Chemoimmunotherapy for Patients with Resectable Non-Small Cell Lung Carcinoma: Real-World Data Analysis from a Surgical Point of View

Niels Michael Dörr-Jerat^1,2*, Miriam Möller³, Stanislav Hajduch¹, Claus Jürgen May¹, Stephan Eisenmann⁴, Wolfgang Schütte³, Kevin Rudolph⁵, Marcus Krüger^1,2

¹Department of Thoracic Surgery, Martha – Maria Hospital Halle – Dölau, Halle (Saale), Germany
²University Hospital Halle. Medical Faculty of the Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
³Department of Pneumology, Martha – Maria Hospital Halle – Dölau, Halle (Saale), Germany
⁴Department of Pneumology, University Hospital Halle, Halle (Saale), Germany
⁵Department of Neurosurgery, BG Klinikum Bergmannstrost, Halle,  Halle (Saale), Germany

*Correspondence author: Niels Michael Dörr-Jerat, Department of Thoracic Surgery, Martha – Maria Hospital Halle – Dölau, Halle (Saale), Germany and University Hospital Halle. Medical Faculty of the Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; Email: [email protected]  

Citation: Dörr-Jerat NM, et al. Chemoimmunotherapy for Patients with Resectable Non-Small Cell Lung Carcinoma: Real-World Data Analysis from a Surgical Point of View. J Surg Res Prac. 2025;6(3):1-12.

Copyright^© 2025 by Dörr-Jerat NM, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Table 1: Clinical trials on perioperative chemoimmunotherapy.

Table 2: Baseline characteristics.

Table 3: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Discussion

PD-L1 Status

Nivolumab is the first immune checkpoint inhibitor approved by the European Medicines Agency (EMA) for the neoadjuvant therapy of resectable NSCLC patients with a high risk of recurrence (size ≥5 cm; N+ status) and a tumoral PD-L1 expression ≥1%. The approval for PD-L1-positive NSCLC patients was based on subgroup analysis of the Checkmate816 trial. Across the PD-L1 subgroups, CIT was shown to be beneficial. Moreover, the use of PD-L1 expression as an immune checkpoint inhibitor biomarker is particularly controversial. Indeed, numerous trials have demonstrated the efficacy of IT in patients with PD-L1-negative tumors [18]. According to the Danish cohort study published 2021 by Cronin-Fenton et al., tumoral PD-L1 expression in stage III unresected NSCLC tumors was not associated with OS or disease progression. However, PD-L1 expression in tumor-infiltrating immune cells and the extent of PD-L1 expression in tumors are associated with survival benefit [19]. Other authors argue that the combination of immunotherapy with platinum-based chemotherapy in the first-line setting is beneficial regardless of the tumoral PD-L1 status [20]. For example, in 2024, Sorin et al published a systemic review and meta-analysis that included 8 randomized clinical trials. The author’s findings suggest that even patients with resectable NSCLC with tumor PD-L1 levels <1% may have an event-free survival benefit from neoadjuvant chemoimmunotherapy [21]. Even true, the methods and assays used for the assessment of PD-L1 expression via immunohistochemistry are variable, and tumoral PD-L1 expression appears to be highly heterogeneous. Some studies have shown higher PD-L1 expression in immune cells than in tumor cells, even in the same tumor region [22]. Treatment-related adverse events and treatment discontinuation are related to CIT. Thus, indications for CIT need further research addressing biomarkers other than the tumoral PD-L1 status. From a surgical perspective, we recommend safe decision-making at the individual patient level. Consequently, since numerous publications [23, 24] have shown the safety of immunotherapy in the neoadjuvant setting, indications, such as the tumoral PD-L1 status, should not be made on a currently uncertain basis. In addition to other biomarkers, further treatment individualization in the sense of multimodal neoadjuvant therapy could also improve patient outcomes. Since 2024, perioperative pembrolizumab has been approved by the EMA for resectable NSCLC without limitations based on PD-L1 expression (16). However, Peng et al. emphasized the benefits of nivolumab plus ipilimumab plus chemotherapy for NSCLC patients with PD-L1-negative expression, and nivolumab plus chemotherapy plus bevacizumab both appear to be the most effective therapeutic strategies for this population [25]. However, further research comparing treatment options in PD-L1-negative patients is needed.

Assessment of Resectability

Advanced tumors are more likely to need thoracotomy than smaller localized tumors are. The median tumor size in the VATS subgroup was 53 cm (range 26-71) versus 63 cm (range 9-112) in the thoracotomy subgroup. We included six patients with advanced NSCLC (≥ UICC stadium IIIA). Three patients presented with distant metastases (pulmonal and cerebral), one with abdominal lymph node metastasis. Two patients had UICC stage IIIB disease because of cN2 disease. All patients with distant metastases underwent local metastasectomy before thoracic surgery. Despite adjuvant IC with pembrolizumab, one of these patients presented with local recurrence of cerebral metastasis 12 months after diagnosis of NSCLC and 6 months after lung surgery. Consequently, three other patients are alive without recurrence despite having advanced disease. One of those patients had PD-L1 positivity. advanced squamous cell carcinoma of the left upper lobe of the lung. The patient presented with evidence of mediastinal and abdominal lymph node metastases as well as synchronous colon carcinoma. After hemicolectomy, he was treated with 3 cycles of neoadjuvant CIT before VATS lobectomy. Leukopenia and enterocolitis with ulceration occurred within the CIT. However, the patient was discharged 7 days after lung surgery. A complete pathological response was reported.

A total of 39% (n=7) of our patients had a cN2 status. Patients with traditionally advanced NSCLC with distant metastases or contralateral lymph node metastases (cN3 status) were excluded from curative resection. According to Raman et al., surgery as part of a multimodal approach in clinical N3-stage NSCLC is associated with similar or worse short-term but improved long-term survival compared with chemoradiation. Thus, in a selected group of patients with N3-stage NSCLC, surgery may be useful in a multimodal therapy setting [26]. No patients with N3 carcinoma were included in our study. However, all included clinical N2-stage NSCLC patients had pathological ypN0-carcinoma (χ²(4) = 3.49, p = 0.479, φ = 0.44) with at least a major pathological response (χ²(2) = 4.55, p = 0.103, φ = 0.50).

Our findings demonstrated that CIT in patients with locally advanced potentially resectable NSCLC, followed by major oncologic lung resection, may be a beneficial approach. Peer et al. emphasized that preneoadjuvant bulky mediastinal disease (lymph nodes > 20 mm), persistent postoperative N2 disease, R1 resection, preoperative N2 multistation disease and postoperative stage IIIA emerged as negative predictive factors for patients with major oncologic lung resection after neoadjuvant chemotherapy or chemoradiation in potentially resectable stage III NSCLC [27]. However, further research is needed to determine the relevance of preneoadjuvant bulky mediastinal disease, preoperative clinical N2 multistation disease and N3-stage NSCLC after neoadjuvant CIT. However, the variability of patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many ways [28]. Patient safety should be considered when deciding on indications. Although the statement is arbitrary, Daly et al. recommend oncologic lung resection in the context of multimodal treatment approaches for advanced stage III NSCLC only in departments with perioperative mortality ≤5% [29]. Early evidence suggested that surgery after neoadjuvant CIT is feasible and can be performed safely [6], although surgery may be more complex and challenging than usual, and we do not yet know the impact of a general change in the indication for surgery in the CIT setting beyond stage IIIA NSCLC.

Response Evaluation

Changes in tumor burden after CIT were termed the response. The radiological response criterion (called the Response Evaluation Criteria in Solid Tumors [RECIST]) before surgery (Table 3) obtained by CT scans was distinguished from the pathological response achieved by the pathological examination of the tumor itself. Treatment-induced response is used as a surrogate of survival [30]. Thus, criteria for defining response to treatment are crucial. Thoracic surgeons need to know how to address the discordance between postoperative pathological and preoperative radiological responses obtained via CT scans. The challenge is to find a priori features that can distinguish pseudoprogression from progressive disease. Thus, we are able to determine whether the risk of extensive tumor resection is justified and which patients may not benefit from surgery.

During CIT, lesions may present a large spectrum of heterogeneous responses that vary in terms of form, timing, and duration. If the tumor enlarges before shrinking, this process is known as pseudoprogression (pPD). pPD is typically associated with the activation of tumor-infiltrating lymphocytes [31]. Another described effect, called “nodal immune flare”, also results in pPD. This radiological nodal progression is based on immune cell infiltration and granulomas, without evidence of malignancy on pathological examination [32]. Thus, the RECIST criteria are limited in their ability to predict patient response [33] and might underestimate the benefit of CIT [34].

According to the 2019 meta-analysis published by Lu et al., tissue assessment of PD-L1 was the best response biomarker for predicting response to checkpoint blockade [35]. Currently, we know that the expression of a biomarker is heterogeneous, comprising only a part of the whole population, and provides a snapshot, which therefore does not correspond to reality or tumor biology. Furthermore, tissue biopsy is an invasive diagnostic test with inherent risk. Research on biomarkers such as circulating tumor DNA (ctDNA), circulating HLA-DRlow monocytes or dendritic cells and radiomics are promising features for overcoming this gap [36-38]. Yue et al. emphasized the high concordance between ctDNA and pathological response. The authors also set out to determine the prognostic value of perioperative ctDNA levels in predicting recurrence [36]. An alternative approach to predicting response is to analyze the patient’s microbiome to monitor the response to CIT [39]. We included a male patient in our series who needed lower bilobectomy with chest wall resection for right-sided central NSCLC despite a partial response to CIT (ca. 30% increase in tumor size). According to the pathological assessment, there was evidence of a complete pathological response (no vital tumor). The patient is alive without recurrence after almost 5 years of follow-up. We currently do not know whether these patients or comparable patients would have an equivalent oncological outcome with a less extensive surgical procedure. Currently, surgery is indispensable. An ambitious goal will be to identify patients with NSCLC who will benefit entirely from avoiding local therapy.

Conclusion

Until the total neoadjuvant CIT for NSCLC in selected patients is part of clinical practice, surgery remains a prerequisite for improving the prediction and meaning of response rates as an endpoint of upcoming research. Thus, we recommend exploration whenever feasible and safe. Because operations after CIT are often more challenging than upfront surgery, oncologic lung resection should be performed by an experienced thoracic surgeon in high-volume departments with low perioperative mortality.

Conflict of Interest

The authors declare no conflict of interest.

Funding

The authors declared no funding was received during the writing of this manuscript.

Ethics Approval and Consent to Participate

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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The ethics committee of the medical chamber of the state of Saxony-Anhalt (Headquarter Dessau-Rosslau) approved the study protocol (approval number: 66/23). Written and informed consent was obtained for the conduct of the study with anonymous clinical data analysis.

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Author’s Contribution

NMDJ analyzed and interpreted the patient data and wrote the manuscript; MM analyzed and interpreted the patient data and wrote the manuscript; SH and CJM operated on the patients and supervised the perioperative course; SE and WS supervised and indicated immunotherapy; and KR advised on the preparation of the statistics. MK supervised the whole interpretation and writing process, operated the patients and supervised the perioperative course.

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