Unlocking the potential of immunotherapy for patients with resectable non–small cell lung cancer

Following positive results in advanced and metastatic non–small cell lung cancer (NSCLC), there has been a move toward the application of immunotherapy in the treatment of locally advanced, resectable, oncogene driver–negative disease. To date, there have been eight Phase III trials across the adjuvant, neoadjuvant, and perioperative settings that demonstrate benefit with (chemo)-immunotherapy in patients with resectable NSCLC. Given the wealth of immunotherapy treatment regimens both available and under investigation in this setting, there is a need to determine the optimal timing of immunotherapy treatment (neoadjuvant, perioperative, or adjuvant) across disease stages to aid clinical decision-making. Established treatment guidelines often diverge, highlighting the need for a multidisciplinary team approach and consensus decision-making based on the latest evidence in the resectable setting. Finally, there is an unmet need surrounding the role of key predictive factors and response assessments, to assist clinicians in selecting patients for immunotherapy regimens. The aim of this review is to evaluate the current data and key considerations surrounding immunotherapy for the treatment of resectable NSCLC, including key parameters to inform de-escalating and escalating treatment approaches.

GRAPHICAL ABSTRACT

Graphical Abstract. *In the absence of actionable EGFR and ALK alterations. MRD, minimal residual disease; NSCLC, non–small cell lung cancer; PD-L1, programmed death-ligand 1.

1 Introduction

Of the estimated 2.2 million people diagnosed with lung cancer each year, roughly 85% are diagnosed with non–small cell lung cancer (NSCLC); of these, 25%–30% are considered resectable (1–3). Surgery has traditionally been the standard of care for these patients; however, recurrence rates with surgery alone are high (30%–55%) (4–6). Patients with resected NSCLC also experience a higher risk of distant metastasis than local or regional recurrence, highlighting the need to target systemic control from the outset of treatment (7, 8). Compared with surgery alone, the addition of neoadjuvant or adjuvant chemotherapy is associated with only a modest improvement in 5-year survival (of approximately 4%–5%) in patients with resectable, locally advanced disease and can bring additional issues related to poor tolerability (8, 9). Therefore, there remains a need for more efficacious therapeutic options to improve survival in this population.

Following the success of immunotherapy in advanced and metastatic NSCLC, there has been a shift toward the application of immunotherapy (primarily, immune checkpoint inhibitors [ICIs] targeting programmed-death protein 1 [PD-1] or its ligand [PD-L1]) as first-line treatment for resectable disease without detectable EGFR or ALK mutations (10). A neoadjuvant regimen containing immunotherapy is thought to prime antitumorigenic activity to enhance systemic control and improve post-surgical outcomes (7). In the adjuvant setting, immunotherapy facilitates targeting of residual and/or micrometastatic disease following resection, leading to improvements in long-term disease control (7). However, determining the optimal approach to immunotherapy across disease stages, including the timing and duration of treatment, remains a challenge.

The aim of this review is to provide an overview of immunotherapy strategies in oncogene driver–negative, resectable NSCLC, including the current breadth of data available across adjuvant, neoadjuvant, and perioperative settings and the factors that can guide clinicians in selecting the optimal immunotherapy treatment approach.

2 Current immunotherapy guidelines for Stage II/III resectable NSCLC

Neoadjuvant, adjuvant, and perioperative approval of immunotherapeutic agents for the treatment of resectable NSCLC are shown in Figure 1. The National Comprehensive Cancer Network (NCCN) and International Association for the Study of Lung Cancer (IASLC) updated their guidelines in 2024 and 2025, respectively, to reflect this changing landscape (both based on the American Joint Committee on Cancer [AJCC] and the Union for International Cancer Control [UICC] 8^th edition of lung cancer staging), and in 2024 the American Society of Clinical Oncology (ASCO) issued updated guidance on the treatment of Stage III disease (based on AJCC-UICC 7^th edition) (6, 7, 11, 12). To date, ASCO guidelines have not yet been updated to include perioperative immunotherapy (11, 12).

Figure 1

Figure 1. Timeline of key approvals of immunotherapy for the treatment of resectable NSCLC. CheckMate 816, IMpower010, and PEARLS/KEYNOTE-091 approvals followed enrollment based on the American Joint Committee on Cancer and the Union for International Cancer Control 7^th edition. AEGEAN, CheckMate 77T, and KEYNOTE-671 approvals followed enrollment based on the American Joint Committee on Cancer and the Union for International Cancer Control 8^th edition. CT, chemotherapy; NSCLC, non–small cell lung cancer; PD-L1, programmed-death ligand 1.

In all patients, testing for PD-L1 expression as well as for EGFR or ALK alterations is recommended prior to treatment initiation (6, 7, 11). Immunotherapy is not recommended for patients with actionable EGFR or ALK alterations, for which targeted adjuvant therapies are the standard of care. Only the NCCN guidelines refer to driver mutations other than ALK or EGFR, with targeted therapies remaining the recommended approach for these patients (6).

2.1 Stage III disease

For resectable Stage IIIA disease, recommendations for neoadjuvant chemoimmunotherapy are clear, with IASLC, ASCO, and NCCN guidelines recommending neoadjuvant chemoimmunotherapy for patients regardless of PD-L1 status. There is also broad agreement on the use of adjuvant chemoimmunotherapy in patients with PD-L1 ≥1% who did not receive neoadjuvant therapy; however, notably, the PEARLS/KEYNOTE-091 regimen is approved for an all-comer population (6, 7, 11). Where these guidelines differ is in their recommendation of perioperative chemoimmunotherapy. The NCCN guidelines recommend perioperative immunotherapy in accordance with the United States Food and Drug Administration (FDA) label (6). The IASLC guidelines do not discuss this approach in detail, stating that adjuvant immunotherapy can be considered following neoadjuvant chemoimmunotherapy, but to date these only cite inconsistent efficacy data in PD-L1 <1% and 1%–49% subgroups in adjuvant/perioperative trials (7).

2.2 Stage II disease

Recommendations for ICI treatment in resectable Stage II NSCLC diverge further. The NCCN guidelines on neo-/adjuvant ICI make no distinction between Stage II and Stage IIIA disease (6). However, the IASLC guidelines could not reach a consensus on neoadjuvant chemoimmunotherapy treatment of Stage II patients. Only 65% of the panel supported recommending neoadjuvant chemoimmunotherapy regardless of PD-L1 expression. Opponents cited a lack of sufficiently convincing or robust evidence supporting chemoimmunotherapy in these patients, as well as a risk that some patients may not then proceed to surgery (5, 7).

3 Resectability

The results of staging and resectability decisions directly inform the downstream management of the patient. Patients with resectable, oncogene driver–negative tumors are offered surgery with the option of adjuvant treatment, or neoadjuvant treatment followed by surgery and the potential for adjuvant therapy, as appropriate (7). By contrast, per the NCCN guidelines, chemoradiotherapy followed by consolidation immunotherapy represents the current standard of care for patients with Stage III unresectable tumors (6). As a result, accurate staging is essential to ensure that patients receive optimal treatment.

Preoperative, invasive staging of the hilar and mediastinal lymph nodes is commonly performed to assess the extent of spread to the intrapulmonary (N1) and mediastinal (N2 and N3) lymph nodes and is considered critical to inform optimal management for patients with potentially resectable NSCLC (13, 14). Minimally invasive techniques have become increasingly relied upon as accurate and cost-effective replacements for invasive staging procedures; however, there remain concerns over their sensitivity compared with traditional staging methodology (15). The latest guidelines on mediastinal staging from the European Society of Thoracic Surgeons recommend that if computed tomography (CT) or positron emission tomography results are suggestive of spread to mediastinal lymph nodes, tissue confirmation is required via minimally invasive techniques such as endosonography (endobronchial and/or esophageal ultrasonography) with fine needle aspiration or, in the case of negative results, invasive staging (16). Patients who are found to have extracapsular disease (visualized via mediastinoscopy) or bulky N2 disease (revealed by CT staging) are currently deemed to be unresectable (16).

Locally advanced NSCLC (Stages IIIA–IIIC) historically represents a challenging patient subset when determining resectability (17). Locally advanced disease may be classified as resectable, borderline resectable, or unresectable depending on local guidelines and the level of experience of the examining thoracic surgeon, potentially leading to discrepancies in the treatment that patients receive between surgeons, centers, and countries (17). Furthermore, the timing of assessment with respect to treatment is a critical factor influencing resectability determination.

In recent years, the use of neoadjuvant therapy to downstage borderline unresectable NSCLC has been explored to allow patients to access surgical resection (18). In particular, neoadjuvant chemoimmunotherapy has proven viable as conversion therapy in Stage IIIA–IIIB NSCLC (19). Although this represents an exciting option for patients with upfront unresectable disease, there remains a need to more accurately identify patients who would benefit and for further data on the validity of this approach. As a result, the use of neoadjuvant tumor downstaging is not currently recommended by the Society of Thoracic Surgeons, and neoadjuvant and perioperative immunotherapeutic approaches should be restricted to patients who are resectable at the time of initial workup (20).

Determination of tumor resectability and the operability of the patient is primarily the responsibility of the thoracic surgeon (20). However, given the increasing interplay between treatment and surgery, input from multiple specialties is crucial to decide optimal treatment options, including the feasibility and appropriateness of resection as well as the suitability of induction therapy or alternative treatment (20). As such, guidelines increasingly recommend the need for input from a multidisciplinary team spanning the lung cancer care pathway to accurately stratify patients and develop a personalized treatment plan (6, 7, 21).

4 Current evidence supporting immunotherapy treatment for resectable NSCLC

4.1 Adjuvant immunotherapy

Owing to high rates of recurrence after surgery in patients with locally advanced NSCLC, adjuvant systemic therapy is recommended for patients with resected Stage II–IIIA disease and may be considered for patients with Stage IB T2a tumors measuring 4 cm (AJCC-UICC 8^th edition) (6). Immunotherapy has been investigated in the adjuvant setting for resectable NSCLC, with clinically meaningful benefits in disease-free survival (DFS) identified in Phase III trials (Table 1) (22–25). The majority of trials investigate immunotherapy with sequential or concurrent chemotherapy in Stage IB–IIIA NSCLC and resectable Stage IIIB NSCLC (10). To date, the only Phase III trials that have read out positively in this setting are IMpower010 and PEARLS/KEYNOTE-091, which both enrolled patients per AJCC-UICC 7^th edition (22, 24). These trials demonstrated that adjuvant atezolizumab or pembrolizumab significantly improved DFS in patients with Stage IB–IIIA NSCLC following complete resection and platinum-based chemotherapy as compared with best supportive care (BSC) or placebo, respectively. In IMpower010, immature overall survival (OS) data did not indicate benefit in the intention-to-treat (ITT) population (stratified hazard ratio [HR]: 0.97 [95% confidence interval (CI): 0.78–1.22]) but were suggestive of benefit in patients with PD-L1 ≥50% Stage II–IIIA NSCLC (HR: 0.47 [95% CI: 0.28–0.77]) (23). In PEARLS/KEYNOTE-091, median OS was not reached in either group at the time of the interim analysis (HR: 0.87 [95% CI: 0.67–1.15]; p = 0.17) (24). Atezolizumab and pembrolizumab were subsequently approved for the adjuvant treatment of resectable NSCLC by both the FDA and the European Medicines Agency (EMA); however, the labels for atezolizumab differ in their restriction by PD-L1 expression level (tumor cell ≥1% for the FDA and ≥50% for the EMA), and the FDA label for pembrolizumab is restricted by tumor size (≥4 cm) (26–29). Notably, PEARLS/KEYNOTE-091 also revealed no DFS benefit in the subgroup of patients who did not receive adjuvant chemotherapy prior to treatment with adjuvant pembrolizumab (HR: 1.16 [95% CI: 0.73–1.84]) (7, 24, 30). As a result, guidelines from the IASLC and NCCN currently recommend that immunotherapy is received after adjuvant platinum-containing chemotherapy (6, 7).

Table 1

Table 1. Key Phase III adjuvant immunotherapy trials in resectable NSCLC.

The only other Phase III trial that has read out in this setting is the ADJUVANT BR.31 trial of durvalumab versus placebo in patients with Stage IB–IIIA NSCLC (AJCC-UICC 7^th edition) who had received surgery with or without adjuvant platinum-based chemotherapy. ADJUVANT BR.31 failed to meet the primary endpoint of improved DFS with adjuvant durvalumab in patients with PD-L1 ≥25%, and it remains to be determined if the demanding surgical requirements influenced this negative result (31). An additional two trials investigating adjuvant durvalumab in resectable disease, MERMAID-1 and MERMAID-2, were terminated shortly after initiation owing to multiple approvals in the perioperative setting and barriers in implementing sensitive and practically manageable tumor-informed minimal residual disease (MRD) measurements, which resulted in inconclusive efficacy data because of the small sample size and limited follow-up (32–34). Further trials (including the ANVIL trial of nivolumab following adjuvant chemotherapy in Stage IB–IIIA NSCLC (AJCC-UICC 7^th edition), the ALCHEMIST trial of concurrent adjuvant pembrolizumab plus platinum-based chemotherapy in Stage IIA–IIIB NSCLC (AJCC-UICC 8^th edition), the open-label NADIM-ADJUVANT trial of adjuvant nivolumab plus chemotherapy followed by maintenance nivolumab in Stage IB–IIIA NSCLC (AJCC-UICC 8^th edition), and the LungMate-008 trial of adjuvant toripalimab plus chemotherapy in Stage II–IIIB NSCLC (AJCC-UICC 8^th edition), will continue to inform on the feasibility of adjuvant immunotherapy in this setting (35–38).

4.2 Neoadjuvant immunotherapy

There is a strong rationale supporting the evaluation of ICIs in the neoadjuvant setting, as immunotherapy is known to prime the immune system to target tumor cells (39). Early induction of an antitumorigenic response in the neoadjuvant setting could therefore facilitate timely and sustained targeting of micrometastatic disease, reducing the risk of metastasis following surgery (39). Furthermore, it is thought that an increased immunological response and enhanced immunogenic cell death takes place when the localized tumor is intact, as this represents a large antigen burden and facilitates more comprehensive T-cell activation (40–42). Taken together, the earlier and stronger immune response with neoadjuvant therapy facilitates more effective suppression of metastasis and helps to prevent recurrence following surgical resection (39, 42).

Neoadjuvant immunotherapy for resectable NSCLC was first investigated in a single-arm pilot study by Forde PM, et al. in 2018 (39). In this study, two cycles of neoadjuvant nivolumab followed by surgery resulted in a major pathologic response (MPR) rate of 45% compared with a historical 15% MPR rate with neoadjuvant chemotherapy (39). Following this pilot, a number of Phase II trials began to investigate immunotherapy as monotherapy and in combination with other agents (7).

In particular, impressive results have been found when evaluating neoadjuvant chemoimmunotherapy for resectable NSCLC; these are summarized in Table 2. Notably, CheckMate 816 was the first Phase III trial to evaluate neoadjuvant chemoimmunotherapy in this setting, investigating three cycles of neoadjuvant nivolumab plus platinum-doublet chemotherapy in patients with Stage IB–IIIA NSCLC (AJCC-UICC 7^th edition) (5). At the first pre-specified analysis, the study found an event-free survival (EFS) benefit for the combination regimen compared with neoadjuvant chemotherapy alone following a minimum of 21 months of follow-up (HR: 0.63 [97.38% CI: 0.43–0.91]; p =0.005) (5). The study yielded impressive landmark EFS results, with 2-year EFS rates of 63.8% versus 45.3% and 3-year EFS rates of 57% versus 43% in the treatment versus control arms, respectively (45). In addition, the rate of pathologic complete response (pCR) was significantly higher with neoadjuvant chemoimmunotherapy than with chemotherapy alone (odds ratio: 13.94 [99% CI: 3.49–55.75]; p< 0.001) (5). At the latest (4-year) update, EFS benefits of added nivolumab persisted (4-year EFS rates: 49% for neoadjuvant nivolumab plus chemotherapy versus 38% for neoadjuvant chemotherapy; HR for EFS: 0.66 [95% CI: 0.49–0.90]) (43). At the pre-planned, final, 5-year analysis of CheckMate 816, a statistically significant and clinically meaningful OS benefit was demonstrated in resectable NSCLC (HR: 0.72 [95% CI: 0.523–0.998]; p = 0.048) (44). At this timepoint, median OS had not yet been reached in the nivolumab arm, compared with 73.7 months (95% CI: 47.3–NR) in the chemotherapy arm. Nivolumab represents the only immunotherapy agent approved for neoadjuvant use in resectable NSCLC in combination with platinum-doublet chemotherapy; although it is approved for all patients with either node-positive disease or tumors ≥4 cm in the United States, the EMA label is restricted to PD-L1 ≥1% in this setting (46, 47).

Table 2

Table 2. Key Phase III neoadjuvant immunotherapy trial in resectable NSCLC.

Although the advent of immunotherapy-based neoadjuvant treatment has increased the number of patients with improved outcomes following surgery, it is associated with several challenges. Primarily, these center around the risk that patients may be unable to proceed with planned surgery owing to treatment-related toxicities or disease progression that occurs while they are receiving the neoadjuvant treatment, or withdrawal of patient consent (48). Across trials that include neoadjuvant chemoimmunotherapy, up to 20% of patients do not proceed to surgery owing to disease progression, treatment-related toxicity, patient or investigator decision, or later classification of tumors as inoperable. In addition, the complexity of surgery may be increased following receipt of neoadjuvant immunotherapy, owing to the potential for inflamed lymph nodes, hilar fibrosis, and increased frailty of pulmonary and vascular structures (49, 50). Rates of surgical cancellations, surgical delays, and conversion rates from minimally invasive to open procedures vary in the published literature; however, overall, neoadjuvant immunotherapy is not considered to substantially affect surgical outcomes in suitably selected patients (51). Finally, there is also a need to define the role of radiotherapy for patients eligible for a neoadjuvant immunotherapy–containing regimen. Phase II trial data have indicated that sub-ablative stereotactic radiotherapy may enhance the immune response to neoadjuvant immunotherapy (52). Future studies in a larger patient population will be important to inform on the role of radiotherapy in combination with immunotherapy.

4.3 Perioperative immunotherapy

A perioperative regimen makes use of immunotherapy in both the neoadjuvant and the adjuvant phases, to ensure continued targeting of micrometastatic disease with the intent of reducing the incidence of post-surgical recurrence (53). Several Phase III trials have been conducted to date (Table 3) and have revealed positive results; based on these, both the NCCN and the IASLC recommend that patients with Stage IB–IIIA NSCLC (AJCC-UICC 8^th edition) be evaluated for perioperative immunotherapy (6, 7).

Table 3

Table 3. Key Phase III perioperative immunotherapy trials in resectable NSCLC.

All perioperative immunotherapy trials summarized in Table 3 have demonstrated an EFS benefit of immunotherapy versus comparator. Of these, pembrolizumab was the first immunotherapy approved in the perioperative setting in both Europe and the United States, based on the KEYNOTE-671 trial of perioperative pembrolizumab with neoadjuvant platinum-doublet chemotherapy compared with perioperative placebo plus neoadjuvant chemotherapy in patients with Stage II, IIIA, or IIIB NSCLC (AJCC-UICC 8^th edition) (62). Dual primary endpoints in KEYNOTE-671 were EFS and OS. In the planned interim analysis, the EFS endpoint was met, with a median EFS of 47.2 months (95% CI: 32.9 – not reported [NR]) with pembrolizumab versus 18.3 months (95% CI: 14.8–22.1) with placebo (HR: 0.59 [95% CI: 0.48–0.72]; p< 0.0001) (62). After a median follow-up of 3 years, KEYNOTE-671 became the first perioperative trial to demonstrate significant OS improvement (HR: 0.72 [95% CI: 0.56–0.93]; one-sided p = 0.0052 [one-sided threshold p = 0.0054]) (7, 54). At approximately 4 years of follow-up, the 48-month OS rate was 68.0% (95% CI: 63.0%–72.5%) with perioperative pembrolizumab versus 56.7% (95% CI: 51.2%–61.8%) with chemotherapy alone, and median OS had not been reached in either treatment arm (55). Most recently, tislelizumab was approved for use in the perioperative setting in Europe, based on the results of the RATIONALE-315 trial of neoadjuvant chemotherapy with either perioperative tislelizumab or perioperative placebo (63, 64). At interim analysis, RATIONALE-315 met its primary endpoints of improved MPR (between-group difference: 41% [95% CI: 33%–49%]; p < 0.0001) and improved EFS (HR: 0.56 [95% CI: 0.40–0.79]; p = 0.0003), alongside higher pCR (between-group difference: 35% [95% CI: 28%–42%]; p < 0.0001) (60). At final analysis, RATIONALE-315 became the second trial of perioperative immunotherapy to demonstrate statistically significant OS benefit in patients with resectable NSCLC (HR: 0.65 [95% CI: 0.45–0.93]; p = 0.009) (54, 61).

While significant OS results have not yet been reported, FDA and EMA approvals have been received for perioperative durvalumab and nivolumab based on the Phase III AEGEAN and CheckMate 77T trials, respectively (46, 47, 65, 66). Both trials met their primary endpoint of improved EFS versus chemotherapy alone, with an HR of 0.68 (95% CI: 0.53–0.88; p = 0.004) for durvalumab and 0.58 (97.36% CI: 0.42–0.81; p < 0.001) for nivolumab (56, 58). Furthermore, the NEOTORCH trial of neoadjuvant chemotherapy with either perioperative toripalimab or perioperative placebo showed improved EFS (HR: 0.40 [95% CI: 0.28–0.57]; p < 0.0001) and MPR (between-group difference: 13.0% [95% CI: 8.7%–17.6%]; p < 0.001) (57).

Although some of the clinical challenges associated with perioperative immunotherapy are similar to those that apply in the neoadjuvant setting, there are additional considerations influencing the use of perioperative therapy. Crucially, it remains to be determined how best to select patients who will benefit most from adjuvant immunotherapy following an initial neoadjuvant course of chemoimmunotherapy and thus avoid overtreatment (see Selecting between treatment approaches in resectable NSCLC) (48). Although retrospective analyses have found that patients who achieve pCR following neoadjuvant therapy may not experience additional benefit from further treatment in the adjuvant setting, this has not yet been tested prospectively (see Response assessment in NSCLC and the potential for de-escalation/escalation of treatment) (67). In addition, there is a need to define the optimal duration of neoadjuvant treatment in a perioperative regimen (48). To date, Phase III trials have primarily investigated three cycles (CheckMate 816) or four cycles (AEGEAN, KEYNOTE-671, and CheckMate 77T) of neoadjuvant chemoimmunotherapy (39, 56, 58). NEOTORCH investigated three cycles of neoadjuvant chemoimmunotherapy, followed by one cycle of adjuvant chemoimmunotherapy prior to adjuvant immunotherapy (57). Finally, RATIONALE-315 investigated between three and four cycles of chemoimmunotherapy in the neoadjuvant setting (60). This question will be examined prospectively in the Phase III neoSCORE II trial, which will explore three versus four cycles of neoadjuvant chemoimmunotherapy in patients with resectable squamous NSCLC, followed by adjuvant immunotherapy (48). Finally, the optimal duration of the adjuvant course of immunotherapy remains to be defined, although the majority of regimens complete postoperative immunotherapy at 1 year (48). As trials investigating perioperative immunotherapy mature, these data will be important to inform on these current challenges.

5 Key predictors of response

5.1 PD-L1 expression

PD-L1 is currently the most established and widely used predictive biomarker for immunotherapy in advanced NSCLC, and many trials in resectable NSCLC stratify patients based on PD-L1 expression status (68). Measurement of PD-L1 expression is recommended by the NCCN, ASCO, and IASLC guidelines prior to initiating treatment, along with EGFR and ALK mutational status (6, 7, 11). Although widely used, PD-L1 has been described as an imperfect biomarker because of its heterogeneous and dynamic expression and the varying cut-off values used to define PD-L1 positivity (68). Indeed, the prognostic value of PD-L1 expression for chemoimmunotherapy outcomes is not yet established, in part because of apparently conflicting evidence of immunotherapy benefit in patients with PD-L1 expression <1%, particularly in the adjuvant setting (5, 22, 62, 69).

IMpower010 and KEYNOTE-091 present a contrasting picture of the benefit of adjuvant immunotherapy across PD-L1 expression subgroups. In IMpower010, final DFS data revealed benefit with adjuvant atezolizumab versus BSC in patients with Stage II–IIIA NSCLC (AJCC-UICC 7^th edition) and PD-L1 ≥1%, which appeared to be driven by a benefit in the PD-L1 ≥50% population (Table 1) (22, 25). While not formally statistically tested, immature OS data were not suggestive of benefit in the ITT population (HR: 0.97 [95% CI: 0.78–1.22]) but trended towards benefit in the PD-L1 ≥50% subpopulation (HR: 0.43 [95% CI: 0.27–0.68]) (23). In contrast, in the KEYNOTE-091 trial, DFS was significantly improved in patients receiving pembrolizumab in the all-comer population, regardless of PD-L1 expression, but patients with PD-L1 expression ≥50% did not appear to exhibit a survival benefit owing to an unexpected overperformance of the control arm in this subgroup (Table 1) (24). Based on the sum of this evidence, guidelines from ASCO, the NCCN, and the IASLC recommend adjuvant immunotherapy for patients with PD-L1 expression ≥50% in tumor cells (6, 7, 11).

In the neoadjuvant setting, several neoadjuvant-only and perioperative studies indicate greater EFS/pCR outcomes with higher PD-L1 expression (Tables 2, 3) (5, 57, 62). Indeed, based on the data from CheckMate 816, the EMA approved nivolumab in combination with platinum-based chemotherapy for patients with resectable NSCLC and tumor cell PD-L1 ≥1% (Table 2) (47). This restriction is not included in the FDA indication, and ex-European treatment guidelines recommend neoadjuvant immunochemotherapy regardless of PD-L1 expression (6, 7, 11, 46). Meta-analyses of studies evaluating neoadjuvant chemoimmunotherapy support the potential prognostic value of PD-L1 expression (70, 71). Mo D-C, et al. demonstrated that neoadjuvant chemoimmunotherapy was associated with improved pCR and EFS regardless of PD-L1 expression, compared with neoadjuvant chemotherapy; however, patients with higher PD-L1 expression may have a lower risk of disease progression than those with lower PD-L1 expression (71). Similarly, Banna GL, et al. demonstrated improved rates of pCR and 2-year EFS regardless of PD-L1 expression with neoadjuvant chemoimmunotherapy compared with neoadjuvant chemotherapy alone, as well as an apparent trend that higher PD-L1 expression was associated with increased rates of 2-year EFS compared with lower PD-L1 expression (70). The prognostic role of PD-L1 expression on OS is difficult to determine given the immaturity of the relevant data; however, there are indicators that improved OS following neoadjuvant chemoimmunotherapy is restricted to patients with PD-L1-positive tumors (71). Based on subgroup analyses of CheckMate 816, OS benefit with nivolumab plus chemotherapy appeared to be greatest in patients with PD-L1 expression ≥1% (HR: 0.51 [95% CI: 0.31–0.84]), although patients with PD-L1-negative tumors can still achieve pCR and durable remission while receiving this treatment regimen (5, 44).

Many studies of perioperative immunotherapy have also shown EFS improvement in patients with tumor cell PD-L1 ≥1% (Table 3) (54, 56, 58, 60). For AEGEAN and CheckMate 77T, EFS benefit appears to be driven by the PD-L1 ≥50% population (56, 58, 59). Furthermore, subgroup analysis of OS in KEYNOTE-671 indicated greatest benefit with perioperative pembrolizumab versus chemotherapy in patients with PD-L1 ≥50% (HR: 0.55 [95% CI: 0.33–0.92]) (54). Pembrolizumab was approved as a perioperative regimen in resectable NSCLC for an all-comer population by both the FDA and the EMA (26, 27, 54). By contrast, while the FDA approved perioperative nivolumab without PD-L1 restriction, the Committee for Medicinal Products for Human Use (CHMP) recently adopted a positive opinion for perioperative nivolumab for patients with PD-L1 ≥1% (46, 72). More mature data across perioperative trials will be important to inform the use of PD-L1 as a biomarker for patient selection.

As chemoimmunotherapy trials in resectable NSCLC further mature, it is likely that so too will the value of PD-L1 expression as a prognostic tool, further reinforcing the need to assess PD-L1 expression prior to treatment initiation. However, given the treatment benefit of chemoimmunotherapy observed in some PD-L1-negative patients, it will be important to identify additional predictive markers in patients with EGFR and ALK wild-type resectable NSCLC.

5.2 Clinical stage

Clinical stage has emerged as a potential prognostic factor for chemoimmunotherapy in resectable EGFR and ALK wild-type NSCLC. Stage IIIA NSCLC remains the clinical stage with the most consistent data, with EFS/DFS benefit in favor of neoadjuvant/perioperative chemoimmunotherapy demonstrated across Phase III trials (Tables 2 and 3) (5, 54, 56, 58, 60). Although Phase III adjuvant (chemo)-immunotherapy trials have reported significant DFS benefit versus chemotherapy (IMpower010 and KEYNOTE-091), neither have established clear benefit in patients with Stage III disease to date (Table 1) (22, 24). Currently, there is limited evidence for the survival benefit of immunotherapy in patients with Stage IIIB disease; no data have been reported for this subgroup to date in either the adjuvant or the neoadjuvant setting (Tables 1, 2). Data from perioperative trials remain conflicted in Stage IIIB NSCLC (AJCC-UICC 8^th edition). No clear EFS benefit was observed for this subgroup in AEGEAN (HR: 0.83 [95% CI: 0.52–1.32]); however, EFS benefit for patients with Stage IIIB NSCLC was observed in NEOTORCH (HR: 0.30 [95% CI: 0.15–0.56]; p <0.001) and KEYNOTE-671 (HR: 0.57 [95% CI: 0.36–0.90]) (7, 56, 57). Sub-stage analyses of Stage IIIB NSCLC have not yet been reported for CheckMate 77T and will be important to provide further evidence on the utility of a perioperative approach in these patients.

Although it is clear that immunotherapy regimens have the potential to benefit patients with resectable Stage II NSCLC (AJCC-UICC 8^th edition), further data are required to inform on optimal treatment strategy. Subgroup analyses of the CheckMate 816 trial provided inconclusive evidence of a treatment benefit for the addition of nivolumab to neoadjuvant chemotherapy in patients with Stage IB or II NSCLC (AJCC-UICC 7^th edition; these would all be classified as Stage II per the AJCC-UICC 8^th edition) (5, 44). Although there was no clear EFS or OS benefit demonstrated (EFS HR: 0.87 [95% CI: 0.48–1.56]; OS HR: 0.77 [95% CI: 0.44–1.35]), pCR benefit was observed in this subpopulation (difference: 21.4% [95% CI: 9.0%–33.6%]). Recent meta-analyses suggest that neoadjuvant chemoimmunotherapy may result in a longer EFS in patients with Stage IIIA NSCLC than in those with Stage II NSCLC (70, 73). Despite this, a meta-analysis of eight randomized controlled trials suggested that neoadjuvant chemoimmunotherapy improved 2-year EFS compared with chemotherapy alone in Stage II NSCLC (HR: 0.75 [95% CI: 0.57–0.97]) (70). These data, along with the lack of sub-analyses by PD-L1 expression within Stage II disease, have resulted in some uncertainty in the best approach to treat Stage II patients (AJCC-UICC 8^th edition), as discussed in the IASLC treatment guidelines (7). In the perioperative setting, KEYNOTE-671 (HR: 0.59 [95% CI: 0.40–0.88]) and RATIONALE-315 (HR: 0.47 [95% CI: 0.26–0.87]) represent the only Phase III trials to demonstrate a clear EFS benefit in patients with Stage II NSCLC (54, 60). This benefit appeared to be mirrored by the Stage II OS findings in both trials (KEYNOTE-671 HR: 0.67 [95% CI: 0.41–1.10]; RATIONALE-315 HR: 0.58 [95% CI: 0.31–1.06]) (7, 61). Finally, in the adjuvant setting, KEYNOTE-091 found DFS benefit with pembrolizumab versus chemotherapy in patients with Stage II NSCLC (HR: 0.70 [95% CI: 0.55–0.91]), whereas IMpower010 found that DFS benefit with atezolizumab versus chemotherapy in Stage II NSCLC appeared to be restricted patients with Stage IIA, rather than Stage IIB, disease (Table 1) (22–24).

Stage III N2 disease represents a subgroup of particular clinical interest owing to its potentially curable nature, although prognosis is historically poor and optimal treatment remains undefined (74). In an exploratory analysis of CheckMate 77T, patients with Stage III NSCLC appeared to experience EFS benefit regardless of nodal status, with particular benefit in patients with N2 NSCLC (HR: 0.48 [95% CI: 0.32–0.72]) (59). Immature data showed that patients with and without N2 disease showed higher rates of pCR following treatment with perioperative nivolumab versus chemotherapy (22.0% versus 5.6%, and 25.5% versus 5.3%, respectively) (75). Surgical feasibility also appeared to be similar between patients with and without N2 disease, and over half of patients with Stage III NSCLC experienced nodal downstaging with perioperative nivolumab (75). In AEGEAN, exploratory analysis revealed that patients with N2 disease showed EFS benefit with perioperative durvalumab versus chemotherapy (HR: 0.63 [95% CI: 0.43–0.90]), with higher rates of pCR (16.6% versus 4.9%, respectively) and MPR (32.6% versus 15.1%, respectively) (76). The presence of N2 disease did not appear to have a significant impact on delays to surgery or the type of surgery received (76).

Finally, of clinical interest is the treatment of Stage III single-station versus multi-station N2 NSCLC. Patients undergoing surgical resection of Stage III single-station N2 NSCLC were found to have a higher rate of 5-year OS relative to those with multi-station N2 NSCLC (~35% versus 20%, respectively), leading some to propose that single- versus multi-station disease may be useful as a prognostic factor for survival outcomes (77). In the Phase II NADIM II trial, approximately two-thirds of the patients had pathologically confirmed N2 disease and 38.4% had multi-station N2 (78). Patients with single-station N2 (n=8/86) experienced pCR benefit with perioperative chemoimmunotherapy versus neoadjuvant chemotherapy alone (unweighted difference: 42.1% [95% CI: 19.9%–64.3%]), whereas benefit appeared to be lower in multi-station disease (unweighted difference: 26.4% [95% CI: −1%, 53.7%]) (78). In the Phase III CheckMate 77T trial, patients with N2 NSCLC appeared to experience EFS benefit with perioperative chemoimmunotherapy versus chemotherapy alone, regardless of whether this was single-station (HR: 0.50 [95% CI: 0.30–0.83]) or multi-station (HR: 0.48 [95% CI: 0.25–0.94]) disease (59). These EFS data were mirrored in the AEGEAN trial, but pCR benefit was less pronounced in patients with multi-station disease (difference in pCR rate: single-station N2, 13.9% [95% CI: 6.6–21.7]; multi-station N2, 3.8% [95% CI: −9.2, 18.8]) (76). Given the latest data, the proposed AJCC-UICC 9^th edition of TNM staging aims to reflect differences in clinical stage depending on whether patients are found to have single-station (N2a) or multi-station (N2b) disease across levels T1a–T3, which will be important to inform differences in management strategy (79).

It is important to note that the utility of clinical stage for determining optimal treatment approach is limited by the accuracy of upfront staging. A large, retrospective examination of patients with cT1cN0M0 NSCLC (categorized as clinical Stage I per AJCC-UICC 8^th edition) found that as high as 14.5% of patients who received lobectomy and 6.6% who received segmentectomy had pathologic nodal upstaging to pN1+ (Stage II+ per AJCC-UICC 8^th edition) (80). A UK-based retrospective evaluation found that one-third of patients with single-station N2 Stage III NSCLC by endobronchial ultrasound were upstaged to multi-station disease (81). These results were similar to those reported by a prior study in patients from the control group of randomized controlled trials of neoadjuvant chemotherapy in clinical Stage I–IIIA disease, which estimated that the discrepancies between clinical and pathologic T and N staging may have led to different treatment decisions in 10% and 38% of patients, respectively (82). Accurate, comprehensive staging is therefore critical to inform appropriate treatment strategies for all patients with NSCLC.

6 Response assessment in NSCLC and the potential for de-escalation/escalation of treatment

DFS and EFS are accepted surrogate endpoints in NSCLC, allowing an early evaluation of clinical benefit (83). Research is also focusing on providing actionable response assessments through alternative endpoints with more rapid readouts, enabling clinicians to escalate or de-escalate therapy in a personalized approach that could potentially improve outcomes while managing the risk of over- or undertreatment in resectable NSCLC (84).

6.1 Pathologic endpoints

Pathologic endpoints permit evaluation of response to therapy without the need for long time frames and are becoming routinely integrated into immunotherapy trials with a neoadjuvant component (5, 85). In a 2024 meta-analysis of randomized Phase III trials of chemoimmunotherapy versus chemotherapy alone in resectable NSCLC, there was a robust patient-level correlation observed between pCR and MPR and 2-year EFS (R² = 0.82 and 0.81, respectively) (86). Notably, this study did not find correlation between pathologic assessment and 2-year OS (R² = 0.55 for pCR and R² = 0.52 for MPR). A second meta-analysis (also published in 2024) of neoadjuvant treatment (including targeted therapies, chemotherapy, and concomitant radiotherapy) found that OS was higher in patients who achieved pCR and MPR than in those who did not (HR: 0.49 [95% CI: 0.42–0.57] and HR: 0.36 [95% CI: 0.29–0.44], respectively) (87). Further data are needed to comprehensively validate pathologic response as an adequate surrogate for OS in immunotherapy trials; despite this, given the strong patient-level association observed, pathologic assessments yield valuable data to inform treatment decision-making by clinicians (86, 87).

In particular, pCR has been proposed as a response biomarker to guide the use of adjuvant immunotherapy after neoadjuvant chemoimmunotherapy and surgery, theoretically limiting exposure to potential treatment-related toxicities in patients who would not benefit from continued treatment (88, 89). At present, pCR assessment appears to show high reproducer reliability, with strong inter-rater agreement demonstrated between pulmonary pathologists when assessing slides from patients with resected NSCLC who have received neoadjuvant immunotherapy (inter-rater agreement: 0.94 [95% CI: 0.89–0.98]) (90). This supports the feasibility of pCR as a response biomarker; however, it is worth noting that it can be challenging to identify the tumor bed, and interobserver variability may occur (particularly between community pathologists) (91). Additionally, pCR is not a perfect biomarker, as a significant proportion of patients who achieve pCR will still experience disease recurrence (91). Finally, based on exploratory analyses from KEYNOTE-671 and CheckMate 77T, patients appeared to experience EFS benefit from perioperative immunotherapy plus neoadjuvant chemotherapy regardless of pCR status, relative to neoadjuvant chemotherapy alone (58, 62). This was mirrored by an exploratory, indirect patient-matched analysis from the CheckMate 816 versus CheckMate 77T trials, which found that patients appeared to experience EFS benefit from perioperative versus neoadjuvant immunotherapy regardless of pCR status (pCR: HR: 0.58; 95% CI: 0.14–2.40; non-pCR: HR: 0.65; 95% CI: 0.40–1.06) (92). In the 5-year analysis of CheckMate 816, exploratory analyses indicated that pCR status was prognostic for OS (pCR versus no pCR, HR: 0.11 [95%: 0.04–0.36]) (44). Taken together, the available data are currently insufficient to support utilization of pCR status to guide receipt of adjuvant immunotherapy following a neoadjuvant chemoimmunotherapy regimen, and clinicians should continue to make treatment decisions based on individual patient assessment (91). Although there are currently no Phase III trials designed to prospectively evaluate stratification of adjuvant treatment based on pCR status in NSCLC, a Phase III trial of adjuvant pembrolizumab versus observation in patients with breast cancer who have achieved pCR with neoadjuvant pembrolizumab plus chemotherapy is currently recruiting (as of the timing of publication of this review) and may yield some insights into this approach (93).

6.2 Liquid biopsy (MRD)

Liquid biopsy represents a minimally invasive method to detect biomarkers in fluids (e.g. blood and cerebrospinal fluid). Liquid biopsy allows detection of circulating tumor DNA (ctDNA) in patients with solid tumors, derived from cells that slough off the primary tumor/metastatic sites and enter the bloodstream (94). Tumor-informed assays involve using a tumor sample to inform the tracking of mutations in ctDNA and are associated with higher sensitivity than tumor-agnostic assays, which rely on a predefined panel of lung cancer–associated alterations for ctDNA tracking (95). Selecting between these approaches is primarily driven by tumor tissue availability (95). Detection of ctDNA by liquid biopsy represents an exciting tool to help determine the presence of MRD following curative-intent treatment in resectable NSCLC, facilitating response monitoring and risk stratification. Of particular relevance in the resectable setting, MRD monitoring presents the opportunity to tailor the adjuvant treatment strategy according to a patient’s response to neoadjuvant therapy.

A 2023 meta-analysis of ctDNA for MRD detection in lung cancer found that ctDNA represents a highly specific tool to detect disease recurrence, with ctDNA positivity following treatment associated with worse relapse-free survival (RFS; HR: 8.32) and OS (HR: 4.73) compared with ctDNA negativity (96). In resectable NSCLC specifically, post-treatment MRD positivity by landmark analysis correlated significantly with time to progression (p< 0.001), DFS (p < 0.001), EFS (p = 0.01), RFS (p < 0.001), and OS (p< 0.001), with strong prognostic value for both node-positive and node-negative patients (97, 98). Data from both CheckMate 77T and CheckMate 816 indicate that around half of patients who show ctDNA clearance do not achieve pCR, suggesting that ctDNA clearance may not represent a suitable prognostic factor for pathological outcomes following neoadjuvant chemoimmunotherapy (44, 59). However, data from CheckMate 816 suggest that failure to clear ctDNA may be associated with poorer 5-year OS, indicating its potential as a biomarker to guide future treatment intensification strategies (44).

In CheckMate 816, tumor-informed ctDNA negativity following three cycles of neoadjuvant nivolumab plus chemotherapy numerically correlated with higher rates of EFS and pCR, although this was not statistically evaluated (5). Furthermore, at the 5-year analysis, exploratory ctDNA analyses suggested that ctDNA clearance was associated with longer OS (ctDNA clearance versus no ctDNA clearance, HR: 0.38 [95% CI: 0.15–1.00); however, small patient numbers limit interpretation of these data (44). The AEGEAN trial found that earlier ctDNA negativity was associated with a higher likelihood of pCR (durvalumab: 50.0% versus 15.1%; placebo: 14.3% versus 3.1%) and MPR (durvalumab: 66.7% versus 35.8%; placebo: 38.1% versus 12.5%) (99). In the adjuvant setting, postoperative and post-chemotherapy tumor-informed ctDNA positivity in IMpower010 was found to be a negative prognostic factor for DFS, over 5 years of follow-up (100). However, MRD has been found to have poor sensitivity (pooled sensitivity: landmark, 0.41 [95% CI: 0.35–0.46]; surveillance, 0.76 [95% CI: 0.70–0.82]), indicating that negative ctDNA alone is not sufficient to indicate the absence of relapse in all patients (96). In an exploratory biomarker analysis of CheckMate 77T, achieving both ctDNA clearance and pCR appeared to be associated with higher EFS than either factor alone for patients treated with perioperative nivolumab plus chemotherapy (59). These data suggest that the use of the two response assessments together may be suitable as a prognostic factor for EFS and may represent an interesting avenue for further research.

Qiu B, et al. proposed that ctDNA positivity could be used as a prognostic marker to guide adjuvant chemotherapy in Stage II–III resected NSCLC, finding that patients who were ctDNA-positive following surgery experienced RFS benefit from adjuvant chemotherapy (p < 0.05), whereas patients who were ctDNA-negative had a low risk of relapse regardless of whether or not chemotherapy was administered (p = 0.46) (101). They found that a combinatorial approach (a so-called ‘joint model’) encompassing ctDNA, radiologic imaging, and clinical monitoring outperformed the traditional Cox models in predicting recurrence status at both 12 and 15 months following surgery. A combination of ctDNA and radiological tumor volume analysis has also been proposed to improve the low sensitivity of ctDNA analysis alone; this combination was found to accurately stratify patients as high versus low risk of relapse and survival in early-stage NSCLC (102). In the future, multifactorial approaches such as these may facilitate more timely therapeutic intervention and personalized treatment approaches in resectable NSCLC; however, ctDNA utility is currently restricted to prognostication only, as it is not yet a sensitive enough biomarker to guide treatment decisions.

7 Selecting between treatment approaches in resectable NSCLC

Both neoadjuvant and adjuvant chemoimmunotherapy approaches have demonstrated the potential to cure some patients without the need for a perioperative approach (5, 22, 24). However, to date, there are no head-to-head trials comparing these different treatment approaches, nor have sufficiently robust predictors of response been established to identify patients likely to be cured.

Forde PM, et al. conducted a patient-level data analysis of CheckMate 77T and CheckMate 816 to provide an indirect comparison between neoadjuvant nivolumab and perioperative nivolumab (92). Eligible patients received neoadjuvant nivolumab plus chemotherapy followed by definitive surgery and ≥1 dose of adjuvant nivolumab in CheckMate 77T, or neoadjuvant nivolumab plus chemotherapy as part of the CheckMate 816 trial. Perioperative nivolumab was found to be associated with improved EFS compared with neoadjuvant nivolumab (HR: 0.61 [95% CI: 0.39–0.97]). In addition, the subgroup of patients with PD-L1 <1% appeared to benefit from perioperative immunotherapy (EFS HR: 0.51 [95% CI: 0.28–0.93]), whereas data in patients with PD-L1 ≥1% were suggestive of no discernible difference (EFS HR: 0.86 [95% CI: 0.44–1.70]). Perioperative versus neoadjuvant nivolumab was associated with a numerical improvement in EFS, regardless of tumor stage (staging was aligned between the 7^th and 8^th AJCC-UICC criteria used by the CheckMate 77T and CheckMate 816 studies, respectively; Stage IB–II HR: 0.53 [95% CI: 0.25–1.11]; Stage III HR: 0.63 [95% CI: 0.37–1.07]). Finally, patients with pCR showed a risk reduction for EFS with perioperative versus neoadjuvant nivolumab, compared with those who did not achieve pCR (see Response assessment in NSCLC and the potential for de-escalation/escalation of treatment) (92). Patients in both trials showed similar rates of all-cause adverse events (AEs), with higher rates of AEs leading to discontinuation, treatment-related AEs, and serious AEs with perioperative nivolumab, although a slightly higher rate of surgery-related AEs (defined as AEs reported within 90 days of definitive surgery) was experienced with neoadjuvant nivolumab (92).

As the gold-standard endpoint in NSCLC, landmark OS data from neoadjuvant and perioperative trials may help to inform clinical decision-making. CheckMate 816 reported 5-year OS rates of 65.4% with neoadjuvant nivolumab plus chemotherapy versus 55.0% with chemotherapy alone, and a significant OS improvement (43, 44). To date, KEYNOTE-671 represents the only perioperative trial with a comparable duration of follow-up, reporting 4-year OS rates of 68.0% with perioperative pembrolizumab versus 56.7% with chemotherapy alone. Although the validity of cross-trial comparisons is limited, a clearer picture of the optimal treatment approach in resectable NSCLC may begin to emerge as data from more trials mature.

Notably, the FDA has determined that the traditional two-arm design of current perioperative trials does not allow for within-trial assessment of the relative contribution of neoadjuvant versus adjuvant phases of treatment, without which it remains challenging to establish the potential for overtreatment (103). Furthermore, as approaches evolve and add-on therapies are considered for an immunotherapy backbone in the resectable stage, the optimal duration and timing of therapy may become less and less clear (103). As a result, the FDA has called for use of alternative trial designs, including multi-arm trials or trials that incorporate re-randomization of patients following surgery, to allow direct comparison of treatment effect in the neoadjuvant versus adjuvant portion of the trial (103). The planned open-label, randomized, Phase III ADOPT-lung trial is designed to determine whether additional adjuvant treatment with durvalumab following neoadjuvant durvalumab plus chemotherapy yields a DFS benefit, and the results will be important for guiding the optimal treatment approach in this setting (104). Clinicians should continue to assess risk–benefit on an individual patient basis to guide treatment decisions in the curative-intent setting, based on the robust, long-term benefit conferred with the appropriate utilization of immunotherapy in the resectable setting.

8 Conclusions

There is clear rationale for the use of immunotherapy treatment for resectable NSCLC; however, the optimal timing of treatment (adjuvant, neoadjuvant, or perioperative) remains to be determined. The current evidence is of limited maturity, with inconsistencies in patient outcomes between clinical trials and a lack of head-to-head data between different immunotherapy regimens. As a result, there is a lack of alignment between current treatment guidelines (e.g. IASLC and NCCN), and updates to recommendations from other organizations are pending (e.g. ASCO and the European Society for Medical Oncology), leaving clinicians to interpret data based on trends observed between clinical trials (6, 7, 11, 21, 105).

Several factors may inform the optimal use of immunotherapy. Firstly, as a key biomarker, PD-L1 expression level appears to have prognostic utility in the neoadjuvant setting; however, patients appear to experience benefit from neoadjuvant immunotherapy regardless of PD-L1 status (5, 62, 71, 106). Patients with higher PD-L1 expression appear to experience greater benefit from chemoimmunotherapy in the perioperative setting; however, results differ between regimens (54, 56, 58, 60). In the adjuvant setting, there remains insufficient evidence to recommend immunotherapy in patients with PD-L1-negative tumors (22, 24). Secondly, when considering the role of clinical stage in patient selection, patients with Stage III NSCLC appear to experience the most benefit from immunotherapy-containing regimens (70, 73). In patients with Stage II NSCLC, meta-analyses indicate that neoadjuvant immunotherapy is beneficial, although the only trials to show clear benefit with a neoadjuvant-containing regimen to date are the perioperative trials KEYNOTE-671 and RATIONALE-315 (5, 56, 58, 60–62). Furthermore, evolving data on the influence of N2 involvement may provide nuance to the determination of optimal immunotherapy timing by clinical stage. Presently, data in patients with N2 disease are restricted to the perioperative setting and indicate that, although EFS benefit may be observed regardless of nodal stage, pCR benefit with perioperative chemoimmunotherapy may be greatest in patients with single-station involvement (56, 78). Future studies, including those that stage patients according to the more granular AJCC-UICC 9^th edition of TNM staging, will be important to inform on the potential benefit of immunotherapy by clinical and nodal stage.

Identifying reliable response biomarkers is similarly important. Although not yet validated as a surrogate survival endpoint in this setting, pCR is widely recognized as a useful measure to assess short-term treatment outcomes with neoadjuvant immunotherapy (86, 87). In the future, pCR may aid the identification of patients who could be spared subsequent adjuvant immunotherapy (88). Assessment of MRD via liquid biopsy represents a highly specific mechanism to identify the presence of tumor cells following neoadjuvant treatment and surgery; however, it currently lacks sufficient sensitivity as a standalone tool to guide treatment decision-making in resectable NSCLC (53, 96). With further study and refinement, MRD may be best used alongside clinical and radiologic outcomes to guide the optimal treatment approach (102).

Given the current challenges facing clinicians in the determination of optimal treatment strategy, multidisciplinary team assessment is recommended to guide the application of immunotherapy for patients with resectable NSCLC (6, 7). The close interplay between neoadjuvant treatment and resectability, as well as between pathologic responses and patient outcomes in the adjuvant setting, emphasizes the need for interdisciplinary alignment on the timing of immunotherapy (20, 21). As prognostic and response biomarkers continue to evolve, personalization of treatment approaches becomes an ever more realistic goal; as such, it is essential that multidisciplinary working practices are established and refined to optimize immunotherapy treatment and drive improved patient outcomes in resectable NSCLC.

Author contributions

SPP: Writing – original draft, Writing – review & editing, Conceptualization. JG: Writing – original draft, Writing – review & editing. SK: Writing – original draft, Writing – review & editing. S-HL: Writing – original draft, Writing – review & editing. TM: Writing – original draft, Writing – review & editing. RS: Writing – original draft, Writing – review & editing. CZ: Writing – original draft, Writing – review & editing. SP: Writing – original draft, Writing – review & editing, Conceptualization, Supervision, Validation.

Funding

The author(s) declared financial support was received for this work and/or its publication. Medical writing support and the article processing charge were funded by BeOne Medicines Ltd.

Acknowledgments

Medical writing support, under the guidance of the authors, was provided by Emily Morton, BSc, of Porterhouse Medical Group Ltd, Reading, UK, and was funded by BeOne Medicines, Ltd (formerly BeiGene, Ltd) in accordance with Good Publication Practice guidelines (GPP 2022 guidelines. Ann Intern Med (2022) 175:1298–1304. doi: 10.7326/M22-1460).

Conflict of interest

Medical writing support and the article processing charge were funded by BeOne Medicines Ltd. S Patel has received grants or contracts (institutional research support) from: Amgen Inc., AstraZeneca PLC, A2bio, Bristol-Myers Squibb Pharmaceuticals Ltd, Corbus Pharmaceuticals Holdings Inc., Eli Lilly and Company, Fate Therapeutics Inc., Gilead Sciences Inc., Iovance Biotherapeutics Inc., Merck KGaA, Pfizer Inc., F. Hoffman-La Roche AG / Genentech; consulting fees from: Amgen Inc., AstraZeneca PLC, BeOne Medicines Ltd, Bristol-Myers Squibb Pharmaceuticals Ltd, Genentech, Gilead Sciences Inc., Pfizer Inc. J Gainor has received grants or contracts from: Moderna Inc., Novartis AG; consulting fees from: AstraZeneca PLC, Nuvalent Inc., Pfizer Inc., Novocure Ltd., AI Proteins Inc., Novartis AG, Silverback Therapeutics Inc., Sanofi SA, Blueprint Medicines Corporation, Bristol-Myers Squibb Pharmaceuticals Ltd., Genentech/F. Hoffman-La Roche AG, Gilead Sciences Inc., Revolution Medicines Inc., Janssen-Cilag Ltd., a Johnson & Johnson Company, iTeos Therapeutics Inc., Rigel Pharmaceuticals Inc., Eli Lilly and Company/Loxo Oncology Inc., BeOne Medicines Ltd; payment or honoraria from: Pfizer Inc.; leadership or fiduciary role (paid or unpaid) from: AI Proteins Inc. (SAB); stock or stock options for: AI Proteins Inc., Alkeus Pharmaceuticals Inc. (spouse), Ironwood Pharmaceuticals Inc. (spouse); other financial or non-financial interests: spouse is an employee of Alkeus Pharmaceuticals Inc. S Kao has received payment or honoraria from: Merck, Sharp & Dohme LLC, Bristol-Myers Squibb Pharmaceuticals Ltd, F. Hoffman-La Roche AG, AstraZeneca PLC, Pfizer Inc., Boehringer Ingelheim International GmbH, BeOne Medicines Ltd, Daiichi Sankyo Company Ltd; support attending meetings and/or travel from: Pfizer Inc.; participation on a data safety monitoring or advisory board from: AstraZeneca PLC, Pfizer Inc., Merck, Sharp & Dohme LLC, Bristol-Myers Squibb Pharmaceuticals Ltd, F. Hoffman-La Roche AG, Amgen Inc., BeOne Medicines Ltd, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company Ltd. SH Lee has received grants or contracts from: AstraZeneca PLC, Daiichi Sankyo Company Ltd, Lunit Inc., Merck, Sharp & Dohme LLC; consulting fees from: Albion Laboratories Ltd, AstraZeneca PLC, BeOne Medicines Ltd, Bristol-Myers Squibb Pharmaceuticals Ltd., Daiichi Sankyo Company Ltd, Eli Lilly and Company, IMB Dx Inc., ImmuneOncia Therapeutics Inc., Janssen-Cilag Ltd., a Johnson & Johnson Company, Merck & Co. Inc., Merck, Sharp & Dohme LLC, Novartis AG, Pfizer Inc., F. 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Ltd, Amgen Inc., Amoy Diagnostics Co. Ltd., AstraZeneca PLC (before 1/1/19), BeOne Medicines Ltd, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Pharmaceuticals Ltd, Daiichi Sankyo Company Ltd, The Daz Group Ltd, Fishawack Facilitate Ltd, InMed Pharmaceuticals Ltd, Janssen-Cilag Ltd., a Johnson & Johnson Company, Jiahui Holdings Co., LiangYiHui Healthcare/Suzhou Liangyihui Network Technology Co. Ltd, Eli Lilly and Company, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck & Co. Ltd (HK), Merck, Sharp & Dohme LLC, MiRXES Pte Ltd, Novartis AG, OrigiMed (Shanghai) Co. Ltd., P. Permanyer SL, PeerVoice UK Ltd, Physicians’ Education Resource LLC, Pfizer Inc., PrIME Oncology LLC, Research to Practice, F. Hoffman-La Roche AG/ Diagnostics/ Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co. Ltd, Taiho Pharmaceutical Co. Ltd, Takeda Pharmaceutical Company Ltd, Touch Independent Medical Education Ltd; support attending meetings and/or travel from: (Institution only) Pfizer Inc., (Institution and personal) Novartis AG, F. Hoffman-La Roche AG, (personal) AstraZeneca PLC, Daiichi Sankyo Company Ltd, Takeda Pharmaceutical Company Ltd, MiRXES Pte Ltd, Pfizer Inc., Novartis AG, AbbVie Inc., Zai Lab Ltd, Liangyhui, Luye Pharma Ltd, BeOne Medicines, Ltd, Merck, Sharp & Dohme LLC, F. Hoffman-La Roche AG; participation on a data safety monitoring or advisory board from: AbbVie Inc., ACEA Therapeutics Inc., Amgen Inc., AstraZeneca PLC, Alentis Therapeutics AG, BerGenBio ASA, Berry Oncology Co. Ltd, Blueprint Medicines Corporation, Boehringer Ingelheim International GmbH, Bowtie Life Insurance Co Ltd, Bristol-Myers Squibb Pharmaceuticals Ltd., C4 Therapeutics Inc, Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Company Ltd Inc., Eisai Co. Ltd, Erasca Inc., Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology Inc., Guardant Health Inc., geneDecode Co. Ltd. (uncompensated), Hengrui Therapeutics Inc., HutchMed (China) Ltd, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata Ltd, IQVIA Holdings Inc., Janssen-Cilag Ltd., a Johnson & Johnson Company, LakeShore Biopharma Co. Ltd, Eli Lilly and Company, Loxo Oncology Inc., Lunit Inc., Merck & Co. Inc./EMD Serono, Merck Sharp & Dohme LLC, Mirati Therapeutics Inc., MiRXES Pte Ltd, Novartis AG, OrigiMed Shanghai Co. Ltd, Phanes Therapeutics Inc., Pfizer Inc., Prenetics Global Ltd, Puma Biotechnology Inc., F. Hoffman-La Roche AG / Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis/Sanofi SA (R&D), SFJ Pharmaceuticals Inc., Simcere of America Inc., Simcere Zaiming Inc., Takeda Pharmaceutical Company Ltd, Vertex Pharmaceuticals Inc., Virtus Medical Group/Virtus Health Limited, XENCOR Inc., Yuhan Corporation; leadership or fiduciary role (paid or unpaid) for: AstraZeneca PLC, HutchMed (China) Ltd, Aurora Pharma Ltd, Epoch Biosciences Inc., Insighta; stock or stock options for: AstraZeneca PLC, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed (China) Ltd, Prenetics Global Ltd, D3 Bio Ltd, Lunit Inc., Bowtie Life Insurance, LakeShore Biopharma Co. Ltd, Loxo Oncology Inc., Virtus Medical Group/Virtus Health Ltd, Yinson Capital Pte. Ltd., Phanes Therapeutics Inc., Insighta, Alentis Therapeutics AG, Epoch Biosciences Pte. Ltd. R Shah has received consulting fees from: F. Hoffman-La Roche AG (UK), AstraZeneca PLC, Merck, Sharp & Dohme LLC, Eli Lilly and Company, Bristol Myers-Squibb Pharmaceuticals Ltd; payment or honoraria from: F. Hoffman-La Roche AG UK, AstraZeneca PLC, Merck, Sharp & Dohme LLC, Bristol Myers-Squibb Pharmaceuticals Ltd, Eli Lilly and Company; support for attending meetings and/or travel from: F. Hoffman-La Roche AG, Merck, Sharp & Dohme LLC, Eli Lilly and Company, Bristol Myers-Squibb Pharmaceuticals Ltd; participation on a data safety monitoring or advisory board from: AstraZeneca PLC; leadership or fiduciary role (paid or unpaid) from: British Thoracic Oncology Group, ALK+ UK, EGFR UK. C Zhou has received consulting fees from: Qilu Pharmaceutical Co. Ltd, Amoy Diagnostics Co. Ltd; payment or honoraria from: Amoy Diagnostics Co. Ltd, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Innovent Biologics Inc., Eli Lilly and Company (China), Luye Pharma Group Ltd, Merck, Sharp & Dohme LLC, QiLu Pharmaceutical Co. Ltd, F. Hoffman-La Roche AG, TopAlliance Biosciences Inc., Johnson & Johnson. S Peters has received grants or contracts from: Principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen Inc., Arcus, AstraZeneca PLC, BeOne Medicines Ltd, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Pharmaceuticals Ltd, Eli Lilly and Company, GSK PLC, iTeos Therapeutics Inc., Merck, Sharp and Dohme Inc., Mirati Therapeutics, Pharma Mar SA, Pfizer Inc., Promontory Therapeutics Inc., F. Hoffman-La Roche AG / Genentech, Seattle Genetics/Seagen Inc.; consulting fees from: AbbVie Inc., Amgen Inc., Arcus, AstraZeneca PLC, Bayer AG, BeOne Medicines Ltd, BioNTech SE, BerGenBio ASA, Bicycle Therapeutics PLC, Biocartis Group NV, BioInvent International AB, Blueprint Medicines Corporation, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Pharmaceuticals Ltd, Clovis Oncology Ltd, Daiichi Sankyo Company Ltd, Debiopharm International SA, Eli Lilly and Company, F-Star Therapeutics Inc./F-Star Therapeutics Ltd, Foundation Medicine Inc., Genmab A/S, Genzyme Corporation, Gilead Sciences Inc., GSK PLC, Hutchmed, Illumina Inc., Incyte Corporation, Ipsen SA, iTeos Therapeutics Inc., Janssen-Cilag Ltd., a Johnson & Johnson Company, Qlucore AB, Merck, Sharp and Dohme Inc., Merck & Co. Inc./EMD Serono, Merrimack Pharmaceuticals Inc., Mirati Therapeutics, Nuvation Bio Inc., Nykode Therapeutics ASA, Novartis AG, Novocure Ltd., Pharma Mar SA, Promontory Therapeutics, Pfizer Inc., Regeneron Pharmaceuticals Inc., F. Hoffman-La Roche AG / Genentech, Sanofi SA, Seattle Genetics/Seagen Inc., Takeda Pharmaceutical Company Ltd, Zymeworks Inc.; payment or honoraria from: AstraZeneca PLC, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Pharmaceuticals Ltd, Eli Lilly and Company, Foundation Medicine, GSK PLC, Illumina Inc., Ipsen SA, Merck, Sharp and Dohme Inc., Mirati Therapeutics, Novartis AG, Pfizer Inc., F. Hoffman-La Roche AG / Genentech, Sanofi SA, Seattle Genetics/Seagen Inc., Takeda Pharmaceutical Company Ltd; support for attending meetings and/or travel from: AstraZeneca PLC, Bristol-Myers Squibb Pharmaceuticals Ltd, Daiichi Sankyo Company Ltd, Eli Lilly and Company, Merck, Sharp and Dohme Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche AG / Genentech, Takeda Pharmaceutical Company Ltd; participation on a data safety monitoring or advisory board from: AbbVie Inc., Amgen Inc., Arcus, AstraZeneca PLC, Bayer AG, BeOne Medicines Ltd, BioNTech SE, BerGenBio, Bicycle Therapeutics PLC, Biocartis Group NV, BioInvent International AB, Blueprint Medicines Corporation, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Pharmaceuticals Ltd, Clovis Oncology Ltd, Daiichi Sankyo Company Ltd, Debiopharm Internationals AB, Eli Lilly and Company, F-Star Therapeutics Inc./F-Star Therapeutics Ltd, Foundation Medicine Inc., Genmab A/S, Genzyme Corporation, Gilead Sciences Inc., GSK PLC, Hutchmed, Illumina Inc., Incyte Corporation, Ipsen SA, iTeos Therapeutics Inc., Janssen-Cilag Ltd., a Johnson & Johnson Company, Qlucore AB, Merck, Sharp and Dohme Inc., Merck & Co. Inc. /EMD Serono, Merrimack Pharmaceuticals Inc., Mirati Therapeutics, Nuvation Bio Inc., Nykode Therapeutics ASA, Novartis AG, Novocure Ltd., Pharma Mar SA, Promontory Therapeutics, Pfizer Inc., Regeneron Pharmaceuticals SA, F. Hoffman-La Roche AG / Genentech, Sanofi SA, Seattle Genetics/Seagen Inc., Takeda Pharmaceutical Company Ltd, Zymeworks Inc.; leadership or fiduciary role (paid or unpaid) from: Galenica SA, Board of Director.

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References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2021) 71:209–49. doi: 10.3322/caac.21660

PubMed Abstract | Crossref Full Text | Google Scholar

2. Cagle PT, Allen TC, and Olsen RJ. Lung cancer biomarkers: present status and future developments. Arch Pathol Lab Med. (2013) 137:1191–8. doi: 10.5858/arpa.2013-0319-CR

PubMed Abstract | Crossref Full Text | Google Scholar

3. Le Chevalier T. Adjuvant chemotherapy for resectable non-small-cell lung cancer: where is it going? Ann Oncol. (2010) 21:vii196–8. doi: 10.1093/annonc/mdq376

PubMed Abstract | Crossref Full Text | Google Scholar

4. Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, Vansteenkiste J, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. (2017) 28:iv1–21. doi: 10.1093/annonc/mdx222

PubMed Abstract | Crossref Full Text | Google Scholar

5. Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. (2022) 386:1973–85. doi: 10.1056/NEJMoa2202170

PubMed Abstract | Crossref Full Text | Google Scholar

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer (Version 11.2024). Available online at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (Accessed April 16, 2025).

Google Scholar

7. Spicer JD, Cascone T, Wynes MW, Ahn M-J, Dacic S, Felip E, et al. Neoadjuvant and adjuvant treatments for early stage resectable NSCLC: consensus recommendations from the International Association for the Study of Lung Cancer. J Thorac Oncol. (2024) 19:1373–414. doi: 10.1016/j.jtho.2024.06.010

PubMed Abstract | Crossref Full Text | Google Scholar

8. Liang W, Cai K, Cao Q, Chen C, Chen H, Chen J, et al. International expert consensus on immunotherapy for early-stage non-small cell lung cancer. Transl Lung Cancer Res. (2022) 11:1742–62. doi: 10.21037/tlcr-22-617

PubMed Abstract | Crossref Full Text | Google Scholar

9. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. (2014) 383:1561–71. doi: 10.1016/S0140-6736(13)62159-5

PubMed Abstract | Crossref Full Text | Google Scholar

10. Tang W-F, Ye H-Y, Tang X, Su J-W, Xu K-M, Zhong W-Z, et al. Adjuvant immunotherapy in early-stage resectable non–small cell lung cancer: a new milestone. Front Oncol. (2023) 13:1063183. doi: 10.3389/fonc.2023.1063183

PubMed Abstract | Crossref Full Text | Google Scholar

11. Daly ME, Singh N, and Ismaila N. Management of Stage III NSCLC Guideline Expert Panel. Management of stage III non–small cell lung cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. (2024) 42:3058–60. doi: 10.1200/JCO-24-01324

PubMed Abstract | Crossref Full Text | Google Scholar

12. Pisters K, Kris MG, Gaspar LE, and Ismaila N. Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA NSCLC Guideline Expert Panel. Adjuvant systemic therapy and adjuvant radiation therapy for stage I-IIIA completely resected non–small-cell lung cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. (2022) 40:1127–9. doi: 10.1200/JCO.22.00051

PubMed Abstract | Crossref Full Text | Google Scholar

13. Dunne EG, Fick CN, and Jones DR. Mediastinal staging in non–small-cell lung cancer: saying goodbye to mediastinoscopy. J Clin Oncol. (2023) 41:3785–90. doi: 10.1200/jco.23.00867

PubMed Abstract | Crossref Full Text | Google Scholar

14. Leiro-Fernández V and Fernández-Villar A. Mediastinal staging for non-small cell lung cancer. Transl Lung Cancer Res. (2021) 10:496–505. doi: 10.21037/tlcr.2020.03.08

PubMed Abstract | Crossref Full Text | Google Scholar

15. Czarnecka-Kujawa K and Yasufuku K. The role of endobronchial ultrasound versus mediastinoscopy for non-small cell lung cancer. J Thorac Dis. (2017) 9:S83–97. doi: 10.21037/jtd.2017.03.102

PubMed Abstract | Crossref Full Text | Google Scholar

16. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. (2014) 45:787–98. doi: 10.1093/ejcts/ezu028

PubMed Abstract | Crossref Full Text | Google Scholar

17. Kim F, Borgeaud M, Addeo A, and Friedlaender A. Management of stage III non-small-cell lung cancer: rays of hope. Explor Target Antitumor Ther. (2024) 5:85–95. doi: 10.37349/etat.2024.00206

PubMed Abstract | Crossref Full Text | Google Scholar

18. Kalvapudi S, Vedire Y, Yendamuri S, and Barbi J. Neoadjuvant therapy in non-small cell lung cancer: basis, promise, and challenges. Front Oncol. (2023) 13:1286104. doi: 10.3389/fonc.2023.1286104

PubMed Abstract | Crossref Full Text | Google Scholar

19. Martins RS, Razi SS, Alnajar A, Poulikidis K, Latif MJ, Luo J, et al. Neoadjuvant vs adjuvant chemoimmunotherapy for stage II-IIIB non-small cell lung cancer. Ann Thorac Surg. (2024) 118:672–81. doi: 10.1016/j.athoracsur.2024.01.004

PubMed Abstract | Crossref Full Text | Google Scholar

20. Kim SS, Cooke DT, Kidane B, Tapias LF, Lazar JF, Awori Hayanga JW, et al. The Society of Thoracic Surgeons expert consensus on the multidisciplinary management and resectability of locally advanced non-small cell lung cancer. Ann Thorac Surg. (2025) 119:16–33. doi: 10.1016/j.athoracsur.2024.09.041

PubMed Abstract | Crossref Full Text | Google Scholar

21. Vansteenkiste J, Crinò L, Dooms C, Douillard JY, Faivre-Finn C, Lim E, et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. Ann Oncol. (2014) 25:1462–74. doi: 10.1093/annonc/mdu089

PubMed Abstract | Crossref Full Text | Google Scholar

22. Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, 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. doi: 10.1016/S0140-6736(21)02098-5

PubMed Abstract | Crossref Full Text | Google Scholar

23. Wakelee HA, Altorki NK, Zhou C, Csőszi T, Vynnychenko IO, Goloborodko O, et al. IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. (2024) 42:LBA8035. doi: 10.1200/JCO.2024.42.17_suppl.LBA8035

Crossref Full Text | Google Scholar

24. O’Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, 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. doi: 10.1016/S1470-2045(22)00518-6

PubMed Abstract | Crossref Full Text | Google Scholar

25. Goss G, Darling GE, Westeel V, Nakagawa K, Massuti Sureda B, Perrone F, et al. LBA48 CCTG BR.31: a global, double-blind placebo-controlled, randomized phase III study of adjuvant durvalumab in completely resected non-small cell lung cancer (NSCLC). Ann Oncol. (2024) 35:S1238. doi: 10.1016/j.annonc.2024.08.2289

Crossref Full Text | Google Scholar

26. Merck Sharp & Dohme (UK) Limited. KEYTRUDA 25 mg/mL concentrate for solution for infusion – summary of product characteristics. London, UK: Merck Sharp & Dohme (UK) Limited. Available online at: https://www.medicines.org.uk/emc/product/2498/smpc (Accessed April 16, 2025).

Google Scholar

27. Merck Sharp & Dohme LLC. KEYTRUDA^® (pembrolizumab) injection, for intravenous use – prescribing information. Rahway, NJ, USA: Merck Sharp & Dohme LLC. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/125514s172lbl.pdf (Accessed April 16, 2025).

Google Scholar

28. Roche Products Limited. Tecentriq 840 mg concentrate for solution for infusion – summary of product characteristics. Welwyn Garden City, UK: Roche Products Limited. Available online at: https://www.medicines.org.uk/emc/product/10697/smpc (Accessed April 16, 2025).

Google Scholar

29. Genentech, Inc. TECENTRIQ^® (atezolizumab) injection, for intravenous use – prescribing information. South San Francisco, CA, USA: Genentech, Inc. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761034s043lbl.pdf (Accessed April 16, 2025).

Google Scholar

30. Oselin K, Shim BY, Okada M, Bryl M, Bonanno L, Demirag G, et al. Pembrolizumab vs placebo for early-stage non‒small-cell lung cancer after resection and adjuvant therapy: subgroup analysis of patients who received adjuvant chemotherapy in the phase 3 PEARLS/KEYNOTE-091 study. J Clin Oncol. (2023) 41:8520. doi: 10.1200/JCO.2023.41.16_suppl.8520

Crossref Full Text | Google Scholar

31. AstraZeneca. Update on ADJUVANT BR.31 phase III trial of Imfinzi in non-small cell lung cancer (2024). Available online at: https://www.astrazeneca.com/media-centre/press-releases/2024/update-on-imfinzi-adjuvant-br31-trial.html (Accessed April 16, 2025).

Google Scholar

32. Bestvina CM, Garassino MC, Neal JW, Wakelee HA, Diehn M, and Vokes EE. Early-stage lung cancer: using circulating tumor DNA to get personal. J Clin Oncol. (2023) 41:4093–96. doi: 10.1200/JCO.23.00258

PubMed Abstract | Crossref Full Text | Google Scholar

33. AstraZeneca. Phase III study to determine the efficacy of durvalumab in combination with chemotherapy in completely resected stage II-III non-small cell lung cancer (NSCLC) - MERMAID-1. Available online at: https://www.astrazenecaclinicaltrials.com/study/D910LC00001/ (Accessed April 16, 2025).

Google Scholar

34. AstraZeneca. Phase III study to determine efficacy of durvalumab in stage II-III non-small cell lung cancer (NSCLC) after curative intent therapy. - MERMAID-2. Available online at: https://www.astrazenecaclinicaltrials.com/study/D910MC00001/ (Accessed April 16, 2025).

Google Scholar

35. ClinicalTrials.gov. Nivolumab after surgery and chemotherapy in treating patients with stage IB-IIIA non-small cell lung cancer (an ALCHEMIST treatment trial) (ANVIL) (2025). Available online at: https://clinicaltrials.gov/study/NCT02595944 (Accessed April 16, 2025).

Google Scholar

36. ClinicalTrials.gov. Testing the addition of a type of drug called immunotherapy to the usual chemotherapy treatment for non-small cell lung cancer, ALCHEMIST trial (2025). Available online at: https://clinicaltrials.gov/study/NCT04267848 (Accessed April 16, 2025).

Google Scholar

37. ClinicalTrials.gov Adjuvant toripalimab plus chemotherapy for EGFR/ALK mutation negative stage II-IIIB(N2) NSCLC (LungMate-008) (2021). Available online at: https://clinicaltrials.gov/study/NCT04772287 (Accessed April 16, 2025).

Google Scholar

38. ClinicalTrials.gov. New adjuvant trial of chemotherapy vs chemo-immunotherapy (NADIM-ADJUVANT) (2025). Available online at: https://clinicaltrials.gov/study/NCT04564157 (Accessed April 16, 2025).

Google Scholar

39. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. (2018) 378:1976–86. doi: 10.1056/NEJMoa1716078

PubMed Abstract | Crossref Full Text | Google Scholar

40. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. (2014) 346:251–6. doi: 10.1126/science.1253462

PubMed Abstract | Crossref Full Text | Google Scholar

41. McGranahan N and Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. (2015) 27:15–26. doi: 10.1016/j.ccell.2014.12.001

PubMed Abstract | Crossref Full Text | Google Scholar

42. Uprety D, Mandrekar SJ, Wigle D, Roden AC, and Adjei AA. Neoadjuvant immunotherapy for NSCLC: current concepts and future approaches. J Thorac Oncol. (2020) 15:1281–97. doi: 10.1016/j.jtho.2020.05.020

PubMed Abstract | Crossref Full Text | Google Scholar

43. Spicer J, Girard N, Provencio M, Wang C, Mitsudomi T, Awad MM, et al. Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816. J Clin Oncol. (2024) 42:LBA8010. doi: 10.1200/JCO.2024.42.17_suppl.LBA8010

Crossref Full Text | Google Scholar

44. Forde PM, Spicer JD, Provencio M, Mitsudomi T, Awad MM, Wang C, et al. Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. New Engl J Med. (2025) 0. doi: 10.1056/NEJMoa2502931

PubMed Abstract | Crossref Full Text | Google Scholar

45. Forde PM, Spicer J, Girard N, Provencio M, Lu S, Wang C, et al. 84O Neoadjuvant nivolumab (N) + platinum-doublet chemotherapy (C) for resectable NSCLC: 3-y update from CheckMate 816. J Thorac Oncol. (2023) 18:S89–90. doi: 10.1016/S1556-0864(23)00338-6

Crossref Full Text | Google Scholar

46. Bristol-Myers Squibb Company. OPDIVO (nivolumab) injection, for intravenous use – prescribing information (2025). Princeton, NJ, USA: Bristol-Myers Squibb Company. Available online at: https://packageinserts.bms.com/pi/pi_opdivo.pdf (Accessed November 03, 2025).

Google Scholar

47. Bristol-Myers Squibb Pharma EEIG. OPDIVO 10 mg/mL concentrate for solution for infusion – summary of product characteristics. Dublin, Ireland: Bristol-Myers Squibb Pharma EEIG. Available online at: https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf (Accessed November 03, 2025).

Google Scholar

48. Houda I, Dickhoff C, Uyl-de Groot CA, Damhuis RAM, Reguart N, Provencio M, et al. Challenges and controversies in resectable non-small cell lung cancer: a clinician’s perspective. Lancet Reg Health Eur. (2024) 38:100841. doi: 10.1016/j.lanepe.2024.100841

PubMed Abstract | Crossref Full Text | Google Scholar

49. Minervini F, Kestenholz PB, Kocher GJ, and Azenha F. Thoracic surgical challenges after neoadjuvant immunotherapy for non-small cell lung cancer: a narrative review. AME Surg J. (2023) 3:15. doi: 10.21037/asj-21-77

Crossref Full Text | Google Scholar

50. Aguado C, Chara L, Antoñanzas M, Matilla Gonzalez JM, Jiménez U, Hernanz R, et al. Neoadjuvant treatment in non-small cell lung cancer: new perspectives with the incorporation of immunotherapy. World J Clin Oncol. (2022) 13:314–22. doi: 10.5306/wjco.v13.i5.314

PubMed Abstract | Crossref Full Text | Google Scholar

51. Takada K, Takamori S, Brunetti L, Crucitti P, and Cortellini A. Impact of neoadjuvant immune checkpoint inhibitors on surgery and perioperative complications in patients with non–small-cell lung cancer: a systematic review. Clin Lung Cancer. (2023) 24:581–90.e5. doi: 10.1016/j.cllc.2023.08.017

PubMed Abstract | Crossref Full Text | Google Scholar

52. Altorki NK, Walsh ZH, Melms JC, Port JL, Lee BE, Nasar A, et al. Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial. Nat Commun. (2023) 14:8435. doi: 10.1038/s41467-023-44195-x

PubMed Abstract | Crossref Full Text | Google Scholar

53. Qiu B, Cai K, Chen C, Chen J, Chen K-N, Chen Q-X, et al. Expert consensus on perioperative immunotherapy for local advanced non-small cell lung cancer. Transl Lung Cancer Res. (2021) 10:3713–36. doi: 10.21037/tlcr-21-634

PubMed Abstract | Crossref Full Text | Google Scholar

54. Spicer JD, Garassino MC, Wakelee H, Liberman M, Kato T, Tsuboi M, et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. (2024) 404:1240–52. doi: 10.1016/S0140-6736(24)01756-2

PubMed Abstract | Crossref Full Text | Google Scholar

55. Majem M, Garassino MC, Zhao G, Mennecier B, Grohe C, Ikeda N, et al. LBA3 Perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) in early-stage non-small-cell lung cancer (NSCLC): a 4-year update of KEYNOTE-671. Immunooncol Technol. (2024) 24:101027. doi: 10.1016/j.iotech.2024.101027

Crossref Full Text | Google Scholar

56. Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, et al. Perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med. (2023) 389:1672–84. doi: 10.1056/NEJMoa2304875

PubMed Abstract | Crossref Full Text | Google Scholar

57. Lu S, Zhang W, Wu L, Wang W, Zhang P, Neotorch Investigators, 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. doi: 10.1001/jama.2023.24735

PubMed Abstract | Crossref Full Text | Google Scholar

58. Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med. (2024) 390:1756–69. doi: 10.1056/NEJMoa2311926

PubMed Abstract | Crossref Full Text | Google Scholar

59. Cascone T, Awad MM, Spicer J, He J, Lu S, Tanaka F, et al. Perioperative nivolumab (NIVO) vs placebo (PBO) in patients (pts) with resectable NSCLC: Updated survival and biomarker analyses from CheckMate 77T. J Clin Oncol. (2025) 43:LBA8010–LBA8010. doi: 10.1200/JCO.2025.43.17_suppl.LBA8010

Crossref Full Text | Google Scholar

60. Yue D, Wang W, Liu H, Chen Q, Chen C, Liu L, et al. Perioperative tislelizumab plus neoadjuvant chemotherapy for patients with resectable non-small-cell lung cancer (RATIONALE-315): an interim analysis of a randomised clinical trial. Lancet Respir Med. (2025) 13:119–29. doi: 10.1016/S2213-2600(24)00269-8

PubMed Abstract | Crossref Full Text | Google Scholar

61. Yue D, Wang W, Liu H, Chen Q, Chen C, Liu L, et al. Perioperative tislelizumab for resectable non-small cell lung cancer: Final analysis of RATIONALE-315. 2025 IASLC World Conf Lung Cancer (WCLC); 2025 Sep 6–9; Barcelona Spain. (2025).

Google Scholar

62. Wakelee H, Liberman M, Kato T, Tsuboi M, Lee S-H, Gao S, et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. (2023) 389:491–503. doi: 10.1056/NEJMoa2302983

PubMed Abstract | Crossref Full Text | Google Scholar

63. BeOne Medicines. European Commission Approves TEVIMBRA® as Neoadjuvant/Adjuvant NSCLC Treatment Ahead of Late-Breaking Data Presentation at WCLC 2025 (2025 October 29, 2025). Available online at: https://ir.beonemedicines.com/news/european-commission-approves-tevimbrar-as-neoadjuvantadjuvant-nsclc-treatment-ahead-of-late-breaking-data-presentation-at-wclc/0d7553af-93d0-4616-a02b-ac223e497bca (Accessed October 29, 2025).

Google Scholar

64. BeOne Medicines Ireland Limited. Tevimbra 100 mg concentrate for solution for infusion – summary of product characteristics . Dublin, Ireland: BeOne Medicines Ireland Limited. Available online at: https://www.ema.europa.eu/en/medicines/human/EPAR/tevimbra (Accessed October 29, 2025).

Google Scholar

65. AstraZeneca UK Limited. IMFINZI^® (durvalumab) injection, for intravenous use – prescribing information (2025). Cambridge, England: AstraZeneca UK Limited. Available online at: https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/9496217c-08b3-432b-ab4f-538d795820bd/9496217c-08b3-432b-ab4f-538d795820bd_viewable_rendition:v.pdf (Accessed April 16, 2025).

Google Scholar

66. AstraZeneca AB IMFINZI^® (durvalumab) injection, for intravenous use – summary of product characteristics. Sweden, July: AstraZeneca AB; Södertälje. Available online at: https://www.ema.europa.eu/en/documents/product-information/imfinzi-epar-product-information_en.pdf (Accessed November 03, 2025).

Google Scholar

67. Zhao J, Li Y, Li R, Yao X, Dong X, Su L, et al. Adjuvant treatment after neoadjuvant immunotherapy in patients with non-small cell lung cancer. iScience. (2024) 27:111281. doi: 10.1016/j.isci.2024.111281

PubMed Abstract | Crossref Full Text | Google Scholar

68. Mathew M, Safyan RA, and Shu CA. PD-L1 as a biomarker in NSCLC: challenges and future directions. Ann Transl Med. (2017) 5:375. doi: 10.21037/atm.2017.08.04

PubMed Abstract | Crossref Full Text | Google Scholar

69. Paz-Ares LG, Ramalingam SS, Ciuleanu T-E, Lee J-S, Urban L, Caro RB, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol. (2022) 17:289–308. doi: 10.1016/j.jtho.2021.09.010

PubMed Abstract | Crossref Full Text | Google Scholar

70. Banna GL, Hassan MA, Signori A, Giunta EF, Maniam A, Anpalakhan S, et al. Neoadjuvant chemo-immunotherapy for early-stage non–small cell lung cancer: a systematic review and meta-analysis. JAMA Netw Open. (2024) 7:e246837. doi: 10.1001/jamanetworkopen.2024.6837

PubMed Abstract | Crossref Full Text | Google Scholar

71. Mo D-C, Huang J-F, Lin P, Huang S-X, Wang H-L, Luo P-H, et al. The role of PD-L1 in patients with non-small cell lung cancer receiving neoadjuvant immune checkpoint inhibitor plus chemotherapy: a meta-analysis. Sci Rep. (2024) 14:26200. doi: 10.1038/s41598-024-78159-y

PubMed Abstract | Crossref Full Text | Google Scholar

72. European Medicines Agency. Summary of opinion (post authorisation): Opdivo (nivolumab) (2025). Available online at: https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-opdivo-ii-140_en.pdf (Accessed May 15, 2025).

Google Scholar

73. Sorin M, Prosty C, Ghaleb L, Nie K, Katergi K, Shahzad MH, et al. Neoadjuvant chemoimmunotherapy for NSCLC: a systematic review and meta-analysis. JAMA Oncol. (2024) 10:621–33. doi: 10.1001/jamaoncol.2024.0057

PubMed Abstract | Crossref Full Text | Google Scholar

74. Putora PM, Leskow P, McDonald F, Batchelor T, and Evison M. International guidelines on stage III N2 nonsmall cell lung cancer: surgery or radiotherapy? ERJ Open Res. (2020) 6:00159–2019. doi: 10.1183/23120541.00159-2019

PubMed Abstract | Crossref Full Text | Google Scholar

75. Provencio M, Awad MM, Spicer J, Janssens A, Moiseenko FV, Gao Y, et al. Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: results from the phase 3 CheckMate 77T study. J Clin Oncol. (2024) 42:LBA8007. doi: 10.1200/JCO.2024.42.17_suppl.LBA8007

Crossref Full Text | Google Scholar

76. Heymach J, Reck M, Mitsudomi T, Taube JM, Spira AI, Chaft JE, et al. Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): an exploratory subgroup analysis of AEGEAN. J Clin Oncol. (2024) 42:8011. doi: 10.1200/JCO.2024.42.16_suppl.8011

Crossref Full Text | Google Scholar

77. Rusch VW, Crowley J, Giroux DJ, Goldstraw P, Im J-G, Tsuboi M, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM Classification for Lung Cancer. J Thorac Oncol. (2007) 2:603–12. doi: 10.1097/JTO.0b013e31807ec803

PubMed Abstract | Crossref Full Text | Google Scholar

78. Provencio M, Nadal E, González-Larriba JL, Martínez-Martí A, Bernabé R, Bosch-Barrera J, et al. Perioperative nivolumab and chemotherapy in stage III non–small-cell lung cancer. N Engl J Med. (2023) 389:504–13. doi: 10.1056/NEJMoa2215530

Crossref Full Text | Google Scholar

79. Rami-Porta R, Nishimura KK, Giroux DJ, Detterbeck F, Cardillo G, Edwards JG, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for revision of the TNM Stage Groups in the forthcoming (ninth) edition of the TNM Classification for Lung Cancer. J Thorac Oncol. (2024) 19:1007–27. doi: 10.1016/j.jtho.2024.02.011

PubMed Abstract | Crossref Full Text | Google Scholar

80. Jacobs RC, Rabin EE, Logan CD, Bharadwaj SN, Yang HC, Bell RD, et al. Pathologic upstaging and survival outcomes for patients undergoing segmentectomy versus lobectomy in clinical stage T1cN0M0 non–small cell lung cancer. JTCVS Open. (2025) 24:394–408. doi: 10.1016/j.xjon.2025.01.014

PubMed Abstract | Crossref Full Text | Google Scholar

81. Craig C, Johnston J, Goodley P, Bishop P, Al-Najjar H, Brown L, et al. What is the accuracy of clinical staging for stage III-single-station N2 NSCLC? A multi-centre UK study. JTO Clin Res Rep. (2024) 5:100694. doi: 10.1016/j.jtocrr.2024.100694

PubMed Abstract | Crossref Full Text | Google Scholar

82. Navani N, Fisher DJ, Tierney JF, Stephens RJ, Burdett S, and NSCLC Meta-analysis Collaborative Group. The accuracy of clinical staging of stage I-IIIa non-small cell lung cancer: an analysis based on individual participant data. Chest. (2019) 155:502–09. doi: 10.1016/j.chest.2018.10.020

PubMed Abstract | Crossref Full Text | Google Scholar

83. Blakely CM, Weder W, Bubendorf L, He J, Majem M, Shyr Y, et al. Primary endpoints to assess the efficacy of novel therapeutic approaches in epidermal growth factor receptor-mutated, surgically resectable non-small cell lung cancer: a review. Lung Cancer. (2023) 177:59–72. doi: 10.1016/j.lungcan.2023.01.002

PubMed Abstract | Crossref Full Text | Google Scholar

84. Ghorani E, Quartagno M, Blackhall F, Gilbert DC, O’Brien M, Ottensmeier C, et al. REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment. Lancet Oncol. (2023) 24:e219–27. doi: 10.1016/S1470-2045(23)00095-5

PubMed Abstract | Crossref Full Text | Google Scholar

85. Deutsch JS, Cimino-Mathews A, Thompson E, Provencio M, Forde PM, Spicer J, et al. Association between pathologic response and survival after neoadjuvant therapy in lung cancer. Nat Med. (2024) 30:218–28. doi: 10.1038/s41591-023-02660-6

PubMed Abstract | Crossref Full Text | Google Scholar

86. Hines JB, Cameron RB, Esposito A, Kim L, Porcu L, Nuccio A, et al. Evaluation of major pathologic response and pathologic complete response as surrogate end points for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable in NSCLC. J Thorac Oncol. (2024) 19:1108–16. doi: 10.1016/j.jtho.2024.03.010

PubMed Abstract | Crossref Full Text | Google Scholar

87. Waser NA, Quintana M, Schweikert B, Chaft JE, Berry L, Adam A, et al. Pathological response in resectable non–small cell lung cancer: a systematic literature review and meta-analysis. JNCI Cancer Spectr. (2024) 8:pkae021. doi: 10.1093/jncics/pkae021

PubMed Abstract | Crossref Full Text | Google Scholar

88. Chaft JE, Dziadziuszko R, and Haddock Lobo Goulart B. Moving immunotherapy into the treatment of resectable non–small cell lung cancer. Am Soc Clin Oncol Educ Book. (2024) 44:e432500. doi: 10.1200/EDBK_432500

PubMed Abstract | Crossref Full Text | Google Scholar

89. Zhou Y, Li A, Yu H, Wang Y, Zhang X, Qiu H, et al. Neoadjuvant-adjuvant vs neoadjuvant-only PD-1 and PD-L1 inhibitors for patients with resectable NSCLC: an indirect meta-analysis. JAMA Netw Open. (2024) 7:e241285. doi: 10.1001/jamanetworkopen.2024.1285

PubMed Abstract | Crossref Full Text | Google Scholar

90. Dacic S, Travis W, Redman M, Saqi A, Cooper WA, Borczuk A, et al. International Association for the Study of Lung Cancer study of reproducibility in assessment of pathologic response in resected lung cancers after neoadjuvant therapy. J Thorac Oncol. (2023) 18:1290–302. doi: 10.1016/j.jtho.2023.07.017

PubMed Abstract | Crossref Full Text | Google Scholar

91. Uprety D, Roden AC, and Peters S. Adjuvant immunotherapy should be used in patients with non-small cell carcinoma with a pathologic complete response to neoadjuvant immunotherapy. J Thorac Oncol. (2025) 20:34–8. doi: 10.1016/j.jtho.2024.11.004

PubMed Abstract | Crossref Full Text | Google Scholar

92. Forde PM, Peters S, Donington J, Meadows-Shropshire S, Tran P, Lucherini S, et al. PL02.08 Perioperative vs neoadjuvant nivolumab for resectable NSCLC: patient-level data analysis of CheckMate 77T vs CheckMate 816. J Thorac Oncol. (2024) 19:S2. doi: 10.1016/j.jtho.2024.09.014

Crossref Full Text | Google Scholar

93. ClinicalTrials.gov Pembrolizumab vs. observation in people with triple-negative breast cancer who had a pathologic complete response after chemotherapy plus pembrolizumab (2025). Available online at: https://www.clinicaltrials.gov/study/NCT05812807 (Accessed April 16, 2025).

Google Scholar

94. Moding EJ, Nabet BY, Alizadeh AA, and Diehn M. Detecting liquid remnants of solid tumors: circulating tumor DNA minimal residual disease. Cancer Discovery. (2021) 11:2968–86. doi: 10.1158/2159-8290.CD-21-0634

PubMed Abstract | Crossref Full Text | Google Scholar

95. Martínez-Castedo B, Camblor DG, Martín-Arana J, Carbonell-Asins JA, García-Micó B, Gambardella V, et al. Minimal residual disease in colorectal cancer. Tumor-informed versus tumor-agnostic approaches: unraveling the optimal strategy. Ann Oncol. (2025) 36:263–76. doi: 10.1016/j.annonc.2024.12.006

PubMed Abstract | Crossref Full Text | Google Scholar

96. Zhong R, Gao R, Fu W, Li C, Huo Z, Gao Y, et al. Accuracy of minimal residual disease detection by circulating tumor DNA profiling in lung cancer: a meta-analysis. BMC Med. (2023) 21:180. doi: 10.1186/s12916-023-02849-z

PubMed Abstract | Crossref Full Text | Google Scholar

97. Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discovery. (2017) 7:1394–403. doi: 10.1158/2159-8290.CD-17-0716

PubMed Abstract | Crossref Full Text | Google Scholar

98. Gale D, Heider K, Ruiz-Valdepenas A, Hackinger S, Perry M, Marsico G, et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer. Ann Oncol. (2022) 33:500–10. doi: 10.1016/j.annonc.2022.02.007

PubMed Abstract | Crossref Full Text | Google Scholar

99. Reck M, Gale D, Harpole D, Taube JM, Mitsudomi T, Hochmair MJ, 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. doi: 10.1016/j.annonc.2023.10.055

Crossref Full Text | Google Scholar

100. Wakelee H, Reck M, Felip E, Altorki NK, Vallieres E, Liersch R, et al. 1211P IMpower010: ctDNA status and 5y DFS follow up in patients (pts) with resected NSCLC who received adjuvant chemotherapy (chemo) followed by atezolizumab (atezo) or best supportive care (BSC). Ann Oncol. (2024) 35:S779–80. doi: 10.1016/j.annonc.2024.08.1270

Crossref Full Text | Google Scholar

101. Qiu B, Guo W, Zhang F, Lv F, Ji Y, Peng Y, et al. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun. (2021) 12:6770. doi: 10.1038/s41467-021-27022-z

PubMed Abstract | Crossref Full Text | Google Scholar

102. Tran HT, Heeke S, Sujit S, Vokes N, Zhang J, Aminu M, 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. doi: 10.1016/j.annonc.2023.11.008

PubMed Abstract | Crossref Full Text | Google Scholar

103. United States Food and Drug Administration and Oncologic Drugs Advisory Committee (ODAC) Meeting. Combined FDA and applicant ODAC briefing document (2024). Available online at: https://www.fda.gov/media/180242/download (Accessed April 16, 2025).

Google Scholar

104. European Thoracic Oncology Platform (ETOP)–International Breast Cancer Study Group (IBCSG). 25-23 ADOPT-lung: an international, multicentre, open-label randomised phase III trial to evaluate the benefit of adding adjuvant durvalumab after neoadjuvant chemotherapy plus durvalumab in patients with stage IIB-IIIB (N2) resectable NSCLC (2024). Available online at: https://www.etop.ibcsg.org/projects/clinical-trials/open-trials/25-23-adopt-lung (Accessed April 16, 2025).

Google Scholar

105. Eberhardt WE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol. (2015) 26:1573–88. doi: 10.1093/annonc/mdv187

PubMed Abstract | Crossref Full Text | Google Scholar

106. Zhang C, Chen H-F, Yan S, Wu L, Yan L-X, Yan X-L, et al. Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: a multicenter pooled analysis. NPJ Precis Oncol. (2022) 6:66. doi: 10.1038/s41698-022-00301-8

PubMed Abstract | Crossref Full Text | Google Scholar