 12% (Table 2). In subgroup analysis of EFS, pembrolizumab performed the best, benefiting all subgroups including females, never smokers, and PD-L1 ≤1%. Additionally, it is the only perioperative anti-PD-(L)1 agent that has been reported to have an OS benefit in a phase III trial to date, although data are immature for the others. Finally, patient-reported outcomes and quality of life measures were collected for KEYNOTE-671 and AEGEAN, and we await the publication of these important results which may further inform the choice of PD-1 agent. Thus, while AEGEAN generates a potential new indication for durvalumab in resectable NSCLC, it is not necessarily practice-changing.

In addition to addressing the optimal timing and length of therapy, future efforts should explore the combination of PD-(L)1 blockade with novel immunomodulatory agents. The phase II NeoCOAST platform trial found that one cycle of durvalumab + oleclumab (anti-CD73), durvalumab + monalizumab (anti-NKG2A), or durvalumab + danvatirsen (anti-STAT3 antisense oligonucleotide) improved major pathological response (MPR) rate compared with durvalumab alone (24). The NeoCOAST-2 trial, which has a similar platform design, evaluates five different novel perioperative chemoimmunotherapy combinations and is now enrolling (NCT05061550). These trials and others will pave the way for a new era of neoadjuvant immunotherapy in NSCLC and hopefully improve outcomes in the patients where we are not currently achieving pCRs. In time, they may also lead us to question whether traditional chemotherapy can be omitted from the perioperative armamentarium.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-29/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-29/coif). T.F.B. has served as a compensated consultant for DSMB: Advarra, Inc. (Lantern Pharma); Scientific Advisory Board member of (no stock) Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals Inc., Amgen, AstraZeneca, and Takeda Pharmaceuticals U.S.A., Inc.; Scientific Advisory Board and Steering Committee member for Eli Lilly and Company; received consulting fees from Eli Lilly and Company for providing patient case study; and received institutional research funds from Novartis (all to institution). The author apologizes to colleagues in the field for not citing their relevant work due to space limitations. The other author has 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/.

References

1. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 1.2024). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Available online: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res 2014;3:242-9. [PubMed]
3. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-9. [Crossref] [PubMed]
4. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71. [Crossref] [PubMed]
5. Tsuboi M, Herbst RS, John T, et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 2023;389:137-47. [Crossref] [PubMed]
6. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2024;390:1265-76. [Crossref] [PubMed]
7. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-57. [Crossref] [PubMed]
8. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023;34:907-19. [Crossref] [PubMed]
9. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274-86. [Crossref] [PubMed]
10. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
11. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
12. Lu S, Zhang W, Wu L, et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 2024;331:201-11. [Crossref] [PubMed]
13. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
14. Cascone T, Awad MM, Spicer JD, et al. LBA1 CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Ann Oncol 2023;34:S1295. [Crossref]
15. Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020;367:eaax0182. [Crossref] [PubMed]
16. Liu J, Blake SJ, Yong MC, et al. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer Discov 2016;6:1382-99. [Crossref] [PubMed]
17. Patel SP, Othus M, Chen Y, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 2023;388:813-23. [Crossref] [PubMed]
18. Liu J, O'Donnell JS, Yan J, et al. Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome. Oncoimmunology 2019;8:e1581530. [Crossref] [PubMed]
19. Pellini B, Chaudhuri AA. Circulating Tumor DNA Minimal Residual Disease Detection of Non-Small-Cell Lung Cancer Treated With Curative Intent. J Clin Oncol 2022;40:567-75. [Crossref] [PubMed]
20. Tran HT, Heeke S, Sujit S, et al. Circulating tumor DNA and radiological tumor volume identify patients at risk for relapse with resected, early-stage non-small-cell lung cancer. Ann Oncol 2024;35:183-9. [Crossref] [PubMed]
21. Reck M, Gale D, Harpole D, et al. LBA59 Associations of ctDNA clearance and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase III AEGEAN trial. Ann Oncol 2023;34:S1300. [Crossref]
22. Spicer JD, Gao S, Liberman M, et al. LBA56 Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Ann Oncol 2023;34:S1297-8. [Crossref]
23. Provencio M, Nadal E, González-Larriba JL, et al. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:504-13. [Crossref] [PubMed]
24. Cascone T, Kar G, Spicer JD, et al. Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. Cancer Discov 2023;13:2394-411. [Crossref] [PubMed]