Neoadjuvant osimertinib: a new standard in resectable EGFR-mutated non-small cell lung cancer?

Introduction

Perioperative treatment for non-small cell lung cancer (NSCLC) has evolved to overcome the limitations of surgery alone, aiming to reduce recurrences and improve survival outcomes. Since the early 2000s, multiple large international trials have demonstrated that adjuvant chemotherapy after surgery contributes to reducing recurrence and mortality, with an estimated survival advantage of 5% at 5 years (1). Strategies for administering chemotherapy in the neoadjuvant rather than adjuvant setting have also been investigated. Although individual trials often failed to show superiority, a meta-analysis demonstrated a significant overall survival (OS) benefit compared with surgery alone (2). With the advent of molecularly targeted therapies and immune checkpoint inhibitors (ICIs) in the 2000s and 2010s, treatment outcomes for unresectable or recurrent NSCLC markedly improved. More recently, in the 2020s, evidence has emerged supporting the utility of these agents in the perioperative setting, reshaping the landscape of perioperative management.

Several phase III clinical trials have recently shown the efficacy of ICIs in the perioperative settings. The IMpower010 trial demonstrated that in patients with completely resected, programmed death ligand-1 (PD-L1)-positive (≥1%) NSCLC who had received adjuvant chemotherapy, the addition of an anti-PD-L1 antibody atezolizumab improved outcomes (3). The CheckMate 816 trial compared neoadjuvant nivolumab [an anti-programmed death 1 (PD-1) antibody] plus chemotherapy with chemotherapy alone in resectable stage IB–IIIA NSCLC, showing significant improvements in pathologic complete response (pCR) and event-free survival (EFS) in the nivolumab arm (4). The KEYNOTE-671 trial enrolled patients with resectable stage II–IIIB NSCLC and compared perioperative pembrolizumab (neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab monotherapy) with neoadjuvant chemotherapy alone. The perioperative pembrolizumab strategy significantly improved both EFS and OS (5). However, ICI treatment is known to be less effective in EGFR-mutant NSCLC, and the advancement of perioperative treatment for EGFR-mutant tumors has been awaited.

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI), initially approved for NSCLC harboring the EGFR T790M mutation, a common resistance mechanism to first-generation EGFR-TKIs (6). Subsequently, its efficacy as first-line monotherapy was established in patients with locally advanced or metastatic EGFR-mutant NSCLC (7). While earlier-generation EGFR-TKIs had failed to demonstrate perioperative benefit in resectable cases, the ADAURA trial provided the first evidence of efficacy for adjuvant EGFR-TKI therapy (8,9). In ADAURA, adjuvant osimertinib significantly prolonged both disease-free survival and OS in patients with completely resected stage IB–IIIA EGFR-mutant NSCLC.

In contrast, the benefit of EGFR-TKIs in the neoadjuvant setting had remained uncertain. Small-scale phase II studies, including the NEOS trial, had been reported (10), but no phase III trial results were available. In the 2023 report of the phase II NEOS trial, the objective response rate (ORR) was 71.1% (27/38) among those who completed 6 weeks of osimertinib treatment before surgery. The major pathological response (MPR) rate was 10.7% (3/28), and the pCR rate was 3.6% (1/28) (10). More recently, Lee et al. reported the results of the NORA study, in which ORR was 44% (11/25) after 8 weeks of Osimertinib treatment before surgery. The MPR and pCR rates were 24% (6/25), and 0% (0/25), respectively (11).

The NeoADAURA trial, initiated in 2021, was designed as a phase III study to evaluate the efficacy of neoadjuvant osimertinib in resectable EGFR-mutant NSCLC (12), and its results have been awaited (13). And in 2025, the interim analysis of the NeoADAURA trial was reported. Here, we briefly introduce the findings from the manuscript reported by He et al., recently published in the Journal of Clinical Oncology (14).

NeoADAURA trial

The NeoADAURA trial (NCT04351555) is a global, randomized, controlled, phase III study designed to evaluate the efficacy of neoadjuvant osimertinib with or without chemotherapy in resectable EGFR-mutated NSCLC. Eligible patients had stage II–IIIB, EGFR exon 19 deletion or L858R-mutated, nonsquamous NSCLC with ECOG performance status (PS) 0–1. A total of 358 patients were randomized in a 1:1:1 ratio to receive (I) oral daily osimertinib for ≥9 weeks plus platinum-based chemotherapy for three cycles; (II) osimertinib monotherapy; or (III) placebo plus chemotherapy. The primary endpoint was MPR (≤10% viable tumor, assessed by blinded central review). Secondary endpoints were EFS, pCR, and nodal downstaging at surgery. The safety profile was also assessed.

A total of 121 patients were assigned to osimertinib plus chemotherapy, 117 to osimertinib monotherapy, and 120 to placebo plus chemotherapy. The MPR rate was 26% in the osimertinib plus chemotherapy group and 25% with osimertinib monotherapy, both significantly higher compared with 2% in the placebo plus chemotherapy arm. pCR rates were 4%, 9%, and 0%, respectively. Among patients with baseline N2 disease, the rate of downstaging to N0 or N1 at surgery was 53%, 53%, and 21 % respectively. In the interim EFS analysis, with 15% data maturity, the estimated 12-month EFS rates were 93, 95%, and 83% respectively. Although EFS outcomes favoured the osimertinib-containing regimens, the findings from the interim analysis were not statistically significant as per the prespecified statistical significance level. Adverse events (AEs) of any cause occurred in around 90% of patients across the three treatment groups during the neoadjuvant phase, although most AEs were low-grade and non-serious. Grade ≥3 AEs occurred in 36% and 33 % of patients in the osimertinib plus chemotherapy group and the placebo plus chemotherapy group, respectively, whilst 13% in the osimertinib monotherapy group. Osimertinib monotherapy was associated with a lower incidence of high-grade AEs compared with the chemotherapy-containing regimens.

Overall, findings from NeoADAURA demonstrated that neoadjuvant osimertinib with or without chemotherapy significantly increased MPR compared with chemotherapy alone, with an acceptable safety profile.

One of the most intriguing findings from the NeoADAURA results is that the MPR rate did not differ between the osimertinib monotherapy and the osimertinib plus chemotherapy arms. As described above, the MPR rate was 25% after osimertinib monotherapy and 26% after osimertinib plus chemotherapy, while grade ≥3 AEs occurred in 13% after osimertinib monotherapy and 36% after osimertinib plus chemotherapy.

On the other hand, in the FLAURA2 trial, adding chemotherapy to osimertinib showed a survival benefit for locally advanced or metastatic NSCLC with EGFR mutation as a first-line treatment (15). The underlying mechanism explaining the benefit of adding chemotherapy in FLAURA2, which was not evident in the NeoADAURA trial, remains unclear. One could argue that the FLAURA2 study enrolled patients with advanced, often metastatic tumors, while the NeoADAURA study enrolled patients with resectable tumors. Adding chemotherapy to FLAURA2 might improve disease control by killing heterogeneous, potentially TKI-insensitive/metastatic clones upfront, while earlier-stage tumors in NeoADAURA may harbor less intratumor heterogeneity in terms of sensitivity to TKIs. However, NeoADAURA has not reached enough follow-up period for survival analysis, and we cannot yet argue the efficacy of adding chemotherapy to Osimertinib in terms of survival outcome. In fact, the addition of chemotherapy may improve survival by killing the minimal residual disease that has already spread from the main tumor. We need to wait until the study matures and EFS/OS results are reported.

Perspective on other TKI—perioperative alectinib

Although the incidence is less than that of oncogenic EGFR mutations, the anaplastic lymphoma kinase (ALK) fusion gene is another entity of oncogene-addicted NSCLC with recent advancements in targeted therapy. For ALK fusion-positive lung cancer, the ALINA trial demonstrated the efficacy of alectinib as adjuvant therapy (16), and interest is growing in its use as neoadjuvant therapy. The phase II ALNEO trial (NCT06015010), of which final analysis was presented at ASCO 2025, evaluated neoadjuvant alectinib in potentially resectable stage III ALK-positive NSCLC (17). Treatment-naïve patients with ECOG PS ≤1 received two 4-week cycles of neoadjuvant alectinib, followed by surgery and adjuvant alectinib for up to 24 cycles. Thirty-three patients were enrolled across 20 Italian centers, with clinical stage IIIA in 64% and IIIB in 36%. All patients completed the neoadjuvant phase, and 28 (85%) underwent surgery, with an R0 resection rate of 86%. MPR was observed in 46% and pCR in 12%, with an ORR of 67%. After a median follow-up of 15.2 months, 94% of patients were alive; median EFS and OS were not reached, and 18% experienced disease progression. Grade ≥3 AEs occurred in 9% during neoadjuvant therapy. These results suggest that neoadjuvant alectinib is feasible, effective, and well-tolerated as a perioperative strategy in resectable, locally advanced stage III ALK-positive NSCLC, supporting further investigation in this setting. Intriguingly, the reported pathological response rates of ALNEO study were between those reported from NeoADAURA and other recent phase III neoadjuvant trials of ICIs, further described in the next section.

Comparison with other recent phase III neoadjuvant trials (Table 1)

Several key findings from the major recent phase III studies that involve neoadjuvant therapy for resectable NSCLC are summarized in Table 1 (4,5,14,18). A consistent finding across immunotherapy-based trials, such as CheckMate 816, KEYNOTE-671, and AEGEAN, is the relatively high rate of pathologic responses, with MPR rates often exceeding 30–40% and pCR rates of 15–25%. In CheckMate 816, for example, nivolumab plus chemotherapy achieved an MPR rate of 46.8% and a pCR rate of 30.5%. By contrast, the NeoADAURA trial reported numerically lower pathologic response rates: the MPR was 25% with osimertinib monotherapy and 26% with osimertinib plus chemotherapy, with corresponding pCR rates of 9% and 4%, respectively. However, it is important to acknowledge that EGFR-mutant NSCLC accounts for only a small proportion of patients in ICI trials, and we cannot directly compare these values across trials.

Chen et al. reported in their review that recent studies of neoadjuvant ICI treatment for NSCLC have shown a significant association between OS and MPR, but not ORR (19). Based on this report, it has been argued in the previous commentary on NEOS trial that, if OS is associated with MPR but not with ORR in neoadjuvant EGFR-TKI, then the survival benefit of neoadjuvant osimertinib may be limited. Again, we need to wait until the study matures and EFS/OS results are reported from NeoADAURA.

Despite such limitations, the perioperative efficacy of osimertinib should not be underestimated. Rates of definitive surgery were consistently high in NeoADAURA, with 94.9% of patients in the osimertinib monotherapy group and 90% in the osimertinib plus chemotherapy group proceeding to resection, compared with 77.6–83.2% in the chemoimmunotherapy regimen study treatment arms. R0 resection rates were sufficiently high in osimertinib-containing regimens (95% and 91%), not inferior compared with 83.2–94.7% in the chemoimmunotherapy regimen study treatment arms. These results highlight osimertinib’s ability to maintain operability and facilitate complete resections, even in the absence of profound pathologic tumor regression.

As expected, the proportion of grade ≥3 AEs was comparable at 30–40% across the studies when neoadjuvant chemotherapy was given, regardless of TKI, ICI, or placebo. Notably, osimertinib monotherapy demonstrated a remarkably low rate of grade ≥3 AEs (13%), without compromising pathological response rate, surgical outcome, and EFS compared with osimertinib plus chemotherapy.

Circulating tumor DNA (ctDNA)/minimally (molecular) residual disease (MRD) assay in NeoADAURA

None of the phase III trials have yet shown the utility of ctDNA and MRD analyses as a predictive biomarker for perioperative treatment, which may be partly due to the suboptimal sensitivity even with the recent next-generation-sequencing (NGS)-based tissue-informed personalized assays. Similar to other recent clinical trials, ctDNA/MRD data are analysed in NeoADAURA. Unlike other studies, NeoADAURA utilized an ultrasensitive 2^nd-generation ctDNA assay (NeXT Personal^®; Personalis Inc., CA, USA). The preliminary results were presented at WCLC 2025 in September 2025 (20). In the baseline assay in the NeoADAURA cohort involving stage II–IIIB NSCLC, 71% of the 189 patient samples were ctDNA positive using the state-of-the-art method. This sensitivity was much higher than that of the cobas^® assay (Roche Diagnostics, IN, USA), which could detect only 30% of the mutant EGFR gene in plasma. However, the result also demonstrated a 30% potential false-negative rate in stage II–IIIB cases even in the preoperative setting, indicating the limited utility of MRD assays in EGFR-mutant NSCLC. Consistent with this finding, the latest report from the TRACERx study also showed higher negativity of MRD testing at the time of clinical relapse in driver oncogene addicted tumors (21).

Conclusions

Taken together, these findings suggest a nuanced interpretation of NeoADAURA. While neoadjuvant osimertinib, with or without chemotherapy, showed numerically lower pathologic response rates in EGFR-mutant NSCLC than those reported in trials of chemoimmunotherapy given mostly to non-EGFR-mutant NSCLC cases, it achieves high rates of definitive surgery and R0 resection. For EGFR-mutant NSCLC, a setting in which the benefit of ICI is considered limited, osimertinib represents a rational, tolerable, and effective perioperative strategy. Furthermore, osimertinib monotherapy may provide comparable outcomes with osimertinib plus chemotherapy but with markedly fewer serious AEs, suggesting that neoadjuvant chemotherapy may not be necessary for EGFR-mutant NSCLC. The ultimate test will be the long-term EFS and OS results, which will determine whether relatively lower pathologic response rates translate into differences in clinical benefit compared with immunotherapy-based regimens.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-107/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-107/coif). T.K. was supported by the Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowships Program (No. 202060447) from April 2020 to January 2023, which was unrelated to the present manuscript. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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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