Perioperative immunochemotherapy in stage IIIA non-small cell lung cancer: insights on the path forward
Junichi Soh
Keywords: Non-small cell lung cancer (NSCLC); immunochemotherapy; stage IIIA; NADIM
Submitted Jan 06, 2025. Accepted for publication May 06, 2025. Published online May 28, 2025.
doi: 10.21037/tlcr-2025-202
A recent study published in The Lancet Oncology by Provencio et al. reported the 5-year clinical outcomes from the NADIM trial (1), a multicenter, single-arm, phase II study evaluating the impact of perioperative chemoimmunotherapy in patients with resectable stage IIIA non-small cell lung cancer (NSCLC) (2). This trial investigated the efficacy of neoadjuvant paclitaxel plus carboplatin with nivolumab, followed by surgery and adjuvant nivolumab. The AEGEAN, KEYNOTE-671, Neotorch, and CheckMate 77T trials have reported short-term clinical outcomes in patients undergoing perioperative chemoimmunotherapy combined with surgery (Table 1) (3-6). However, long-term survival data remain limited. The NADIM trial was the first to provide critical evidence for long-term durable outcomes associated with neoadjuvant chemoimmunotherapy. Notably, the study reported a 5-year progression-free survival (PFS) rate of 65.0% [95% confidence interval (CI), 49.4–76.9%] and an overall survival (OS) rate of 69.3% (95% CI, 53.7–80.6%), demonstrating a significant improvement compared with previous studies.
Table 1
| Items | NADIM (1,2) | KEYNOTE-671 (3) | AEGEAN (4) | Neotorch (5) | CheckMate 77T (6) |
|---|---|---|---|---|---|
| Phase (NCT) | pII (NCT03081689) | pIII (NCT03425643) | pIII (NCT03800134) | pIII (NCT04158440) | pIII (NCT04025879) |
| Immunotherapy | Nivolumab | Pembrolizumab | Durvalumab | Toripalimab | Nivolumab |
| Neoadjuvant chemotherapy | Platinum-doublet | Platinum-doublet | Platinum-doublet | Platinum-doublet | Platinum-doublet |
| Cycle of neoadjuvant therapy (every 3 weeks) | 3 | 4 | 4 | 3 | 4 |
| Adjuvant immunotherapy | 12 months | Every 3 weeks for 13 cycles | Every 4 weeks for 12 cycles | 1 cycle with chemotherapy & every 3 weeks for 13 cycles | Every 4 weeks for 1 year |
| Number of chemoimmunotherapy | 46 | 397 (vs. 400) | 366 (vs. 374) | 202 (vs. 202) | 229 (vs. 232) |
| Clinical stage of NSCLC | IIIA | II, IIIA, or IIIB (N2) | II, IIIA, or IIIB (N2) | II, IIIA, or IIIB (N2) | IIA (>4 cm) to IIIB (N2) |
| Median age (years) | 63 | 63 (vs. 64) | 65 (vs. 65) | 62 (vs. 61) | 55 (vs. 66) |
| Male | 74% | 70% (vs. 70%) | 69% (vs. 74%) | 90% (vs. 94%) | 73% (vs. 69%) |
| Never smoker | 0% | 14% (vs. 12%) | 14% (vs. 15%) | 14% (vs. 10%) | 7% (vs. 12%) |
| Sq | 35% | 43% (vs. 43%) | 46% (vs. 51%) | 78% (vs. 78%) | 51% (vs. 51%) |
| Clinical stage III | 100% | 70% (vs. 70%) | 71% (vs. 70%) | 100% (vs. 99%) | 64% (vs. 64%) |
| PD-L1 <1% | 36% | 35% (vs. 38%) | 33%/33% | 25% (vs. 27%) | 41% (vs. 40%) |
| Primary endpoint | 2-year PFS (ITT) | EFS, OS | EFS, pCR | EFS, MPR | EFS |
| Secondary endpoint | 5-year PFS, 5-year OS | pCR, MPR | MPR, DFS, OS | OS, pCR | pCR, MPR, OS |
| pCR | 63% | 18.1% (vs. 4.2%) | 17.2% (vs. 4.3%) | 25% (vs. 1%) | 25% (vs. 5%) |
| MPR | 83% | 30.2% (vs. 11.0%) | 33.3% (vs. 12.3%) | 49% (vs. 8%) | 35% (vs. 12%) |
| 2-year EFS | 77.1% | 62.4% (vs. 40.6%) | 63.3% (vs. 52.4%) | 65% (vs. 39%) (IA) | 70.2% (vs. 50.0%) (18 months of IA) |
| The hazard ratio of EFS | – | 0.58 | 0.68 | 0.40 | 0.58 |
| 2-year OS | 81.9% (3-year OS) | 80.9% (vs. 77.6%) | – | 81% (vs. 74%) | – |
| 5-year PFS | 65.0% | – | – | – | – |
| 5-year OS | 69.3% | – | – | – | – |
| Completion rate of neoadjuvant | 98% (45/46) | – | 85%/87% (vs. 87%/89%)† | 87% (vs. 92%) | 85% (vs. 88%) |
| Patients who underwent surgery | 89% | 82% (vs. 79%) | 81% (vs. 81%) | 82% (vs. 73%) | 78% (vs. 77%) |
| No surgery (all) | 11% | 18% (vs. 21%) | 19% (vs. 19%) | 18% (vs. 27%) | 20% (vs. 22%) |
| Adverse event | 0% | 6.3% (vs. 4.2%) | 1.8% (vs. 1.2%) | 3% (vs. 0%) | 3% (vs. 2%) |
| Progressive disease | 0% | 3.8% (vs. 2.1%) | 6.8% (vs. 7.5%) | 3% (vs. 15%) | 6% (vs. 10%) |
| R0 resection (all) | 100% | 92% (vs. 84%) | 95% (vs. 91%) | 96% (vs. 93%) | 89% (vs. 90%) |
| Administration of adjuvant therapy | 80% | 73% (vs. 67%) | 66% (vs. 63%) | 71% (vs. 64%) | 62% (vs. 66%) |
| TRAE G3 or more (all) | 30% | 44.9% (vs. 37.3%) | 48.1% (vs. 47.0%) | 63% (vs. 54%) | 33% (vs. 25%) |
| TRAE G5 (all) | 0% | 1.0% (vs. 0.8%) | 5.7% (vs. 3.8%) | 3% (vs. 2%) | 0.9% (vs. 0%) |
†, number indicates each completion rate of chemotherapy and immunotherapy. DFS, disease-free survival; EFS, event-free survival; IA, interim analysis; ITT, intent-to-treat; MPR, major pathologic response; NCT, national clinical trial; NSCLC, non-small cell lung cancer; OS, overall survival; pCR, pathologic complete response; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; Sq, squamous cell carcinoma; TRAE, treatment-related adverse event.
Historically, patients with clinical stage IIIA NSCLC have been treated using multimodal approaches, including surgery and adjuvant chemotherapy, with a 5-year OS rate of approximately 40% (7). Previous studies have shown no significant differences in OS between neoadjuvant and adjuvant chemotherapy strategies, although neoadjuvant therapy led to higher rates of chemotherapy completion (8). In the NADIM trial, the administration rates of neoadjuvant and adjuvant therapies were similar to those reported in previous clinical trials using only platinum-doublet chemotherapy; however, the 5-year OS rate was approximately 30% higher, highlighting the benefits of incorporating immunotherapy.
Stage IIIA NSCLC encompasses a heterogeneous population with variations in disease burden. Regarding T3/T4 categories, tumors with different characteristics, such as tumor size, invasion into adjacent organs, and pulmonary metastasis, are grouped into a single category because of similar prognoses. However, because surgical approaches vary depending on these conditions, each should be evaluated separately. For example, tumors invading adjacent organs require combined resection of the affected organs, which can be significantly more invasive than standard pulmonary resection. For the node (N) category, the 9th edition of the tumor-node-metastasis (TNM) classification (9) subdivided N2 into single-station (N2a) and multiple-station (N2b). However, conditions with the same N category are highly variable, incorporating factors such as bulky lymph nodes, infiltrative invasion of metastatic lymph nodes, and the extent and number of lymph node metastases. Furthermore, multiple surveys, including those conducted by European Organisation for Research and Treatment of Cancer (EORTC) (10) and Society of Thoracic Surgeons (STS) (11), have revealed that the assessment of resectability varies across institutions and surgeons. Additionally, resectability has been redefined by considering multiple factors: (I) “operability”, which refers to a patient’s surgical tolerance based on complications, cardiopulmonary status, and overall health condition; (II) “narrow-sense resectability”, which is the technical feasibility of achieving complete resection with an adequate surgical margin based on tumor size, location, and extent of local invasion; and (III) “oncologic appropriateness”, which includes various biological factors related to prognosis, short- and long-term surgical risks, and the effectiveness of alternative non-surgical treatments (12).
When interpreting clinical trials targeting resectable stage IIIA NSCLC, considering population heterogeneity is essential. Subset analyses from phase III trials on perioperative chemoimmunotherapy, such as AEGEAN (4) and CheckMate 77T (6), showed no significant differences in hazard ratios (HRs) for event-free survival between patients with multiple station N2 and those with single station N2 (0.69 vs. 0.61 in the AEGEAN trial; 0.43 vs. 0.49 in the CheckMate 77T trial). These findings suggest that multiple station N2, previously considered unresectable, may be eligible for perioperative chemoimmunotherapy if they are technically resectable. Given its rarity, further prospective studies are needed to provide additional insights, ultimately leading to optimal treatment strategies tailored to each disease subtype.
Currently, multiple perioperative treatment strategies, including neoadjuvant chemoimmunotherapy (13) and adjuvant chemotherapy followed by maintenance immunotherapy (14,15), have been approved by the Food and Drug Administration. However, no established guidelines exist for selecting between neoadjuvant and adjuvant therapies or combining both approaches, as each has its advantages and disadvantages (16). A meta-analysis by Zhou et al. (n=2,385) found that adding adjuvant immunotherapy to neoadjuvant chemoimmunotherapy did not significantly improve event-free survival (HR 0.90) but increased treatment-related adverse events [relative risk (RR) 1.08] (17). Conversely, the KEYNOTE-671 trial (3), which is the only perioperative chemoimmunotherapy trial with OS as the primary endpoint, demonstrated that perioperative chemoimmunotherapy significantly improved OS compared with neoadjuvant chemotherapy alone. These findings suggest that adjuvant immunotherapy should be considered for patients who can tolerate intensive treatment, such as younger individuals or those with moderate residual tumors in the resected specimen. However, further investigations are needed to draw clear conclusions.
A key challenge in perioperative management is identifying patients at risk of recurrence. Liquid biopsy, which detects circulating tumor DNA in the bloodstream, is emerging as a promising tool for minimal residual disease (MRD) detection and real-time treatment monitoring (18,19). Although sensitivity remains a problem, next-generation sequencing (NGS) technology enables comprehensive and highly accurate analysis. Methods for detecting postoperative MRD are broadly classified into tumor-agnostic (uninformed, naive) and tumor-informed assays (20). The latter uses NGS to develop patient-specific assays, achieving high sensitivity and accuracy; however, high costs and long turnaround times remain major limitations. In addition to circulating tumor RNA (ctRNA), ctRNA assays are gaining interest as a complementary tool for MRD detection (21). ctRNA may provide additional insights into tumor biology, particularly gene expression profiles and fusion transcripts, which are not always detectable by ctDNA (22). Although technically challenging due to the inherent instability of RNA, improvements in capture methods and bioinformatics are increasing their feasibility in perioperative monitoring (23). As perioperative immunotherapy gains traction (13,14), integrating MRD assessment into treatment algorithms may refine patient selection and guide escalation or de-escalation strategies.
The introduction of immunotherapy in the neoadjuvant setting has led to new considerations in surgical management. Although concerns exist regarding immune-related adverse events (irAEs) that could impact resectability and clinical outcomes, data from NADIM and other studies suggest that neoadjuvant chemoimmunotherapy does not significantly increase surgical morbidity, delay resection, or raise the incidence of severe adverse events (1). However, immune-mediated inflammatory responses can occasionally result in life-threatening situations that require careful perioperative planning and close collaboration among thoracic surgeons, medical oncologists, and radiologists. Multidisciplinary teams should monitor irAEs to optimize clinical outcomes.
The optimal treatment strategy for patients with disease progression despite receiving neoadjuvant therapy remains unresolved. Currently, there are no standardized guidelines for managing this subset of patients. Ongoing and future trials aim to evaluate whether modifying systemic therapy, incorporating novel immunotherapeutic combinations, or intensifying postsurgical surveillance can improve outcomes.
However, several limitations of the NADIM trial should be noted. As a single-arm phase II study conducted exclusively in Spain, its generalizability to broader patient populations is limited. Additionally, the relatively small sample size (n=46) may introduce statistical bias and limit subgroup analysis. PFS was selected as the primary endpoint, which, although relevant in early-phase trials, may not fully capture long-term clinical benefit compared with OS. In contrast, more recent phase III trials such as KEYNOTE-671 (3) and CheckMate 77T (6) have adopted OS or event-free survival as primary endpoints, supporting their role in shaping future treatment standards.
In conclusion, the long-term survival data from the NADIM trial reinforce the paradigm shift toward neoadjuvant chemoimmunotherapy in resectable stage IIIA NSCLC. These findings highlight the need for multidisciplinary collaboration, biomarker-driven treatment strategies, and continued investigation of perioperative immunotherapy sequencing. Future studies should focus on optimizing patient selection, defining the role of adjuvant therapy, integrating MRD monitoring, and managing disease progression after neoadjuvant treatment. With the evolving landscape of NSCLC treatment, the insights gained from the NADIM trial and ongoing studies will play a pivotal role in shaping the future of perioperative immunotherapy strategies.
Acknowledgments
We would like to thank Editage (www.editage.jp) for English language editing.
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-2025-202/prf
Funding: None.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-202/coif). J.S. has no conflicts of interest related to this work. However, J.S. has relationships outside of this work with Chugai Pharmaceutical, including funding grants and participation in speakers’ bureaus. Additionally, J.S. has relationships outside of this work with Johnson & Johnson, Medtronic Inc., Intuitive Surgical Inc., CSL Behring LLC, MSD, and Olympus Corporation, which include participation in speakers’ bureaus. The author has no other conflicts of interest to declare.
Ethical Statement: The author is 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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