Neoadjuvant therapy in early-stage non-small cell lung cancer—pros, cons and future promise: a narrative review

Introduction

Background

Lung cancer is the most common cancer diagnosed worldwide, as well as the leading cause of cancer-related deaths (1). In the United States (US), lung cancer carries a 1.4 to 2.2-fold higher rate of mortality compared to the second ranked (breast in women, prostate in men) and third ranked (colorectal in men, pancreas in women) cancers (2). Advancements in prevention strategies have led to a steady decline in disease incidence in developed countries. Increased access to low-dose computed tomography (CT) imaging and implementation of screening guidelines has enhanced early nodule detection and resulted in decreased mortality from lung cancer in appropriately screened patients by over 20% (3). However, recent data suggests that in the US only 4.5% of those eligible for annual screening with low-dose chest CT underwent imaging in 2022 (3). Not surprisingly, the impact of screening on overall lung cancer mortality in the US has remained modest, and most patients are still diagnosed at a late stage (regional metastasis 22% and distant 44%), when curative treatment options are limited (4,5). Moreover, overall global disease burden continues to rise with increasing rates in females, nonsmokers, and younger patients (6,7).

Lung cancer is an extraordinarily heterogeneous disease, which is broadly classified as either small cell lung cancer (SCLC), accounting for approximately 15% of lung cancers, or non-small cell lung cancer (NSCLC), comprising the remaining 85% (8). NSCLC is further subclassified by histologic subtypes, which have differing prognoses and varying responses to treatment modalities. Surgery continues to afford the best opportunity for long-term survival in NSCLC and achieves the greatest impact in early-stage disease with some reports of up to 95% and 93% overall survival (OS) at 5 years for stage IA1 and IA2 disease, respectively (9,10). Unfortunately 30–55% of patients with resected NSCLC develop recurrent, and often distant metastatic disease, despite curative surgery (11,12). Prognosis is poor for those with recurrent disease, contributing to a cancer-specific survival of 74% and OS of 58% for patients with early stage 1A NSCLC at 10 years after curative lobectomy (12-14).

Rationale and knowledge gap

Given the propensity for high OS rates for early stage I and II disease, the search for a solution to reduce disease recurrence and provide sustainable survival outcomes in critical. To mitigate the risk of recurrence in early-stage, resectable NSCLC, strategies utilizing neoadjuvant induction or adjuvant systemic therapy have been employed. Neoadjuvant therapy can achieve this by reducing tumor burden or minimizing micro-metastases prior to attempted curative resection. In contrast, adjuvant therapy aims to achieve this by eradicating potential minimal disease remaining after surgical resection. Radiation has been studied as an adjunct therapy and is currently utilized primarily in cases of positive margins or as local therapy when no surgical resection is planned. The systemic therapy that is most commonly used and most studied is chemotherapy, which is overwhelmingly comprised of platinum-based chemotherapy. There is no consensus regarding timing of administration of chemotherapy and providers have historically favored adjuvant therapy due to availability of long-term outcomes data (15-18).

In recent years, developments in immunotherapy have revolutionized the management of NSCLC in the metastatic setting and improved both disease-free survival (DFS) and OS (19). Immunotherapy has now moved to earlier stage settings where data continues to mature but improvements in event-free survival (EFS), DFS and OS have now been appreciated. Furthermore, great advancements have been made in precision medicine. In 2017, the National Comprehensive Cancer Network (NCCN) guidelines began recommending broad panel-based biomarker testing for all patients presenting with stage IV non-squamous NSCLC. Indications later expanded in 2021 to include consideration for those with squamous cell cancer (SCC), as well as those with stage IB–IIIA disease (20). Tyrosine kinase inhibitors (TKIs) targeting a variety of actionable genomic alterations (AGAs) have shown significant promise in improving progression-free survival (PFS) and OS in metastatic NSCLC (21). These therapies are now being evaluated in earlier stage disease, with studies showing benefit with both EGFR and ALK mutation targeting TKIs (22-24). As molecular testing modalities continue to improve, initiatives for more comprehensive screening for AGAs are undertaken, and new Food and Drug Administration (FDA)-approved therapies for actionable driver mutations (i.e., NGR1 gene fusions) are identified, prognosis in NSCLC will undoubtedly be extended significantly in the coming years (6,25).

Objective

With the aforementioned advances in systemic therapies, oncologists have been provided new opportunities to address resectable lung cancer and have raised new discussions regarding what the optimal treatment may be for limited stage disease and the role of a multimodal approach. Despite a well-established consensus supporting neoadjuvant therapy in stage III disease, its utility in early-stage I–II NSCLC remains less defined (26). In this review, we discuss the advantages, disadvantages, and current state of neoadjuvant therapy specifically in potentially curable early-stage I and II NSCLC. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-36/rc).

Methods

The PubMed database of the National Library of Medicine at the National Institutes of Health and the ClinicalTrials.gov database were queried on June 10, 2025 by all three authors to identify pertinent studies and clinical trials, and the relevant findings and information summarized (Table 1). Early-stage lung cancer was defined as those with resectable stage I–II disease primarily as defined by the American Joint Committee on Cancer (AJCC) 8th edition staging guidelines as most neoadjuvant trials were conducted after transition to 8th edition staging (27). Limited studies including early-stage disease as defined by AJCC 6th and 7th edition guidelines were also included and are identified accordingly. The primary notable change relevant to this review between editions was the transition of tumors >4 cm, N0 from stage Ib to stage II disease classification with the 8th edition. Of note, as neoadjuvant therapy historically has been studied in patients with borderline resectable stage III disease, and this cohort is therefore often included with early-stage patients in modern trials. To provide a comprehensive review of the current literature, these studies are included however the primary objective of this study is focused on identifying and discussing outcomes specifically pertaining to early stage I–II disease.

Once the articles were retrieved from each database, all three reviewers independently reviewed the article titles and abstracts if necessary to determine topic relevance. Articles approved by all three reviewers were selected for full-text review. Articles with two or more “no” votes were eliminated from further review. Articles with one “no” vote were discussed all reviewers until a consensus was reached regarding its eligibility for full-text review. All three authors then again independently assessed during the full-text studies according to the predefined criteria (Table 1) to determine eligibility for the narrative review. Discrepancies were discussed by all reviewers until a consensus reached.

Advantages of neoadjuvant therapy

Neoadjuvant therapy is systemic therapy given prior to surgical intervention. Neoadjuvant therapy has various advantages over adjuvant therapy: reduction of disease burden prior to definitive surgical intervention, early assessment of tumor response, flexibility in therapy timing, and improvement of regimen adherence and potentially, response.

Neoadjuvant therapy addresses tumor burden in both microscopic and macroscopic levels of disease. Micro-metastatic disease, small amounts of cancer or viable cancer cells shed from the primary malignancy that cannot be appreciated via standard imaging techniques, is believed to lead to underestimation of disease burden and thought to be a major source of recurrence of lung cancer. This type of disease is not amenable to treatment by local therapies directed at gross disease and requires systemic therapy for treatment. Addressing this source of tumor spread is thought to decrease rates of recurrence or disease progression. Recently published studies by Fang et al. and Schmid et al. evaluating recurrence in stage IIIA disease after neoadjuvant therapy and resection suggest a pattern of increased locoregional rather than distant recurrence. These findings support the potential role of neoadjuvant therapy in addressing micro-metastatic disease, though further studies will be required to definitively prove this hypothesis, and particularly in early-stage disease (28,29).

On a macroscopic level, neoadjuvant therapy can decrease tumor burden and help limit the size of resection needed, improve margins of resection, or downstage a previously inoperable tumor to a resectable one. Multiple studies have affirmed that a lower stage translates to improved survival for NSCLC (25,28). Patients with limited stage I or II disease have been shown to have a 34-month survival benefit over those with more advanced stage III disease (28,29). To date, the efficacy of neoadjuvant chemotherapy in downstaging NSCLC has predominantly been studied in the context of borderline resectable locally advanced stage III disease (30,31). In this context, previous studies have found rates of mediastinal downstaging of 20–40% after neoadjuvant chemotherapy alone, and 40–65% with the addition of radiotherapy. It must be noted that the addition of radiotherapy did not translate to improved PFS (32). The utility of neoadjuvant chemotherapy in early-stage I to II disease, however, is much less well-defined (33).

With the addition of neoadjuvant immunotherapy to chemotherapy, the downstaging effect has been noted to be more marked. While inflamed tumors [high expression of programmed death ligand-1 (PD-L1) or tumor-infiltrating immune cells] are associated with improved response to check-point inhibitor therapies, a large proportion (>50%) of NSCLC are unfortunately are unresponsive. Emerging studies suggest this may be due in part to the complex relationship between multiple other drivers of cancer immunity including biomarkers other than PD-L1 and for genomic instability (defined by microsatellite instability or tumor mutational burden) (34). As such, many of the emerging neoadjuvant trials have focused on harnessing the synergistic effects of combination chemoimmunotherapy to amplify immune antitumor responses. The exact mechanism by which combined chemoimmunotherapy enhances tumor immunogenicity in the neoadjuvant setting for NSCLC remains under investigation. Furthermore, the therapeutic efficacy. Proposed mechanisms include chemotherapy-induced increases in tumor immune lymphocyte infiltration, activation of tumor-specific T-cells, and depletion of immunosuppressive cells to alter the tumor immune microenvironment and augment function of immunotherapies (35-37).

While not the intended primary endpoint, subgroup analysis of patients with resected stage Ib-II disease (AJCC 7th edition) in Checkmate-816 showed both improved pathologic complete response (pCR) from 2% with chemotherapy to 24% with chemoimmunotherapy and decreased median residual viable tumor from 70% to 28% respectively (38). Furthermore, patients with lymph node involvement and pCR in those nodes at surgery had comparable survival to those without baseline lymph node involvement (39). Other chemoimmunotherapy trials have also shown improved pCR and are further discussed below. Although these factors play a less clear role in treating limited early-stage disease, notable rates of occult lymph node positive disease, larger early-stage tumors, and high rates of recurrence even in early-stage disease have raised interest in extrapolating from this data to improve outcomes in early-stage disease.

Neoadjuvant therapy also creates an opportunity for earlier intervention, as well as increased time for preoperative work up and optimization. Lung cancer has traditionally had one of the longest median times to treatment as compared to other cancers, at 35 days (40,41). Delayed time to surgery in early-stage NSCLC has been associated with increased risk of upstaging, 30-day mortality, disease recurrence, and decreased median survival (42-45). A recent 2025 study demonstrated median time to surgery in the US is 57 days with worse 5-year mortality (HR 1.19) and higher rate of 1-year recurrence (HR 1.25) for surgeries delayed greater than 8 weeks (46). Reasons for delays in time to surgery are multifactorial. Socioeconomic factors such as insurance status and black race have been associated with prolonged time to treatment. Clinical factors including higher clinical stage with need for invasive mediastinal staging or preoperative medical oncology consult, impaired pulmonary function, older age, history of COPD or stroke, smoking cessation, and cardiac clearance have been associated with prolonged time to treatment as well (47-50). While there is no literature to date comparing time to neoadjuvant therapy in early stage, resectable NSCLC, time to initiating non-surgical therapy is anecdotally more expedient and may be an attractive option for those with complex co-morbidities or more advanced disease.

Additional time from diagnosis to surgery for patients undergoing neoadjuvant therapy also allows for preoperative preparation. Most patients with lung cancer have a strong history of smoking, which can often be seen with many other comorbid conditions. Neoadjuvant therapy increases the preoperative timeframe during which active smokers can be optimized with smoking cessation tools, as studies have shown that even a few weeks of smoking cessation can drastically decrease postoperative complications (51). Lifestyle and medical modifications for those with diabetes can be pursued to optimize glycemic control. Furthermore, standard cardiac work up can be performed with no delay to initiation of cancer-directed treatment.

Earlier studies comparing neoadjuvant and adjuvant chemotherapy regimens, which were predominately indirect comparison metanalyses, have demonstrated comparable oncologic outcomes. In a metanalysis by Lim et al. of 32 randomized control trials, no difference in OS and DFS between neoadjuvant and adjuvant administration of chemotherapy was appreciated (18). These studies did, however, reveal significant improvement in patient compliance of up to 97% with neoadjuvant chemotherapy regimens compared to 66% with adjuvant therapy, suggesting that neoadjuvant chemotherapy may be easier to tolerate and complete than adjuvant therapy (18). Fewer grade 3 or higher adverse events (G ≥3 AEs) were also reported and may have also contributed to increased patient adherence (15,18). The NATCH trial was a prospective phase 3 randomized study that compared neoadjuvant chemotherapy followed by resection, resection alone, and adjuvant chemotherapy in stage I–II disease (AJCC 6th edition). This study also showed no statistically significant difference in DFS or OS among the three study arms. Notably 90.7% of those in the neoadjuvant arm completed the planned three cycles of the carboplatin/paclitaxel doublet compared to only 60.9% in the adjuvant arm. The lack of an appreciable difference in outcomes with the addition of chemotherapy to resection alone may have been influenced by a variety of factors, including the use of carboplatin (instead of cisplatin), the pairing of paclitaxel for all histologic subtypes, and the use of three cycles compared to the accepted current standard of four (52). At this time, there remains no consensus regarding the timing of administering chemotherapy when utilized as monotherapy. Improved patient compliance and tolerance of therapy in the neoadjuvant setting, may perhaps translate to improved patient satisfaction, though in recent years chemotherapy has been utilized more so in the adjuvant setting.

Publication of studies investigating neoadjuvant, perioperative, and adjuvant immunotherapy or combination chemoimmunotherapy are beginning to mature. While neoadjuvant and perioperative chemoimmunotherapy approaches have been shown to be effective, no phase 3 direct studies comparing neoadjuvant chemoimmunotherapy to adjuvant chemoimmunotherapy have been performed leaving the question of ideal timing of therapy unanswered. One study that sought to address these questions is a large retrospective study by Ghelani et al. which utilized the National Cancer Database to compare neoadjuvant and adjuvant chemoimmunotherapy in patients with stage I–III NSCLC and found improved 2- and 5-year OS of 77.9% and 68.8% respectively compared to 68.7% and 42.8% with adjuvant therapy (53). Another recent study by Desai et al. comparing clinical outcomes in stage II–IIIA NSCLC found similar distant metastasis-free survival (DMFS) of 80% and 83% with neoadjuvant and adjuvant chemoimmunotherapy respectively (54). Although not commonly used in lung cancer literature, DMFS has been validated as a surrogate marker for OS in other cancers. As such, DMFS may represent another prospective marker in future studies to measure the success of perioperative therapy in reducing micrometastatic disease (55).

Neoadjuvant therapy also offers potential prognostic benefits over adjuvant therapy as it allows for pathologic evaluation of effect of treatment at the time of surgery. This can help assess patient tumor biology, direct future systemic therapy and can also allow for more rapid assessment of drug development by allowing short course pathologic evaluation of treatment effect (31). The ability to assess tumor response after neoadjuvant therapy affords valuable insight into treatment efficacy prior to surgical resection and can impact choice of adjuvant therapy per physician discretion. While long-term OS remains the principal benchmark for evaluating treatment success, the era of neoadjuvant therapy has highlighted the need for surrogate markers. Histopathological complete response (pCR), major pathologic response (MPR), and radiographic tumor response as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria are currently the main surrogate prognostic endpoints for disease recurrence and survival currently in use (31,39,56,57). pCR has been found to be prognostic but has not been definitively validated as a surrogate marker for long-term outcomes in clinical trials of NSCLC. While pCR holds promise to influence patient management and adjuvant therapy selection, this has not yet become a standard of care and is not advocated by regulatory bodies.

Another theoretical benefit of neoadjuvant therapy is the improved response of immunotherapy in a neoadjuvant compared to the adjuvant setting. Studies in several malignancies, particularly melanoma, have shown improved response to immunotherapy in a neoadjuvant setting. This is thought to be due to the presence of the primary tumor increasing the immune system sensitization and therefore yielding improved response (58). Though this remains under study in NSCLC and other malignancies, it raises the question of importance of timing of immunotherapy and is something we may see play a role in early-stage disease treatment in years to come.

Disadvantages to neoadjuvant therapy

Disadvantages to neoadjuvant therapy exist as well and should be considered in designing treatment regimens. Neoadjuvant therapy can delay definitive surgical intervention, create the risk of tumor progression or upstaging when neoadjuvant therapies are not effective, can have therapeutic adverse effects both pre- and intra-operatively and is not suitable for all patients. Furthermore, given the relative recent advent of neoadjuvant therapy, studies are still underway to evaluate the utility of biomarkers such as PD-L1 status, LDH, tumor mutational burden, genetic alterations, and ctDNA in predicting treatment efficacy and facilitate designing an optimal neoadjuvant regimen (59,60). While there is expert consensus for treatment of more advanced stages of resectable disease, such as those with stage IIIA or IIIB NSCLC, strongly supporting utilization of neoadjuvant chemoimmunotherapy (in patients without contraindications), expert opinion varies considerably as to whether neoadjuvant therapy should be pursued for the stage II patients over up front surgical resection with adjuvant treatment (26).

Standard neoadjuvant therapy regimens vary in length, but all potentially create delays to definitive surgical intervention. Standard regimens include 3–4 cycles of treatment over several weeks/months which are followed by reimaging and generally 4–6 weeks off of treatment prior to surgical resection. During this time, any patient toxicities from therapy, progression of disease or major adverse events can result in delay of or cancellation in surgical resection. In several of the major chemoimmunotherapy trials utilizing neoadjuvant or perioperative therapy, surgery was found to be cancelled in 16–22% of patients, with 2.5–8.8% cancelled due to progression of disease (where evaluated) and the remainder cancelled for patients becoming unfit for surgery, adverse events or other reasons (61).

Adverse events leading to subsequent delays in surgical interventions can be seen in both neoadjuvant chemotherapy and neoadjuvant chemoimmunotherapy. Rates of significant grade 3–4 adverse events from neoadjuvant chemoimmunotherapy have been reported in 22–63% of patients (61). While combination chemoimmunotherapy has been associated with higher rates of G ≥3 AEs when compared to chemotherapy in the adjuvant setting, this trend doesn’t seem to be replicated in the neoadjuvant setting (62,63). A 2024 meta-analysis by Wu et al. comparing neoadjuvant chemoimmunotherapy with neoadjuvant chemotherapy showed a similar G ≥3 AE toxicity rate of 18% [odds ratio (OR) 1.01, 95% confidence interval (CI): 0.67–1.52, P=0.97] but improved pCR rates (OR 7.63; 95% CI: 4.49–12.97, P<0.001), PFS [hazard ratio (HR) 0.51; 95% CI: 0.38–0.67, P<0.001], and OS (HR 0.51, 95% CI: 0.36–0.74, P<0.001) with neoadjuvant chemoimmunotherapy compared to neoadjuvant chemotherapy alone (64). Of note, the phase 3 Checkmate 816 trial (included in Wu’s metanalysis) showed similar adverse effects (AE) rates (34% G ≥3 AEs) with chemoimmunotherapy compared to chemotherapy alone without impacting rate of progression to surgery (38,65,66).

Response to neoadjuvant therapy can sometimes be unclear on restaging. Correlation between noninvasive imaging and histopathologic complete response is highly variable and discordance rates of up to 41% have been reported with both CT and positron emission tomography (PET) (67,68). Furthermore, restaging after immunotherapy has proven particularly challenging as tumor response to immunotherapy can have a delayed response, show hyperprogressive disease, or demonstrate pseudoprogression due to tumor infiltration by immune cells thereby causing an enlarged appearance on imaging. These challenges have led to interest in how to best assess clinical response following neoadjuvant therapy. Modified immune-related imaging criteria are being investigated including immune-related response evaluation criteria in solid tumors (irRECIST), immune response evaluation criteria in solid tumors (iRECIST), and immune-modified response evaluation criteria in solid tumors (imRECIST), and further studies correlating these criteria to disease survival are needed (69). Disease restaging after induction therapy with repeat imaging, generally with contrasted CT of the chest, is performed. If no signs of progressive disease, resection is performed at least 4 weeks following and ideally within 6–8 weeks after completion of treatment. In recent years, studies have also investigated restaging after neoadjuvant therapy with PET-CT and demonstrated improved pathologic concordance, overall response rate, and PFS when utilizing metabolic over morphologic criteria to evaluate therapeutic response (70-72).

Additionally, neoadjuvant therapy can increase the technical difficulty of surgical resection. Anecdotally, many thoracic surgeons feel that chemotherapy or chemoimmunotherapy increases the technical difficulty of surgical resection, though studies investigating this concern have had mixed results (61,73-75). Increased difficulty is thought to be due to inflammation and fibrosis resultant from neoadjuvant treatment that can make resection more challenging. Individual studies and reports have described more difficult resections, higher rates of conversion from minimally invasive to a thoracotomy approach and higher rates of postoperative complications and mortality in patients receiving neoadjuvant chemoimmunotherapy (61,76). When compared to no neoadjuvant treatment, larger studies and metanalyses suggest that there are higher rates of cardiopulmonary complications, ICU needs and transfusion support in patients receiving neoadjuvant therapy but no difference in overall mortality (77,78). When looking at neoadjuvant chemoimmunotherapy vs. chemotherapy no difference in complications has been seen in metanalysis (79).

Perioperative therapy

Selection of perioperative therapy has evolved greatly throughout the years and NCCN guidelines for NSCLC now separate candidates for immunotherapy from those that are not candidates. Patients with EGFR or ALK oncogenic driver mutations are generally not deemed candidates for neoadjuvant immunotherapy as immunotherapy is less effective in this group and can increase the risk of pneumonitis if given before TKI (80). Phase 3 trials regarding TKIs targeting RET or ROS1 mutations are ongoing and NCCN guidelines categorize them as possible contraindications to immunotherapy at this time. Additionally, history of autoimmune disease or immunosuppression are considered relative contraindications and varies depending on severity of autoimmune disease and clinician evaluation of risk (81). Candidates with indications for neoadjuvant immunotherapy are treated with a combination of chemotherapy and immunotherapy while patients with contraindications to immunotherapy are treated with chemotherapy alone.

Chemotherapy

Chemotherapy is the systemic therapy most studied and of longest use in the treatment of lung cancer. Generally, NSCLC is treated with a platinum-based doublet chemotherapy, though this can vary by regimen and by patient needs. Many studies were performed through the 1990’s and early 2000’s to evaluate the effectiveness of adjuvant chemotherapy on lung cancer of all stages. One of the biggest analysis, the LACE pooled analysis, gathered 5 of the largest trials from this analysis and pooled 4,584 patients for evaluation. They found an absolute OS benefit of 5.4% from the addition of chemotherapy. They found these results to be more pronounced for stages II–III, and that chemotherapy was not beneficial for stage IA (HR =1.40; 95% CI: 0.95–2.06) and for IB (HR =0.93; 95% CI: 0.78–1.10), suggesting chemotherapy for stage I disease is of questionable benefit or harm (82). Of note this study and its contemporary studies, were performed under older staging paradigms and under AJCC 8th edition NSCLC staging criteria stage IB >4 cm would be classified as stage II disease. However, The CLAGB-9633 trial found benefit in OS and DFS for adjuvant chemotherapy in stage IB (AJCC 7th edition) patients with >4 cm tumors (83). Current guidelines include consideration of adjuvant chemotherapy for stage IB (AJCC 8th edition) disease with high-risk features, such as poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural involvement or unknown lymph node status (81).

The NSCLC Meta-analysis Collaborative Group performed a metanalysis of 15 randomized control trials investigating the use of neoadjuvant chemotherapy for NSCLC comprising 2,385 patients and found a 13% reduction in relative risk of death and a 5% absolute survival improvement at 5 years. Of these patients studied, about 50% had stage I disease (6% IA, 43% IB), 27% stage II disease and the remainder stage III–IV. 5% absolute survival benefit was found for stage I disease (50% to 55%) and stage II disease (30% to 35%) (84).

Immunotherapy and targeted therapies

In recent years, studies have shifted focus to the promise of immunotherapy and targeted therapies given their great success in advanced or metastatic NSCLC disease. Investigations into the role of immunotherapy in early-stage disease are ongoing.

When given in the neoadjuvant setting, the proposed benefit of immunotherapy lies in the elimination of micro-metastatic disease to reduce risk of disease recurrence. Immune checkpoint inhibitors (ICIs) act to prime and enhance the body’s adaptive immunologic response prior to surgery-induced pro-metastatic changes. By targeting and disrupting inhibiting signaling cascades, ICIs reactivate the host’s immune system to target and eliminate tumor cells. Furthermore, when given in the neoadjuvant setting prior to surgical disruption of tissue and lymphatics, animal studies have shown that the presence of intact lymph nodes and tumor acts to further bolster the immune response. Especially in early-stage disease where tumors are often less heterogenous and host immunity is more robust, having an in situ tumor during treatment enhances release of neoantigens and primes the immune system to expand activation of cytotoxic T-cells, and this has been associated with reduced recurrence and improved survival (85-87).

Forde et al. published one of the first studies in 2018 demonstrating feasibility and improved efficacy of administering neoadjuvant ICI nivolumab compared to chemotherapy in stage I to IIIA disease (88). Subsequent phase 2 studies including NeoCOAST (durvalumab vs. durvalumab + oleclumab/monalizumab), NEOSTAR (nivolumab vs. nivolumab + ipilimumab), and LCMC3 (atezolizumab) trials have not only reaffirmed these findings, but have also shown improved outcomes with ICIs when given as either mono- or dual-ICI therapy in stage I to IIIA disease compared to neoadjuvant chemotherapy (66,89,90) (Table 2). Forde et al. later published the groundbreaking CheckMate 816 study in 2022, which was the first and largest phase 3 trial to date which demonstrated significantly improved EFS and an increased pCR to 24% from 2.2% with combination neoadjuvant chemoimmunotherapy (nivolumab + platinum doublet chemotherapy) compared to chemotherapy alone in resectable stage IB (AJCC 7th edition) to IIIA disease (38). The recently published June 2025 planned analysis of OS in the Checkmate 816 cohort reaffirmed more favorable outcomes with combination chemoimmunotherapy compared to chemotherapy alone. An improved overall 5-year survival of 65.4% in contrast to 55% with chemotherapy alone was reported. This was the first and only solely neoadjuvant chemoimmunotherapy trial to date to have a statistically significant improvement in OS. Those with pCR showed a great and long-lasting response, with a 5-year OS of 95.3% (85). These effects were less pronounced in stage IB/II disease where pCR was found to be 26.2% in the chemoimmunotherapy group vs. 4.2% in the chemotherapy group, but EFS was not found to be significantly improved (38).

Additional RCTs have been performed which have also shown great promise for ICI as perioperative treatment. Early studies investigated the administration of chemoimmunotherapy in the neoadjuvant setting and continuation of immunotherapy alone in the adjuvant setting. As there are no phase 3 direct studies comparing neoadjuvant chemoimmunotherapy to perioperative chemoimmunotherapy, the efficacy and need for adjuvant immunotherapy alone is unclear (91,92). Subsequent studies have focused on perioperative administration of chemoimmunotherapy in perioperatively. There are three major studies investigating this: CheckMate 77T (AJCC 8th edition) studied nivolumab and platinum doublet chemotherapy, AGEAN (AJCC 8th edition) studied durvalumab and platinum doublet chemotherapy and Keynote 671 (AJCC 8th edition) studied pembrolizumab and platinum chemotherapy. These studies, among others, all found improved rates of EFS and pCR in the chemoimmunotherapy arms of their studies (93-95). Keynote-671 became the first and only phase 3 perioperative chemoimmunotherapy study to date to appreciate a statistically significant improvement in OS data at the protocol-specified first interim analysis. Median OS was not reached (NR) in the perioperative chemoimmunotherapy arm and 52.4 months with HR 0.72 (95% CI: 0.56–0.93; P=0.005). Data is still maturing in AGEAN and CheckMate 77T, and other studies are ongoing. Additionally, studies are underway investigating neoadjuvant immunotherapy alone, which show promise as well (Table 2). With regards to early-stage disease, the role for neoadjuvant immunotherapy is less clear. Studies largely have not addressed if there is a role for immunotherapy in stage I disease, resting on earlier chemotherapy studies showing no benefit or sometimes harm in this group. As for stage II disease, Checkmate 816, CheckMate 77T, AGEAN, Rationale 315 (AJCC 8th edition) all show drastic improvements in pCR over chemotherapy alone (21–38% vs. 3–5% for chemo alone) (85,94-96). EFS was also seen to be significantly improved in Keynote-671 and Rationale 315 for stage II disease but was not significant in this group in the other evaluated studies. Of note, many of these studies median EFS was not reached in the earlier group of patients with stage I/II disease, so longer follow up may be needed to assess for true effect of treatment.

Targeted therapies have also demonstrated great success in patients with actionable oncologic driver genomic mutations. While the list of driver mutations continues to grow, the most common mutations studied and targeted in NSCLC include EGFR and ALK. The ADAURA trial, first published in 2020, was a phase III trial which demonstrated marked improvement in DFS at 3 years with adjuvant Osimertinib compared to placebo (utilization of chemotherapy was per treating physician discretion) in patients with common EGFR mutations (L858R or Exon 19 deletions) (22). Subsequent long-term analysis confirmed an improved 5-year OS of 88% with osimertinib compared to 78% in the placebo arm (22,97). Similarly, the ALINA trial demonstrated significantly improved DFS with adjuvant alectinib in resected stage IB (tumors ≥4 cm) to IIIA disease compared to cisplatin-based chemotherapy (98). The efficacy of these targeted therapies in early-stage, resectable NSCLC has primarily been established in the adjuvant setting and again raised the question of whether applications of these therapies in the neoadjuvant setting could have similar outcomes. The recently published results of the 2025 NeoADURA trial has preliminary shown significant improvement in major pathologic response (MPR) rate of 25–26% with use of osimertinib as monotherapy or in conjunction with chemotherapy compared to placebo of 2% (OR 19.82 and 19.28 respectively). EFS was not found to be significantly improved (99). Investigations of neoadjuvant targeted therapies are still early and optimal timing of therapy, duration of treatment, and long-term outcomes—particularly patient OS, remain unclear. Moreover, its role in early-stage disease will be elucidated as data ongoing clinical trials become available.

Strengths, limitations, and future perspectives

The strength of this article derives from the quality and strength of the evidence reviewed by focusing on large-scale and primarily phase III studies clinical trials. Additionally, the authors of this review provide comprehensive input from both a medical and surgical oncology perspective. This review is limited by the lack of data specifically pertaining to early stage I–II disease. Many of the emerging neoadjuvant studies, however, focus on resectable disease which includes stage III disease. In this review, most of the studies evaluated this article include patients with stage III disease with few reporting separate findings for early stage I–II disease specifically. As such, the conclusions of this review are extrapolated from pooled stage I–III data and limits its specificity. Data from these trials also continue to mature and therefore precludes our ability to comment on long-term outcomes including recurrence, mortality, or long-term survival, mortality. Furthermore, therapeutic agents and treatment strategies have also evolved rapidly in the past two decades therefore results from earlier trials, while important for advancing the field, may have limited application as newer results become available. This field is under constant flux and further phase III studies are needed to validate and delineate the appropriate patient populations who may benefit from neoadjuvant therapy over upfront surgical resection specifically in early-stage I and II NSCLC.

Conclusions

NSCLC, even when early-stage and resectable, unfortunately continues to have high recurrence rates. Neoadjuvant therapy in early-stage NSCLC is a promising treatment approach to improve outcomes by upfront treatment of micro-metastatic disease, immune system sensitization with an intact primary tumor, decreased tumor burden prior to resection, and decreased time to treatment initiation. With the advent of newer immunotherapies and targeted therapies, the therapeutic paradigm has shifted to demonstrate a potential larger benefit to utilizing neoadjuvant treatment in many cases of NSCLC with several phase II and II trials showing favorable outcomes in early stage I and II disease. Despite these advantages, several challenges including accurately assessing clinical response, determining optimal duration of therapy, and minimizing post-treatment adverse effects and delays to surgery remain. At present, this review suggests that neoadjuvant therapy should be contemplated in all patients with early-stage, resectable disease. Particular consideration should be given to those with larger or higher risk tumors or who need medical optimization, especially if tumor molecular analysis predicts high likelihood of response to therapy. Individualized treatment plans should be made on a patient by patient basis and ideally with a multidisciplinary team and that team should reconvene after surgery to discuss consideration of additional treatment and surveillance plans.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Taryne A. Imai) for the series “Revolutionizing Lung Cancer Care with Technological Advancements” published in Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-36/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-36/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-36/coif). The series “Revolutionizing Lung Cancer Care with Technological Advancements” was commissioned by the editorial office without any funding or sponsorship. L.J.A. reports consulting fees from AccessHope, payment from OncLive, Dava Oncology and AJMC Institute for Value Based Medicine, and Stock or stock options of Revolution Medicine, Summit Therapeutics and ImmunityBio. The authors have no other conflicts of interest to declare.

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

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

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin 2025;75:10-45. [Crossref] [PubMed]
3. American Lung Association. State of Lung Cancer | Key Findings [Internet]. [cited 2025 Nov 25]. Available online: https://www.lung.org/research/state-of-lung-cancer/key-findings
4. CDC. Lung Cancer. 2025 [cited 2025 Dec 2]. Lung Cancer Statistics. Available online: https://www.cdc.gov/lung-cancer/statistics/index.html
5. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 2020;382:503-13. [Crossref] [PubMed]
6. Lu T, Yang X, Huang Y, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res 2019;11:943-53. [Crossref] [PubMed]
7. Ji Y, Zhang Y, Liu S, et al. The epidemiological landscape of lung cancer: current status, temporal trend and future projections based on the latest estimates from GLOBOCAN 2022. J Natl Cancer Cent 2025;5:278-86. [Crossref] [PubMed]
8. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011;32:605-44. [Crossref] [PubMed]
9. Postmus PE, Kerr KM, Oudkerk M, 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-iv21. [Crossref] [PubMed]
10. Wang C, Shao J, Song L, et al. Persistent increase and improved survival of stage I lung cancer based on a large-scale real-world sample of 26,226 cases. Chin Med J (Engl) 2023;136:1937-48. [Crossref] [PubMed]
11. Potter AL, Costantino CL, Suliman RA, et al. Recurrence After Complete Resection for Non-Small Cell Lung Cancer in the National Lung Screening Trial. Ann Thorac Surg 2023;116:684-92. [Crossref] [PubMed]
12. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res 2014;3:242-9. [Crossref] [PubMed]
13. Potter AL, Senthil P, Keshwani A, et al. Long-term Survival After Lung Cancer Resection in the National Lung Screening Trial. Ann Thorac Surg 2024;117:734-42. [Crossref] [PubMed]
14. Ma Z, Liu Y, Bao Y, et al. Impact of locoregional recurrence versus distant metastasis on overall survival in patients with Non-Small cell lung cancer after Surgery: A secondary analysis of PORT-C RCT. Lung Cancer 2025;199:108063. [Crossref] [PubMed]
15. Brandt WS, Yan W, Zhou J, et al. Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non-small cell lung cancer: A propensity-matched analysis. J Thorac Cardiovasc Surg 2019;157:743-753.e3. [Crossref] [PubMed]
16. Salvà F, Felip E. Neoadjuvant chemotherapy in early-stage non-small cell lung cancer. Transl Lung Cancer Res 2013;2:398-402. [Crossref] [PubMed]
17. Xi J, Du Y, Hu Z, et al. Long-term outcomes following neoadjuvant or adjuvant chemoradiotherapy for stage I-IIIA non-small cell lung cancer: a propensity-matched analysis. J Thorac Dis 2020;12:3043-56. [Crossref] [PubMed]
18. Lim E, Harris G, Patel A, et al. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol 2009;4:1380-8. [Crossref] [PubMed]
19. Desai A, Peters S. Immunotherapy-based combinations in metastatic NSCLC. Cancer Treat Rev 2023;116:102545. [Crossref] [PubMed]
20. Ettinger DS, Wood DE, Aisner DL, et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. J Natl Compr Canc Netw 2021;19:254-66. [Crossref] [PubMed]
21. Bouchard N, Daaboul N. Lung Cancer: Targeted Therapy in 2025. Curr Oncol 2025;32:146. [Crossref] [PubMed]
22. Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:1711-23. [Crossref] [PubMed]
23. Lu S, Kato T, Dong X, et al. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med 2024;391:585-97. [Crossref] [PubMed]
24. Solomon BJ, Ahn JS, Barlesi F, et al. ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 2019;37:TPS8569.
25. Yang CY, Lin YT, Lin LJ, et al. Stage Shift Improves Lung Cancer Survival: Real-World Evidence. J Thorac Oncol 2023;18:47-56. [Crossref] [PubMed]
26. Spicer JD, Cascone T, Wynes MW, 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. [Crossref] [PubMed]
27. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg 2018;155:356-9.
28. Patel P, Flores R, Alpert N, et al. Effect of stage shift and immunotherapy treatment on lung cancer survival outcomes. Eur J Cardiothorac Surg 2023;64:ezad203. [Crossref] [PubMed]
29. Jovanoski N, Bowes K, Brown A, et al. Survival and quality-of-life outcomes in early-stage NSCLC patients: a literature review of real-world evidence. Lung Cancer Manag 2023;12:LMT60. [Crossref] [PubMed]
30. Grant C, Hagopian G, Nagasaka M. Neoadjuvant therapy in non-small cell lung cancer. Crit Rev Oncol Hematol 2023;190:104080. [Crossref] [PubMed]
31. Kalvapudi S, Vedire Y, Yendamuri S, et al. Neoadjuvant therapy in non-small cell lung cancer: basis, promise, and challenges. Front Oncol 2023;13:1286104. [Crossref] [PubMed]
32. Martin LW, Mehran RJ. Perspectives on the effect of nodal downstaging and its implication of the role of surgery in stage IIIA (N2) non-small cell lung cancer. J Thorac Dis 2017;9:E646-52. [Crossref] [PubMed]
33. Song WA, Zhou NK, Wang W, et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 2010;5:510-6. [Crossref] [PubMed]
34. Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity 2020;52:17-35. [Crossref] [PubMed]
35. Chen T, Cao Z, Sun Y, et al. Neoadjuvant Chemoimmunotherapy Increases Tumor Immune Lymphocytes Infiltration in Resectable Non-small Cell Lung Cancer. Ann Surg Oncol 2023;30:7549-60. [Crossref] [PubMed]
36. Galluzzi L, Humeau J, Buqué A, et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 2020;17:725-41. [Crossref] [PubMed]
37. Chen H, Yang H, Guo L, et al. The Role of Immune Checkpoint Inhibitors in Cancer Therapy: Mechanism and Therapeutic Advances. MedComm (2020) 2025;6:e70412.
38. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
39. Deutsch JS, Cimino-Mathews A, Thompson E, et al. Association between pathologic response and survival after neoadjuvant therapy in lung cancer. Nat Med 2024;30:218-28. [Crossref] [PubMed]
40. Guirado M, Fernández Martín E, Fernández Villar A, et al. Clinical impact of delays in the management of lung cancer patients in the last decade: systematic review. Clin Transl Oncol 2022;24:1549-68. [Crossref] [PubMed]
41. Bilimoria KY, Ko CY, Tomlinson JS, et al. Wait times for cancer surgery in the United States: trends and predictors of delays. Ann Surg 2011;253:779-85. [Crossref] [PubMed]
42. Samson P, Patel A, Garrett T, et al. Effects of Delayed Surgical Resection on Short-Term and Long-Term Outcomes in Clinical Stage I Non-Small Cell Lung Cancer. Ann Thorac Surg 2015;99:1906-12; discussion 1913. [Crossref] [PubMed]
43. Cushman TR, Jones B, Akhavan D, et al. The Effects of Time to Treatment Initiation for Patients With Non-small-cell Lung Cancer in the United States. Clin Lung Cancer 2021;22:e84-97. [Crossref] [PubMed]
44. Mayne NR, Elser HC, Darling AJ, et al. Estimating the Impact of Extended Delay to Surgery for Stage I Non-small-cell Lung Cancer on Survival. Ann Surg 2021;273:850-7. [Crossref] [PubMed]
45. Heiden BT, Eaton DB Jr, Engelhardt KE, et al. Analysis of Delayed Surgical Treatment and Oncologic Outcomes in Clinical Stage I Non-Small Cell Lung Cancer. JAMA Netw Open 2021;4:e2111613. [Crossref] [PubMed]
46. Tupper HI, Sarovar V, Banks KC, et al. Time to surgery in early-stage non-small cell lung cancer: Defining the optimal diagnosis-to-resection interval to reduce mortality. J Thorac Cardiovasc Surg 2025;169:1563-1572.e5. [Crossref] [PubMed]
47. Ashrafi A, Ding L, Atay SM, et al. Delays to surgery and worse outcomes: The compounding effects of social determinants of health in non-small cell lung cancer. JTCVS Open 2023;15:468-78. [Crossref] [PubMed]
48. Tang A, Ahmad U, Raja S, et al. How Much Delay Matters? How Time to Treatment Impacts Overall Survival in Early Stage Lung Cancer. Ann Surg 2023;277:e941-7. [Crossref] [PubMed]
49. Maiga AW, Deppen SA, Pinkerman R, et al. Timeliness of Care and Lung Cancer Tumor-Stage Progression: How Long Can We Wait? Ann Thorac Surg 2017;104:1791-7. [Crossref] [PubMed]
50. Zhu J, Kantor S, Zhang J, et al. Timeliness of surgery for early-stage lung cancer: Patient factors and predictors. JTCVS Open 2024;19:325-37. [Crossref] [PubMed]
51. Mills E, Eyawo O, Lockhart I, et al. Smoking cessation reduces postoperative complications: a systematic review and meta-analysis. Am J Med 2011;124:144-154.e8. [Crossref] [PubMed]
52. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010;28:3138-45. [Crossref] [PubMed]
53. Ghelani G, Wong R, Graziano S, et al. Comparative Survival After Neoadjuvant vs Adjuvant Systemic Therapy in Resectable Stage II and Stage III Non-Small Cell Lung Cancer: A Retrospective Study Using the National Cancer Database. J Clin Oncol 2024;42:8075.
54. Desai A, Schwed K, Kalesinskas L, et al. Clinical Outcomes of Perioperative Immunotherapy in Resectable Non-Small Cell Lung Cancer. JAMA Netw Open 2025;8:e2517953. [Crossref] [PubMed]
55. Xie W, Ravi P, Buyse M, et al. Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer. Ann Oncol 2024;35:285-92. [Crossref] [PubMed]
56. Lococo F, Cesario A, Margaritora S, et al. Long-term results in patients with pathological complete response after induction radiochemotherapy followed by surgery for locally advanced non-small-cell lung cancer. Eur J Cardiothorac Surg 2013;43:e71-81. [Crossref] [PubMed]
57. Hellmann MD, Chaft JE, William WN Jr, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol 2014;15:e42-50. [Crossref] [PubMed]
58. Krishnamoorthy M, Lenehan JG, Maleki Vareki S. Neoadjuvant Immunotherapy for High-Risk, Resectable Malignancies: Scientific Rationale and Clinical Challenges. J Natl Cancer Inst 2021;113:823-32. [Crossref] [PubMed]
59. Ren S, Xu A, Lin Y, et al. A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future. Transl Lung Cancer Res 2021;10:3264-75. [Crossref] [PubMed]
60. Pradhan M, Chocry M, Gibbons DL, et al. Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer. Transl Lung Cancer Res 2021;10:590-606. [Crossref] [PubMed]
61. Ugalde Figueroa P, Lacroix V, Van Schil PE. Neoadjuvant Chemoimmunotherapy Complicates Subsequent Surgical Resection and Adjuvant Immunotherapy Is Preferable From the Surgical Standpoint. J Thorac Oncol 2024;19:858-61. [Crossref] [PubMed]
62. Takada K, Takamori S, Mizuki F, et al. Treatment-related adverse events of combination chemoimmunotherapy versus chemotherapy alone in first-line treatment for non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials. J Thorac Dis 2024;16:430-8. [Crossref] [PubMed]
63. Zhou Y, Chen C, Zhang X, et al. Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis. J Immunother Cancer 2018;6:155. [Crossref] [PubMed]
64. Wu Y, Verma V, Gay CM, et al. Neoadjuvant immunotherapy for advanced, resectable non-small cell lung cancer: A systematic review and meta-analysis. Cancer 2023;129:1969-85. [Crossref] [PubMed]
65. Liang W, Cai K, Cao Q, et al. International expert consensus on immunotherapy for early-stage non-small cell lung cancer. Transl Lung Cancer Res 2022;11:1742-62. [Crossref] [PubMed]
66. Cascone T, Kar G, Spicer JD, et al. Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. Cancer Discov 2023;13:2394-411. [Crossref] [PubMed]
67. de Cabanyes Candela S, Detterbeck FC. A systematic review of restaging after induction therapy for stage IIIa lung cancer: prediction of pathologic stage. J Thorac Oncol 2010;5:389-98. [Crossref] [PubMed]
68. William WN Jr, Pataer A, Kalhor N, et al. Computed tomography RECIST assessment of histopathologic response and prediction of survival in patients with resectable non-small-cell lung cancer after neoadjuvant chemotherapy. J Thorac Oncol 2013;8:222-8. [Crossref] [PubMed]
69. Bai R, Li W, Du N, et al. Challenges of evaluating immunotherapy efficacy in solid tumors. Chin J Cancer Res 2019;31:853-61. [Crossref] [PubMed]
70. Komurcuoglu BE. Imaging procedures in the assessment of response to neoadjuvant treatment in non-small cell lung cancer. AME Surg J 2023;3:21.
71. Min SJ, Jang HJ, Kim JH. Comparison of the RECIST and PERCIST criteria in solid tumors: a pooled analysis and review. Oncotarget 2016;7:27848-54. [Crossref] [PubMed]
72. Shang J, Ling X, Zhang L, et al. Comparison of RECIST, EORTC criteria and PERCIST for evaluation of early response to chemotherapy in patients with non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 2016;43:1945-53. [Crossref] [PubMed]
73. Bott MJ, Yang SC, Park BJ, et al. Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg 2019;158:269-76. [Crossref] [PubMed]
74. Minervini F, Kestenholz PB, Kocher GJ, et al. Thoracic surgical challenges after neoadjuvant immunotherapy for non-small cell lung cancer: a narrative review. AME Surg J 2023;3:15.
75. Feldman HA, Zhou N, Deboever N, et al. Intraoperative challenges after induction therapy for non-small cell lung cancer: Effect of nodal disease on technical complexity. JTCVS Open 2022;12:372-84. [Crossref] [PubMed]
76. Trabalza Marinucci B, Mancini M, Siciliani A, et al. Surgical Techniques for Non-Small-Cell Lung Cancer After Neoadjuvant Chemo-Immunotherapy: State of Art and Review of the Literature. Cancers (Basel) 2025;17:638. [Crossref] [PubMed]
77. Brunelli A, Rocco G, Szanto Z, et al. Morbidity and mortality of lobectomy or pneumonectomy after neoadjuvant treatment: an analysis from the ESTS database. Eur J Cardiothorac Surg 2020;57:740-6. [Crossref] [PubMed]
78. Cabañero Sánchez A, Muñoz Molina GM, Fra Fernández S, et al. Impact of neoadjuvant therapy on postoperative complications in non-small-cell lung cancer patients subjected to anatomic lung resection. Eur J Surg Oncol 2022;48:1947-53. [Crossref] [PubMed]
79. Aburaki R, Fujiwara Y, Chida K, et al. Surgical and safety outcomes in patients with non-small cell lung cancer receiving neoadjuvant chemoimmunotherapy versus chemotherapy alone: A systematic review and meta-analysis. Cancer Treat Rev 2024;131:102833. [Crossref] [PubMed]
80. Borgeaud M, Olivier T, Bar J, et al. Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: Navigating early to advanced disease management. CA Cancer J Clin 2025;75:387-409. [Crossref] [PubMed]
81. NCCN [Internet]. [cited 2025 Nov 25]. Guidelines Detail. Available online: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450
82. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-9. [Crossref] [PubMed]
83. Hardavella G, Magouliotis DE, Chalela R, et al. Stage I and II nonsmall cell lung cancer treatment options. Breathe (Sheff) 2024;20:230219. [Crossref] [PubMed]
84. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71. [Crossref] [PubMed]
85. Forde PM, Spicer JD, Provencio M, et al. Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer. N Engl J Med 2025;393:741-52. [Crossref] [PubMed]
86. Cascone T, Hamdi H, Zhang F, et al. Abstract 1719: Superior efficacy of neoadjuvant compared to adjuvant immune checkpoint blockade in non-small cell lung cancer. Cancer Res 2018;78:1719.
87. Cuppens K, Du Pont B, Knegjens J, et al. Immune checkpoint inhibition in early-stage non-small cell lung cancer. Lung Cancer 2024;193:107855. [Crossref] [PubMed]
88. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378:1976-86. [Crossref] [PubMed]
89. Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial. Nat Med 2022;28:2155-61. [Crossref] [PubMed]
90. Cascone T, William WN Jr, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 2021;27:504-14. [Crossref] [PubMed]
91. Shukla N, Hanna N. Neoadjuvant and Adjuvant Immunotherapy in Early-Stage Non-Small Cell Lung Cancer. Lung Cancer (Auckl) 2021;12:51-60. [Crossref] [PubMed]
92. Liu X, Xing H, Liu H, et al. Current status and future perspectives on immunotherapy in neoadjuvant therapy of resectable non-small cell lung cancer. Asia Pac J Clin Oncol 2022;18:335-43. [Crossref] [PubMed]
93. Cascone T, Awad MM, Spicer JD, et al. LBA1 CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Ann Oncol 2023;34:S1295.
94. Heymach JV, Mitsudomi T, Harpole D, et al. Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Clin Lung Cancer 2022;23:e247-51. [Crossref] [PubMed]
95. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
96. Yue D, Wang W, Liu H, et al. VP1-2024: RATIONALE-315: Event-free survival (EFS) and overall survival (OS) of neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC). Ann Oncol 2024;35:332-3.
97. Tsuboi M, Herbst RS, John T, et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 2023;389:137-47. [Crossref] [PubMed]
98. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2024;390:1265-76. [Crossref] [PubMed]
99. He J, Tsuboi M, Weder W, et al. Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer. J Clin Oncol 2025;43:2875-87. [Crossref] [PubMed]