The role of perioperative chemoimmunotherapy in resectable non-small cell lung cancer: insights from the NADIM trial

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, with historical 5-year survival rates for resectable stage IIIA disease below 40% (1,2). While surgery continues to be the cornerstone of treatment for resectable NSCLC, the high risk of recurrence has prompted significant research into perioperative systemic therapies to improve long-term outcomes. The NADIM phase II trial, a pioneering study in this field, explored the combination of neoadjuvant nivolumab with chemotherapy, followed by adjuvant nivolumab. With follow-up data extending to five years, this trial provides valuable insights into the durability of chemoimmunotherapy benefits in resectable NSCLC.

The NADIM trial (3) was one of the first trials to report positive outcomes with using this perioperative chemo-immunotherapy approach and many larger randomized clinical studies have since demonstrated comparable results. Indeed, CheckMate 77T (4), AEGEAN (5), KEYNOTE-671 (6), NeoTORCH (7), and RATIONALE-315 (8) have demonstrated improved event-free survival and increased pathological complete response (pCR) rates with neoadjuvant chemoimmunotherapy compared to chemotherapy alone. However, these trials generally report follow-up periods not exceeding three years, leaving uncertainties about long-term benefits.

The updated NADIM results address this knowledge gap by reporting long-term survival outcomes beyond the 3-year threshold. After a median follow-up of 60 months, the study demonstrated a 5-year overall survival (OS) rate of 69.3% and progression-free survival (PFS) rate of 65%. These results significantly exceed historical benchmarks for chemotherapy alone, where median event-free survival typically does not surpass 15 months (9). Particularly noteworthy is the absence of tumor-related relapses after 29 months, suggesting that patients who remain disease-free beyond this point may have a low risk of recurrence.

In addition to its promising survival outcomes, another important aspect of NADIM’s updated results is the assessment of long-term toxicities. One of the most notable findings is that no late-onset or unexpected long-term toxicities were observed during follow-up, although some adverse events (e.g., adrenal insufficiency) may persist and influence quality of life. Despite the occurrence of grade 3 or higher treatment-related adverse events in 30% of patients during neoadjuvant therapy and 19% during adjuvant therapy, no late-onset toxicities or treatment-related deaths were observed after five years of follow-up. This provides crucial reassurance that patients can potentially benefit from chemoimmunotherapy without evidence of unexpected late-onset toxicities, although some treatment-related effects may be durable.

While the absence of long-term toxicities is a strong point of the NADIM trial, the trial’s limitations in design and sample size mean that these findings should be interpreted cautiously. As a single-arm phase II study with 46 patients, it lacks the statistical power and comparative framework that a randomized controlled trial would provide. While the reported survival rates are encouraging, the absence of a control group makes it challenging to definitively attribute the observed benefits solely to the intervention. The relatively small sample size also increases the possibility of selection bias affecting outcomes. Nevertheless, the trial’s long-term follow-up provides valuable data that complement the shorter-term findings from larger, randomized studies. The results should be viewed as generating important hypotheses that warrant confirmation in appropriately powered phase III trials with longer follow-up periods.

The NADIM trial focused specifically on patients with resectable stage IIIA NSCLC and a good performance status, excluding those with significant comorbidities or functionally unresectable disease. This selective approach, while methodologically understandable, raises questions about the generalizability of findings to the broader NSCLC population encountered in clinical practice. In real-world settings, oncologists frequently treat patients who would not have met the trial’s stringent eligibility criteria. The benefits and risks of perioperative chemoimmunotherapy in these more diverse populations remain uncertain. Future studies should aim to include a wider spectrum of patients, including those with moderate comorbidities and varying degrees of disease burden, to better reflect clinical circumstances.

Optimizing treatment requires identifying patients most likely to benefit from chemoimmunotherapy. In the NADIM trial, circulating tumor DNA (ctDNA) emerged as a promising predictive marker, with baseline levels and post-treatment clearance strongly correlating with survival outcomes. The trial’s pCR rate was 63.4%, markedly higher than those observed in CheckMate 816 (24.0%) (10) and KEYNOTE-671 (18.1%) (6), although patient selection and trial design differences must be considered. Unlike traditional biomarkers such as programmed death ligand-1 (PD-L1) expression or tumor mutational burden (TMB), ctDNA provides real-time insights into residual disease, potentially guiding treatment decisions. Patients with undetectable ctDNA after neoadjuvant therapy demonstrated significantly higher PFS and OS compared to those with detectable ctDNA. This suggests that ctDNA could serve as a dynamic marker to personalize treatment plans—patients with persistent ctDNA post-neoadjuvant therapy might benefit from intensified adjuvant therapy, while those with undetectable ctDNA could potentially avoid further treatment and its associated toxicities. Interestingly, routine biomarkers such as PD-L1 tumor proportion score and TMB did not significantly correlate with long-term survival in the NADIM trial, highlighting the need for multifactorial biomarker models incorporating ctDNA alongside other genomic and immune parameters.

The role of adjuvant therapy warrants reassessment given the efficacy of neoadjuvant chemoimmunotherapy; however, definitive conclusions cannot be drawn from the NADIM design. Among the four (15%) of 26 pCR patients who received fewer than 50% of planned adjuvant cycles, two were censored due to coronavirus disease 2019 (COVID-19)-related deaths, one progressed at 27.3 months and died at 33.2 months, and one remains disease-free at last follow-up (data cutoff). Additional studies are required to determine the true contribution of the adjuvant phase. Notably, two of the four pCR patients who progressed harbored oncogenic driver mutations (EGFR and KEAP1), indicating that pathologic complete response may not eliminate recurrence risk in patients with certain genomic alterations. This raises the possibility of treatment de-escalation for strong responders to neoadjuvant therapy, potentially sparing them from unnecessary toxicity while preserving favorable outcomes. Conversely, adjuvant therapy may remain beneficial for patients at higher relapse risk, such as those with residual disease post-surgery. Future trials should investigate adjuvant therapy through biomarker-based stratification, particularly utilizing non-pCR to identify patients requiring more intensive regimens. An example of such a study is the ongoing ARIAN study of the Spanish Lung Cancer Group led by the same investigators as the NADIM trial (11).

Data updates from other neoadjuvant and perioperative trials, as well as future new randomized controlled trials will be essential to confirm NADIM’s findings and explore chemoimmunotherapy approaches in more diverse patient populations. The clinical utility of ctDNA, pCR and other biomarkers requires validation in larger cohorts. Additionally, investigations into the optimal duration of therapy, particularly the necessity of adjuvant treatment following successful neoadjuvant therapy, represent important areas for future research.

In conclusion, the updated long-term NADIM outcomes provide valuable insights in resectable stage IIIA NSCLC treatment, providing the first comprehensive long-term survival and safety data on perioperative chemoimmunotherapy. Despite methodological limitations inherent to its single-arm design and selective population, its findings suggest that neoadjuvant nivolumab combined with chemotherapy, followed by adjuvant nivolumab, can deliver durable survival benefits without significant long-term toxicity.

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-2025-364/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-2025-364/coif). The authors have no conflicts of interest to declare.

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