Perioperative chemo immunotherapy in non-small-cell lung cancer: what can we learn from the long-term results of NADIM?

Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Only about 25% to 30% of patients are diagnosed with resectable tumors. For NSCLC measuring more than 2 cm, lobectomy with lymph node dissection is the recommended surgical approach, whereas sublobar resection is generally preferred for tumors smaller than 2 cm. However, surgery alone is not curative for a substantial proportion of patients because of the persistent risk of recurrence (1). The recurrence rate varies depending on the stage. For instance, patients with early-stage pT1a [8th tumor-node-metastasis (TNM) edition] have a 5-year survival rate of 90%, while those with stage IIIA have a survival rate of only 41% (2,3). Recent advancements in therapeutic strategies have expanded the treatment armamentarium, leading to significant improvements in postoperative outcomes for selected patients without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) molecular alteration. Immunotherapy targeting the programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) axis has notably shifted the paradigm in the management of resectable NSCLC, with various strategies now being developed and integrated with chemotherapy in the adjuvant, neoadjuvant, and perioperative settings.

The 5-year results of the multicenter, single-arm perioperative Spanish trial NADIM were recently published (4,5). NADIM is a phase II study conducted between 2017 and 2018 that assessed perioperative nivolumab in combination with three cycles of neoadjuvant paclitaxel and carboplatin, followed by 1 year of adjuvant nivolumab in 52 patients. This study is considered a landmark in the field, as it opened the way to new strategies for the treatment of resectable NSCLC, particularly stage III disease. It was among the first to demonstrate the potential of perioperative chemo-immunotherapy and laid the foundation of phase III trials in both the neoadjuvant and perioperative settings, current standards of care in resectable NSCLC. At 5 years the authors of NADIM report a progression-free survival (PFS) rate of 65% [95% confidence interval (CI): 49.4–76.9%] and an overall survival (OS) rate of approximately 70% in 46 patients in intention to treat (ITT). Disease progression occurred in 11 (24%) patients. 14 patients died including 9 patients (20%) from disease relapse. These results underscore the durability of clinical benefit with no disease progression since the previously published 3-year data, a high pathological complete response (pCR) rate, and the absence of emerging long-term safety concerns such as delay in surgery, treatment related deaths, and unexpected toxicity. Nevertheless, its single-arm design and relatively small sample size inevitably limit its statistical power compared with more recent phase III randomized trials (Table 1). Although the NADIM trial design may now appear dated, its rich translational research component [particularly biomarker analyses related to pathological response and circulating tumor DNA (ctDNA)] continues to inform current perioperative strategies. Thus, the NADIM trial supports pCR (0% viable tumor in resected lung and lymph nodes) as a meaningful surrogate endpoint, demonstrating a strong association with OS and PFS. At 5 years OS was 95.8% (95% CI: 73.9–99.4%) and PFS was 92% (95% CI: 70.5–97.9%) in pCR group and OS was 66.0% (95% CI: 36.5–84%) and PFS was 60.0 % (95 % CI: 31.8–79.7%) in non-pCR group. The NADIM study highlights the prognostic role of ctDNA as a marker of residual micrometastatic disease. At diagnosis, a mutant allele fraction (MAF) ≥1% in ctDNA was associated with shorter PFS and lower OS, with 36-month PFS rates of 41.7% in patients with MAF ≥1% compared to 93.6% in those with MAF <1%, and 36-month OS rates of 58.3% vs. 100%, respectively. These results suggest that baseline ctDNA levels may serve as a strong prognostic biomarker. Furthermore, patients who achieved ctDNA clearance defined as undetectable ctDNA following neoadjuvant treatment and prior to surgery demonstrated significantly prolonged PFS and improved OS, with 5-year PFS and OS rates reaching approximately 90% and 95%, respectively. These benefits were observed independently of pathological response, including in patients who did not achieve a complete pathological response. In contrast, patients with persistent ctDNA had markedly worse outcomes with respectively 5 years PFS and OS of 60.6% (95% CI: 29.4–81.4%) and 59.2% (95% CI: 27.9–80.7%) compared with 85.2% (95% CI: 65.2–94.2%) and 92.3% (95% CI: 72.5–98.0%) in the group with ctDNA clearance group. These findings indicate that ctDNA clearance could be an early marker of treatment efficacy and led the authors to suggest that ctDNA could serve as an important tool to stratify patients according to prognostic risk, tailor treatment intensity and enable early detection of relapse. This tool would be particularly useful for high-risk patients who did not achieve a pCR, were ineligible for surgery, or for whom pathological response data are unavailable.

The long-term results of the NADIM trial contribute to redefining the role of perioperative chemo-immunotherapy, at a time when adjuvant immunotherapy strategies have yielded rather modest outcomes, whereas neoadjuvant approaches have consistently demonstrated robust and durable benefit.

The limitation of adjuvant therapy

Although data from adjuvant trials have been promising, they remain insufficient to be relied upon at this stage due to inconsistent and non-reproducible results across clinical studies. Two phase III trials, testing PD-L1 inhibitor atezolizumab (IMpower 010) and pembrolizumab (KEYNOTE-091/PEARLS), have demonstrated a disease-free survival (DFS) benefit with an adjuvant postoperative immunotherapy strategy after adjuvant chemotherapy. IMpower010 showed a significant improvement in DFS which was observed in patients with PD-L1-positive stage II–IIIA NSCLC, with the greatest benefit seen in those with PD-L1 expression ≥50% [hazard ratio (HR) 0.43; 95% CI: 0.27–0.68] on post hoc analysis, whereas no meaningful benefit was observed in patients with PD-L1 expression <1% (HR 0.97; 95% CI: 0.71–1.31). Stratification based on PD-L1 expression was not pre-specified and represents a significant methodological limitation (6). The KEYNOTE-091/PEARLS trial evaluated adjuvant pembrolizumab vs. placebo in patients with resected stage IB–IIIA NSCLC, regardless of PD-L1 expression. At a median follow-up of 35.6 months, pembrolizumab significantly improved DFS (HR 0.76), but this benefit was not found with the PD-L1 >50%. Final analysis at 51.7 months confirmed sustained DFS benefit (HR 0.82); OS results are not yet mature (7). Another phase III trial BR31 has recently drawn significant attention, challenging the role of adjuvant immunotherapy. This randomized study (2:1) evaluated adjuvant durvalumab (administered every 28 days for 1 year) vs. placebo, with or without prior chemotherapy. A total of 1,415 patients with completely resected stage IB, II, or IIIA NSCLC (TNM 7th edition) were enrolled, with stratification based on disease stage, PD-L1 expression, prior chemotherapy, and study center. After a median follow-up of 60 months, the trial failed to meet its primary endpoint in the PD-L1 ≥25%, EGFR−/ALK− population, with a DFS of 70 vs. 60 months (HR 0.94; 95% CI: 0.71–1.25), indicating no significant benefit. The findings from the BR.31 trial have thus called into question the strength of evidence underlying adjuvant treatment approaches, suggesting that these strategies in adjuvant may be suboptimal and associated with uncertain benefit (8). The principal phase III trials of adjuvant treatment with immune checkpoint inhibitors (ICIs) for resected disease are summarized in Table 2.

The benefit of neoadjuvant therapy

Supported by stronger levels of evidence, neoadjuvant approaches have become the Gold Standard for the management of patients with resectable NSCLC greater than 4 cm in size and/or with nodal involvement and without EGFR or ALK mutations. CheckMate 816 trial is one of the first and only randomized phase III trials evaluating neoadjuvant immunotherapy. This trial compared three cycles of neoadjuvant Nivolumab combined with platinum-based chemotherapy vs. chemotherapy alone in 358 patients with resectable stage IB (tumors >4 cm) to IIIA NSCLC (according to the 7th TNM classification), all negative for EGFR and ALK alterations. The study demonstrated a significant improvement in both co-primary endpoints: pCR was achieved in 24% of patients in the chemo-immunotherapy arm vs. 2.2% with chemotherapy alone [odds ratio (OR), 13.94], and median event-free survival (EFS) was extended to 31.6 months compared to 20.8 months (HR 0.63; 97.38% CI: 0.43–0.91). The observed benefit appeared more pronounced in patients with higher-stage disease and elevated PD-L1 expression. Importantly, this strategy was associated with a favorable safety profile and did not compromise surgical feasibility (9). Presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the planned final analysis of 5 years OS data confirmed the long-term benefit of a neoadjuvant strategy. The median OS was not reached (95% CI: not reached) in the combination arm vs. 73.7 months (95% CI: 47.3–not reached) in the chemotherapy-alone arm, HR of 0.72 (95% CI: 0.523–0.998; P=0.0479). The 5-year OS rate was 65% in the combination group compared to 55% in the chemotherapy-alone group. Furthermore, the combination of nivolumab plus chemotherapy continued to improve EFS compared to chemotherapy alone, with a median EFS of 59.6 months (95% CI: 31.6–not reached) vs. 21.1 months (95% CI: 16.5–36.8), and an HR of 0.68 (95% CI: 0.51–0.91). The 5-year EFS rates were 49% in the combination group vs. 34% in the chemotherapy-alone group (HR 0.68; 95% CI: 0.51–0.91). No new safety signals were observed during this extended follow-up period (10).

The place of perioperative strategies

Evidence of efficacy confirmed by large randomized trials after NADIM

Several phase 3 randomized trials conducted in perioperative settings have been published after NADIM all with similar designs. In each interventional arm, three to four cycles of chemoimmunotherapy were administered prior to surgery, followed by adjuvant immunotherapy. PD-1/PD-L1 inhibitors in the perioperative setting, included toripalimab, nivolumab, pembrolizumab, durvalumab, and tislelizumab (11-15). For example, the phase III AEGEAN trial evaluated perioperative durvalumab plus chemotherapy vs. chemotherapy alone in resectable stage II–IIIB NSCLC, showing a significant improvement in EFS (median not reached vs. 25.9 months; HR 0.68) and higher pCR rates (17.2% vs. 4.3%). The KEYNOTE-671 trial similarly demonstrated that perioperative pembrolizumab improved EFS (HR 0.58) and OS (HR 0.72) compared with chemotherapy alone. Across these studies, consistent improvements were observed in both EFS and pCR, with comparable 2-year EFS rates of around 65% and pCR rates approaching 20%. The main phase III trials evaluating neoadjuvant and perioperative ICI strategies in resectable disease are summarized in Table 1.

Is adjuvant therapy necessary for all patients?

The impressive outcomes in terms of PFS and pCR following neoadjuvant therapy raise questions about the added value of adjuvant treatment within perioperative strategies, especially given the relatively modest benefit observed with adjuvant immunotherapy alone. In the CheckMate 816 trial, the absence of cancer-related deaths among patients who achieved pCR at 5 years of follow-up supports a surveillance-only approach rather than treatment intensification with immunotherapy, at least for this subgroup. Similarly, in the NADIM trial, the authors had already suggested that adjuvant immunotherapy might not be required for all patients, as those who achieved pCR demonstrated exceptionally high progression-free and OS, which is particularly striking considering that all patients had stage III disease. Conversely, patients who failed to achieve pCR and received incomplete adjuvant therapy had the poorest outcomes, underscoring the benefit importance of the adjuvant phase in this population. Taken together, these findings highlight the need for biomarker-driven patient selection and tailored perioperative strategies to optimize the balance between efficacy and treatment burden.

Management of minimal residual disease (MRD) and ctDNA clearance

ctDNA is gaining recognition as a valuable marker of MRD in resectable NSCLC, with potential to guide adjuvant therapy more precisely. Its prognostic significance has been demonstrated, as ctDNA positivity after surgery strongly correlates with an increased risk of relapse. The most recent meta-analysis, including 13 studies, demonstrated that postoperative detection of ctDNA increases the risk of recurrence sixfold (HR 6.05) and the risk of death by 4.5-fold (HR 4.53) compared with ctDNA-negative patients (16). In addition, ctDNA enables dynamic monitoring of the disease, allowing for earlier detection of recurrence than conventional imaging and opening the door to timely therapeutic intervention. This approach could also support treatment intensification in high-risk patients, while sparing ctDNA-negative individuals from unnecessary toxicity. However, important challenges remain before ctDNA can be incorporated into routine practice. Detection methods still lack standardization, with platforms such as ultra-sensitive next-generation sequencing and digital pCR differing in performance and cost. Reproducibility across laboratories also needs to be ensured, since technical variability can affect the reliability of results. Finally, the clinical benefit of ctDNA-guided strategies must be demonstrated through prospective validation phase III trials before this biomarker can be fully integrated into decision-making for adjuvant therapy.

Comparative analysis between perioperative and neoadjuvant strategies

To date, no comparative trials have definitively favored either a neoadjuvant or perioperative approach. A pooled analysis comparing data from patients who underwent surgery following neoadjuvant chemotherapy plus nivolumab in the CheckMate 816 trial with data from patients enrolled in the perioperative CheckMate 77T trial, who underwent surgery after chemotherapy plus nivolumab and received at least one cycle of adjuvant nivolumab, suggests a benefit of the perioperative strategy over the neoadjuvant approach. Perioperative nivolumab reduced risk of disease recurrence/death by 39–44% with an average treatment effect (ATE) in weighted analysis with HR 0.61 (95% CI: 0.39–0.97). A notable advantage was observed in patients who did not achieve a pCR or in PD-L1 low (<1%) group. This benefit was not observed in the pCR subgroup, reinforcing the role of pCR as a key prognostic marker of treatment efficacy. However, this analysis is exploratory in nature, has a low level of evidence, and is subject to bias (17).

Perspectives in resectable lung cancer

The results of the ETOP IBCSG 25-23 ADOPT-LUNG trial are eagerly awaited, as the study directly compares neoadjuvant vs. perioperative immunotherapy (NCT06284317). ADOPT-LUNG is a global, multicenter, open-label, phase III randomized trial assessing the impact of the adjuvant component of perioperative chemoimmunotherapy with durvalumab on DFS in patients with completely resected stage IIB–IIIB. The treatment protocol consists of 3 to 4 cycles of neoadjuvant durvalumab in combination with platinum-based doublet chemotherapy, followed by surgical resection. Patients undergoing R0 or R1 resection are subsequently randomized postoperatively to receive either adjuvant durvalumab for up to 12 cycles (experimental arm) or no further treatment with active surveillance (control arm). The primary objective of the study is to determine whether additional adjuvant durvalumab improves DFS in patients who do not achieve a pCR following neoadjuvant chemo-immunotherapy (18).

While current guidelines emphasize that neoadjuvant, adjuvant, or perioperative immunotherapy should only be administered to patients initially deemed resectable, the impressive rates of pCR observed in recent trials challenge this paradigm and support the rationale for investigating preoperative downstaging strategies in future studies.

In parallel, new therapeutic strategies combining novel agents (particularly antibody-drug conjugates, anti-TIGIT, anti-LAG-3 antibodies, anti-angiogenic agents, and cancer vaccines) are under development. These innovative approaches raise hopes of increasing the proportion of patients achieving pCR, which is predictive of prolonged survival and a reduced risk of recurrence.

To conclude, the NADIM study confirms the long-term benefit of a perioperative strategy in patients with resectable stage III NSCLC. It also highlights that not all patients derive equal benefit from adjuvant immunotherapy, and provides valuable, timely insights into the ongoing questions and challenges related to neoadjuvant, adjuvant and perioperative treatment strategies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-883/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-883/coif). B.D. reports personal fees from Roche, Pfizer, Astra Zeneca, Chiesi, Amgen, Lilly, Medscape, MSD, and Sanofi; and congress fees from AZ, Pfizer, Oxyvie, and MSD. The other authors have no conflicts of interest to declare.

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

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