Real-world comparison of neoadjuvant pembrolizumab plus chemotherapy versus tislelizumab plus chemotherapy in patients with resectable non-small cell lung cancer: a retrospective cohort study of treatment outcomes

Introduction

Approximately 20–25% of non-small cell lung cancer (NSCLC) is resectable tumor (1). Radical surgical resection is the cornerstone of standard treatment for resectable NSCLC (2). However, the 5-year cumulative recurrence rate among early-stage NSCLC patients who have undergone radical resection reaches a staggering 20% (3). Even with postoperative adjuvant therapy for appropriate patients, 35–44% of stage I, 59% of stage IIIa, and 76% of stage IIIb NSCLC still die within 5 years (1).

Neoadjuvant chemotherapy, aiming at increasing R0 resection rate and improving prognosis, showed an absolute 5% survival benefit at five years for patients with resectable NSCLC when compared with surgery alone (4). Additionally, there was no difference in overall survival (OS) between preoperative and postoperative chemotherapy (5). Immune checkpoint inhibitors-based regimens have currently become the standard of care for resectable NSCLC. A series of phase III clinical trials have demonstrated that patients with resectable NSCLC can significantly benefit from immunotherapy, whether used alone after surgery, alone before surgery, or simultaneously before and after surgery.

Pembrolizumab and tislelizumab are humanized monoclonal antibodies with high specificity and affinity for programmed death 1 (PD-1) that block the interaction between PD-1 and its ligands to strengthen antitumor immunity (6). In a randomized phase III trial (Keynote-671 study), neoadjuvant pembrolizumab plus chemotherapy with adjuvant pembrolizumab significantly improved event-free survival (EFS), OS, major pathological response (MPR), and pathological complete response (pCR) as compared with neoadjuvant chemotherapy alone in patients with resectable NSCLC (7). In another randomized phase III trial, neoadjuvant tislelizumab plus chemotherapy with adjuvant tislelizumab demonstrated a significant benefit for EFS and an OS benefit trend vs. neoadjuvant chemotherapy alone (8). With multiple efficacious treatment options available, it is crucial to discern the disparities in their efficacy and safety profiles, while also balancing the cost of care, to facilitate well-informed clinical decision-making. Despite demonstrating substantial clinical benefits in resectable NSCLC, there has never been a direct head-to-head clinical trial to determine the optimal choice between these two agents. Herein, we reported the real-world clinical outcomes of neoadjuvant pembrolizumab or tislelizumab combined with chemotherapy for resectable NSCLC treated in the Second Xiangya Hospital of Central South University. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-721/rc).

Methods

Patient characteristics

We retrospectively assessed the patients who received neoadjuvant pembrolizumab or tislelizumab plus platinum-based doublet chemotherapy followed by radical resection for resectable NSCLC at the Second Xiangya Hospital of Central South University between December 2017 and August 2023. Patients aged 18 years and above, diagnosed with biopsy-proven and treatment-naïve clinical stage II–IIIb NSCLC were included in the study. Patients with autoimmune disease, pulmonary interstitial disease, acute infection, or systemic immunosuppression were excluded. Patients with unavailable clinicopathological data were also excluded. The decision for patients to receive neoadjuvant chemoimmunotherapy was determined by the Second Xiangya Hospital of Central South University’s multidisciplinary team, including oncologists, thoracic surgeons, respiratory physicians, pathologists, and radiologists.

Study design

This single-center retrospective study was approved by the Institutional Clinical Research Ethics Committee of the Second Xiangya Hospital of Central South University, China (No. 2023101) and was conducted in accordance with the Helsinki Declaration (as revised in 2013). The patients provided their written informed consent to participate in this study. All patients underwent routine baseline tumor diagnosis and staging, including contrast-enhanced computed tomography (CT), CT-guided percutaneous or bronchoscope-guided transbronchial tumor biopsy, brain magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), and invasive mediastinal nodal staging with endobronchial ultrasound or mediastinoscopy if indicated. Neoadjuvant chemoimmunotherapy regimens included pembrolizumab (200 mg) or tislelizumab (200 mg) combined with chemotherapeutic agents administrated intravenously on a 21-day cycle. Usage and dosage of immune-checkpoint inhibitors (ICIs) and postoperative treatment were prescribed at the discretion of the treating physician. Normally, immunotherapy maintenance was routinely recommended as adjuvant therapy for these patients. Preoperative evaluation workup included contrast-enhanced CT or PET-CT, brain MRI, pulmonary function, electrocardiography, bronchoscopy, and invasive mediastinal nodal staging with endobronchial ultrasound if indicated.

Data extraction and evaluation

The following characteristics were extracted from our database, including age, sex, body mass index (BMI), comorbidities, history of smoking, forced expiratory volume in the first second (FEV1), pathologic type, clinical stage at diagnosis, programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS), neoadjuvant therapy dosage, duration from final therapy to surgery and neoadjuvant chemotherapy regimens. Surgical information, including surgical approach, conversion rate, extent of resection, operative time, estimated blood loss, length of postoperative hospitalization and postoperative complications and toxicity profiles, including adverse events and abnormal laboratory findings, were collected as well.

The presence of comorbidities was evaluated using a combination of clinical assessment and the Charlson Comorbidity Index (CCI) (9). Surgical complications were assessed according to the Society of Thoracic Surgeons database criteria. Radiologic response assessment was determined according to Response Evaluation Criteria in Solid Tumors. Primary tumors were evaluated for percentage of residual viable cancer that was identified on routine hematoxylin and eosin staining. Primary tumors with 0% and no more than 10% viable tumor cells were considered to have had a ypT0 and major pathologic response (MPR), respectively. pCR refers to 0% viable tumor cells remaining in residual tumor and resected lymph nodes, whereas ypT0N+ indicates 0% viable tumor cells in residual tumor but with positive resected lymph nodes. Adverse events and laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The Tumor Node Metastasis (TNM) staging was based on the 8th edition of the American Joint Committee on Cancer criteria.

Follow-up strategy

The last follow-up was set in June 2024. The follow-up was conducted through outpatient visits or telephone calls. In the initial two years post-surgery, comprehensive assessments including history taking, physical examinations, peripheral blood oncology marker tests, and chest CT scans were carried out every three months. Between the third and fifth years, follow-up evaluations were conducted every six months. Subsequently, after the fifth year, annual follow-ups were performed. Additionally, abdominal CT scans or ultrasounds, brain MRI or CT scans, and bone scans were conducted annually. Disease-free survival (DFS) was defined as the interval from the day of surgery until disease relapsed or death of any cause or last follow-up. OS was defined as the interval from the day of surgery until death of any cause or last follow-up.

Statistical analysis

All statistical analyses were conducted with the STATA/MP 17.0 software. Normal distribution was evaluated by Shapiro-Wilk Normality test. Normally distributed continuous variables were expressed as mean ± standard deviation (SD) and analyzed by using two-sample t-test, otherwise, they were expressed as median and interquartile range (IQR) and analyzed by using Mann-Whitney U test. Categorical variables were expressed as numbers and percentages and analyzed by using the Pearson’s Chi-squared test. DFS was calculated and compared using Kaplan-Meier method and log-rank test. All patients were dichotomized into two groups: pembrolizumab and tislelizumab groups. The demographic and clinical characteristics were compared between the two groups. All statistical tests were two-sided and P<0.05 was considered statistically significant.

Results

General characteristics

A total of 126 adult patients were included, including nine female and 117 male patients (female-to-male ratio of 0.077:1, Table 1). The mean age at diagnosis was 59.76 years (SD, 7.05 years) and 103 patients (81.75%) were current or former smoker. According to the CCI assessment of the presence of comorbidities, 52 (41.27%) patients had a CCI of 0, 48 (38.10%) a CCI of 1, and 26 (20.63%) a CCI of ≥2. The preoperative clinical staging was as followed: 56 (44.44%) stage IIIa, 46 (36.51%) stage IIIb, 18 (14.29%) stage IIb, and 6 (4.76%) stage IIa. Cycles of neoadjuvant therapy was 2, 3, 4, and 5 in 32 (25.40%), 41 (32.54%), 49 (38.89%), and 4 (3.17%) patients, respectively. Chemotherapy regimens included carboplatin or cisplatin plus paclitaxel in 109 (86.51%) and 17 (13.49%) patients, respectively. Of the histological subtypes, squamous cell carcinoma (SCC, 102, 80.95%) was the most common, followed by adenocarcinoma (18, 14.29%), large cell neuroendocrine carcinoma (2, 1.59%), sarcomatoid carcinoma (2, 1.59%), adenosquamous carcinoma (1, 0.79%), and lymphoepitheliomatoid carcinoma (1, 0.79%).

As shown in Table 1, the two groups were well-balanced in baseline characteristics, including age, sex, BMI at presentation, smoking history, comorbidities, FEV1, clinical stage at presentation and PD-L1 expression. However, the pembrolizumab group had a lower proportion of SCC (72.58% vs. 89.06%, P=0.02), a lower use of paclitaxel (75.81% vs. 96.88%, P=0.004) and a higher proportion of patients receiving four cycles of neoadjuvant therapy (50.00% vs. 28.13%, P=0.01). Conversely, in the tislelizumab group, there was a lower proportion of non-SCC (27.42% vs. 10.94%, P=0.02), a lower use of pemetrexed (24.19% vs. 3.13%, P=0.004) and a higher proportion of patients receiving three cycles of neoadjuvant therapy (42.19% vs. 22.58%, P=0.02). Given the distinct chemotherapy regimens for SCC and non-squamous cell carcinoma (non-SCC) patients, we conducted an additional analysis focusing solely on SCC patients and found that all baseline characteristics were matched between the two groups.

Response assessment

Preoperative radiologic evaluation showed partial response (PR) in 101 patients, stable disease (SD) in 24 and progressive disease (PD) in 1, with an objective response rate (ORR) of 80.16%. Postoperative pathological results revealed an MPR in 68 (53.97%) patients, of whom 51 (40.48%) cases had a pCR and 8 (13.56%) had a ypT0N+. The majority of patients (110, 87.30%) had reduced pathologic staging. Eighty-one (72.97%) patients with clinical N1–2 disease were downstaged to N1 or N0 disease after neoadjuvant therapy. Compared with pembrolizumab group, the incidence of ypT0N+ seemed to be higher in tislelizumab group in overall (22.58% vs. 3.57%, P=0.03) and SCC (24.14% vs. 4.55%, P=0.057) cohorts and no significant differences concerning the other neoadjuvant therapy efficacy indexes was observed between the two groups in both cohorts (see Table 2).

Surgical information

All patients underwent R0 surgery following neoadjuvant therapy. The median interval of time between the last neoadjuvant therapy and surgery was 48 (IQR, 37–64) days. Thirty-nine patients underwent open thoracotomy and the remaining 87 patients under minimally invasive surgery, of whom 63 underwent video-assisted thoracoscopic surgery (VATS) and the other 24 underwent robot-assisted thoracoscopic surgery (RATS). The most common procedure was lobectomy (67.46%), followed by bronchial sleeve lobectomy (15.08%) and bronchovascular sleeve lobectomy (10.32%). The median postoperative hospital stay was 4.85 (IQR, 3.8–6.5) days. The median operative time was 180 (IQR, 140–210) min. The median intraoperative bleeding volume was 80 (IQR, 55–100) mL. No patients experienced perioperative death. Thirty (23.81%) patients developed postoperative complications, the most common of which was oxygen therapy for respiratory failure (11, 8.73%). No significant differences were observed between the two groups in both cohorts regarding postoperative complications (see Table 3).

Toxicity profile

All of the patients developed grade 1/2 treatment-related adverse effects (AEs) during neoadjuvant therapy period (Table 4), the most common of which were alopecia (81, 64.29%), hypoalbuminemia (81, 64.29%) and anemia (80, 63.49%). As shown in Table 4, except for higher incidence of hypercholesterolemia and increased uric acid in pembrolizumab group, no significant differences regarding the other grade 1/2 AEs existed in both groups in both cohorts. Grade 3/4 treatment-related AEs occurred in 29 (23.02%) patients, the most common of which were neutropenia (17, 13.49%), leukopenia (15, 11.90%), hypertriglyceridemia (6, 4.76%) and increased aminotransferases (5, 3.97%). No significant differences regarding the grade 3/4 AEs existed in both groups in both cohorts.

Prognostic information

After a median follow-up of 26.3 months, 16 (12.70%) patients experienced tumor relapse or progression after the surgery. Ten (7.9%) patients died, among of which nine died from tumor relapse or progression and one died from COVID-19 infection on November 2022. The median DFS and OS were not reached. The one-year and two-year DFS rates were 90.4% and 87.8%, respectively and the one-year and two-year OS rates were 94.4% and 91.1%, respectively (Figure 1). Importantly, no significant differences regarding DFS was observed in both groups in overall and SCC cohorts (Figure 2).

Figure 1 DFS and OS curves of overall and SCC patients. DFS, disease-free survival; OS, overall survival; SCC, squamous cell carcinoma.

Figure 2 DFS and OS curves of overall and SCC patients stratified according to ICIs used. DFS, disease-free survival; ICIs, immune-checkpoint inhibitors; OS, overall survival; SCC, squamous cell carcinoma.

Discussion

A series of phase three clinical studies has demonstrated that neoadjuvant chemoimmunotherapy with or without postoperative immunotherapy shows favorable efficacy and manageable safety and becomes an important therapeutic modality for resectable NSCLC (10-14). Pembrolizumab and tislelizumab have demonstrated significant clinical benefits in perioperative treatment of resectable NSCLC (15,16). Keynote-671 study aimed to evaluate perioperative pembrolizumab in patients with early-stage NSCLC and found that neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved OS, EFS, MPR and pCR as compared with neoadjuvant chemotherapy alone followed by surgery (7,17). As shown by RATIONALE-315 interim analysis, perioperative tislelizumab plus neoadjuvant chemotherapy showed statistically significant and clinically meaningful improvements in MPR, pCR rates, and EFS compared with neoadjuvant chemotherapy in resectable NSCLC, as well as tolerable and manageable safety profile (8).

Although pembrolizumab and tislelizumab are both humanized monoclonal antibodies with high specificity and affinity for PD-1, these two agents have different binding orientation to PD-1 and distinct pharmacokinetics (6). Preclinical studies suggested that tislelizumab showed higher affinity to PD-1 when compared with pembrolizumab, with a 100-fold slower off-rate than pembrolizumab (6). For advanced NSCLC, several authors performed an indirect comparison between pembrolizumab and tislelizumab to explore the better choice of chemotherapy partner and found that the efficacy and safety of pembrolizumab combined with chemotherapy were similar to that of tislelizumab combined with chemotherapy (18-20).

This is the first real-world study comparing the efficacy and safety of neoadjuvant chemotherapy plus pembrolizumab versus tislelizumab in resectable NSCLC. Our results showed that there were no significant differences in ORR, percentage of primary tumors with no viable tumor cells, pathologic and lymph node downstaging, pCR, MPR, and DFS between the two groups in both cohorts. Additionally, no significant differences in the postoperative complications and grade 3/4 toxicity profiles existed in both cohorts.

Unlike the routine assessment of the exact percentage of viable tumor cells in primary tumors, pathologic response evaluation of tumor-draining lymph nodes following neoadjuvant chemoimmunotherapy is currently underappreciated (21). Only several trials have merely reported the nodal downstaging rate, ranging from 25% to 70.7% (11,21-25). Nodal downstaging rate was reported to be 74.07% and 78.95% for overall and SCC cohorts in our study, respectively. Such high heterogeneity may be mainly related to different immune checkpoint inhibitors used and distinct preoperative lymph node staging strategies. Zhai et al. recently performed a pooled analysis comparing the pathologic response of primary tumor and nodal downstaging and found that the frequency of nodal downstaging was comparable to that of MPR (21).

Postoperative positive lymph nodes were identified in 8 out of 59 patients whose primary tumor beds had no viable tumor cells, emphasizing the differential therapeutic responses induced by immunotherapy between primary tumor beds and affected lymph nodes. This phenomenon might be explained by the heterogeneity of the in situ immune patterns of T cells and cytotoxic T cells between primary tumors and metastatic lymph nodes (26). Yang et al. recently showed that primary tumor beds and paired tumor-draining lymph nodes exhibited distinct radiologic and metabolic responses to neoadjuvant immunotherapy (27). They further demonstrated that positive lymph nodes had unique characteristics of immune microenvironment, displayed as excluded T lymphocytes, abnormal high endothelial venules and decreased dendritic cells (27). Interestingly, our results showed that the incidence of ypT0N+ seemed to be higher in tislelizumab group in overall and SCC cohorts compared with pembrolizumab group. Obviously, this outcome should be considered with caution. Whether pembrolizumab outperforms tislelizumab in tumor clearance in lymph nodes deserves further investigation.

There are several limitations required to be acknowledged. First, this study is retrospective by design and involves a single institute, with limited sample size. Second, the number of patients included in this study was relatively small and the follow-up duration was quite short. Third, while the baseline characteristics were well-balanced between the two groups in the SCC cohort, there were still some nuanced disparities worth noting. In particular, the tislelizumab group showed a higher proportion of patients who had received three cycles of neoadjuvant therapy and were diagnosed with stage IIa disease. Conversely, the pembrolizumab group had a greater percentage of patients who underwent four cycles of neoadjuvant therapy and presented with stage IIIa disease, although these disparities did not achieve statistical significance. These variations have the potential to introduce selection bias. Fourthly, our study included only 24 patients with non-SCC, with 17 in the pembrolizumab group and seven in the tislelizumab group. The efficacy analysis for non-SCC revealed that both groups were comparable in terms of pathological response, and the tislelizumab group appeared to exhibit a higher ORR rate (52.94% vs. 85.71%, P=0.02). Undoubtedly, the extremely small sample size and the inconsistent chemotherapy regimens between the two groups make these results less reliable (Table S1). Despite these limitations, it is highly unlikely to perform a head-to-head clinical trial to directly compare the efficacy and safety of pembrolizumab and tislelizumab in the neoadjuvant setting, and the results from this study will be meaningful.

Conclusions

In conclusion, our real-world evidence study supports the non-inferiority of neoadjuvant chemotherapy plus pembrolizumab versus tislelizumab in terms of efficacy and safety in patients with resectable NSCLC. We believe that our findings could be an important reference for future studies comparing pembrolizumab- and tislelizumab-based treatment combinations in the neoadjuvant setting.

Acknowledgments

The authors sincerely thank the multidisciplinary team (MDT) of thoracic oncology, the Second Xiangya Hospital of Central South University.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-721/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-721/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-721/prf

Funding: This work was supported by the Changsha Municipal Natural Science Foundation (Grant Nos. kq2208333 and kq2403093), Natural Science Foundation of Hunan Province (Grant No. 2023JJ40825) and Health Commission of Hunan Province (Grant No. W20243218).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-721/coif). The 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. This single-center retrospective study was approved by the Institutional Clinical Research Ethics Committee of the Second Xiangya Hospital of Central South University, China (No. 2023101) and was conducted in accordance with the Helsinki Declaration (as revised in 2013). The patients provided their written informed consent to participate in this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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