The treatment landscape of early-stage non-small cell lung cancer (NSCLC) has evolved significantly with the introduction of immune checkpoint inhibitors (ICIs). Building on the success of immunotherapy in advanced disease, recent trials have explored its role in the perioperative setting for resectable NSCLC. These studies have shown promising improvements in pathological response and event-free survival, leading to regulatory approvals and integration into clinical guidelines [1–17]. However, as immunotherapy moves into earlier stages of disease, critical questions remain regarding its real-world applicability, long-term benefits, patient selection, and potential harms [21–28]. This editorial presents a balanced perspective on the use of immunotherapy in early-stage NSCLC, with arguments in favor and against its widespread implementation.

Given the poor prognosis of patients with non-metastatic, potentially curable lung cancer (stages II–IIIA) through surgery—very different from other tumors at the same stages—various strategies have been developed based on immuno- or chemoimmunotherapy: adjuvant (after surgery), neoadjuvant (before surgery), or perioperative (combining both).

The first study on neoadjuvant PD-1 blockade in resectable NSCLC was conducted by Forde et al. [1]. This study evaluated the feasibility of two cycles of nivolumab in 21 patients with early-stage (I–IIIA) NSCLC. Other monotherapy studies have also been tested, such as the Lung Cancer Mutation Consortium 3 (LCMC3) [2], another phase II trial involving 181 patients with resectable stage IB–IIIB (T3N2) NSCLC. Patients received two doses of atezolizumab before surgery. The primary endpoint was major pathological response (MPR), which was 20.4%.

Perioperative treatment with chemoimmunotherapy was pioneered by the NADIM study [3,4]. This was a phase II, single-arm, open-label, multicenter Spanish trial. It involved 46 patients with resectable stage IIIA N2 NSCLC. The goal was to assess the feasibility, safety, and efficacy of neoadjuvant chemotherapy with paclitaxel and carboplatin plus nivolumab every 3 weeks for 3 cycles before surgery, followed by 1 year of adjuvant nivolumab. The primary endpoint was 24-month progression-free survival (PFS), which was very high: 77.1%. Updated 5-year results published in Lancet Oncology show: overall survival (OS) of 81.2%, 5-year PFS of 69.4%, and R0 resection rates above 90% [5].

The NADIM II trial is a phase II, open-label, randomized, two-arm study that enrolled 90 patients with resectable stage IIIA–IIIB (8th edition) NSCLC to receive nivolumab plus chemotherapy (paclitaxel and carboplatin) or chemotherapy alone, followed by surgery. A total of 86 patients were randomized. The primary endpoint in the ITT population was pathological complete response (pCR) assessed by blinded independent central review. The pCR rate was 37% in the nivolumab plus chemotherapy group versus 7% in the chemotherapy group (p=0.0068). The 24-month PFS was 67.2% in the experimental arm and 40.9% in the control arm (HR 0.47; 95% CI: 0.25–0.88). OS at 24 months was 85.0% in the nivolumab plus chemotherapy arm versus 63.6% in the chemotherapy arm (HR 0.43; 95% CI: 0.19–0.98) [6].

Recently, the CheckMate 816 phase III, multicenter, randomized, open-label trial compared neoadjuvant nivolumab plus chemotherapy with chemotherapy alone in patients with resectable stage IB–IIIA NSCLC. Primary endpoints were event-free survival (EFS) and pCR. Median EFS was 31.6 months in the nivolumab plus chemo group vs. 20.8 months in the control group (HR 0.63; 97.38% CI: 0.43–0.91; p=0.005). The pCR rate was 24% in the experimental group vs. 2.2% in the chemotherapy group (OR 13.94; 99% CI: 3.49–55.75; p<0.0001) [7]. This treatment has been approved as a neoadjuvant option in the US and several other countries for adults with resectable NSCLC (tumors>4cm and/or node-positive) [8]. In Europe, the Committee for Medicinal Products for Human Use (CHMP) recommended nivolumab in combination with platinum-based chemotherapy as neoadjuvant treatment for resectable NSCLC with high recurrence risk in PD-L1≥1% tumors [9]. Recently, positive results from CM 816 in favor of overall survival (OS) have been announced via press release [10].

The KEYNOTE-671 trial also met its primary EFS endpoint in selected patients with resectable stage II, IIIA, and IIIB NSCLC. Results were presented at ASCO 2023 [11] and later published in NEJM [12]. A total of 797 patients were randomized. Median EFS was not reached in the study arm vs. 17 months in the control. OS was also significantly improved, leading to FDA approval [13].

On March 9, 2023, AstraZeneca announced that durvalumab significantly improved EFS in the AEGEAN trial for resectable NSCLC. This trial included 802 patients. Median EFS was not reached in the durvalumab group vs. 25.9 months in the control [14].

The Neotorch study also evaluated perioperative chemoimmunotherapy (with toripalimab), followed by 13 adjuvant toripalimab cycles. It showed significant improvement in EFS compared to chemotherapy alone [15,16].

CheckMate 77T is a phase III study evaluating the perioperative strategy in resectable NSCLC. It showed that neoadjuvant nivolumab+chemotherapy followed by adjuvant nivolumab improves outcomes. The CHMP has recommended this regimen [17].

The Spanish GECP consensus endorses perioperative treatment as a new standard in resectable NSCLC with nodal involvement [18].

Despite compelling data from clinical trials, the real-world implementation of immunotherapy in early-stage non-small cell lung cancer (NSCLC) presents significant challenges. The universal adoption of this strategy may be premature, particularly when considering the current limitations in survival data, surgical completion rates, and the risk of overtreatment.

While trials like CheckMate 816 [7–10], KEYNOTE-671 [11–13] and NADIM II [6] have demonstrated overall survival (OS) gains, these results are not yet representative of the broader body of perioperative immunotherapy trials. The AEGEAN [14], NeoTORCH [15,16], and RATIONALE-315 [19] trials have reported improvements in pathological complete response (pCR) or event-free survival (EFS), but mature OS data remain pending. Furthermore, in the adjuvant setting, the BR31 trial [20] failed to show a disease-free survival (DFS) benefit in an unselected population.

Even in trials where survival gains have been reported, the context must be carefully considered. These studies involve highly selected patients, managed under strict protocols in academic centers with extensive resources. In routine clinical practice, patient populations are more heterogeneous, often with comorbidities, social barriers, and logistical challenges that may limit the applicability of trial results. Therefore, the efficacy demonstrated in trials may not translate to effectiveness in the real world [21].

A growing concern comes from real-world data showing that a significant proportion of patients do not proceed to surgery after receiving neoadjuvant immunotherapy. In a recent U.S. multicenter cohort study, only 63% of patients who began neoadjuvant immune checkpoint inhibitor (ICI) treatment ultimately underwent surgical resection. Reasons included disease progression, treatment-related toxicity, and functional decline [22]. Similarly, in a large study within the U.S. Veterans Affairs (VA) system, 27% of patients failed to complete surgery despite being initially deemed operable [23].

These findings are striking when contrasted with the >90% surgical completion rates typically reported in clinical trials. This discrepancy underscores a significant gap between controlled research environments and real-life clinical practice. If a key goal of neoadjuvant immunotherapy is to improve surgical outcomes, the failure of a substantial number of patients to reach surgery in everyday practice undermines this objective and may compromise curative intent.

In addition to these logistical concerns, there is still uncertainty regarding the true benefit of immunotherapy in non-operable patients. Notably, the KEYNOTE-867 trial—evaluating pembrolizumab plus SBRT in medically inoperable stage I-II NSCLC—was recently discontinued due to lack of improvement in survival outcomes and increased toxicity [24]. This result highlights the risk of applying immunotherapy beyond well-established settings.

Another important consideration is the potential for overtreatment. The addition of ICIs introduces risks of immune-related adverse events (irAEs), including pneumonitis, adrenal insufficiency, thyroid dysfunction, and other endocrinopathies. These toxicities can delay surgery, impair postoperative recovery, or even require lifelong management. In patients with a low risk of recurrence—such as those with small, node-negative tumors—the incremental benefit of immunotherapy may not outweigh these risks [25].

The balance between benefit and harm becomes even more delicate in elderly patients or those with multiple comorbidities. These individuals are often underrepresented in clinical trials, yet they constitute a large proportion of the real-world early-stage NSCLC population. The introduction of neoadjuvant or adjuvant immunotherapy in these patients, without robust survival data, may result in reduced quality of life or treatment-related complications without clear oncologic benefit [26].

Furthermore, immunotherapy has shown limited efficacy in patients with oncogenic driver mutations, such as EGFR or ALK alterations, who represent a clinically significant subset of early-stage NSCLC. In these patients, targeted therapies remain the standard of care, and the benefit of adding ICIs is questionable and potentially harmful [27].

Moreover, access to immunotherapy remains uneven across healthcare systems, raising concerns about equity. High drug costs, limited infrastructure, and variability in multidisciplinary care may restrict access for patients in lower-resource settings, further widening disparities [28].

In summary, while the promise of immunotherapy in early-stage NSCLC is undeniable, its real-world application faces significant barriers. Surgical completion rates are substantially lower outside of trials, mature survival data are lacking for many regimens, and the risk of overtreatment and toxicity in certain subgroups is real. Until ongoing studies provide more definitive answers—and implementation strategies are optimized—it may be premature to adopt immunotherapy as a universal standard in early-stage NSCLC

Perioperative chemoimmunotherapy has been established as a new standard of care in early-stage resectable NSCLC by several international regulatory agencies, including the FDA and EMA, based on robust evidence from pivotal phase III trials demonstrating improvements in pathological response and event-free survival. These advances mark a significant shift in the management of resectable disease and offer new hope for improved long-term outcomes.

Nevertheless, successful implementation in routine clinical practice requires careful patient selection, awareness of potential barriers such as surgical attrition, and attention to specific subgroups—such as those with oncogenic driver mutations—in whom the benefit remains unclear. Continued follow-up of ongoing trials and real-world studies will be essential to optimize treatment algorithms and ensure equitable access to these promising therapies.

All authors have contributed substantially to obtaining the results and preparation of the manuscript in accordance with ICMJE criteria.

During the preparation of this work the author(s) used ChatGPT in order to improve language and readability. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

Felipe Couñago: Sponsored Research: Janssen, Recordati. Consulting, advisory role: Janssen, AstraZeneca. Lectures and educational activities: Janssen, Roche Farma, AstraZeneca, Astellas, Recordati. Ipssen. Travel, Accommodations, Expenses: AstraZeneca, Astellas, Janssen, Roche Farma, Recordati, Ipssen.

Mariano Provencio: Advisory council or committee: Amgen, Pfizer, Daiichi Sankyo, Johnson & Johnson, BMS, Takeda, AstraZeneca, Gilead, MSD, Guardant Health, Ipsen, Incyte Biosciences, Bayer; Honoraria: BMS, Astra Zeneca, MSD, Roche, Takeda, Eli Lilly, F. Hoffman-La Roche, Janssen, Pfizer, Amgen; Consulting fee: BMS, Astra Zeneca, MSD, Roche, Takeda, Eli Lilly, F. Hoffman-La Roche, Janssen, Pfizer, Amgen; Grants or funds: Research funding received from BMS, Astra Zeneca, MSD, Roche, Takeda, Pfizer, Takeda, Boehringer Ingelheim, Amgen, Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, European Commi.ssion, Eli Lilly, F. Hoffman-La Roche, Janssen, Phierre Fabre Pharmaceuticals.