Comparison of the 3 Most Commonly Used Modified PD-1 Inhibitors Plus Chemotherapy in Inoperable Wild-Type Non–Small Cell Lung Cancer

Introduction

Lung cancer remains the leading cause of cancer-related mortality globally, with non–small cell lung cancer (NSCLC) accounting for approximately 85% of cases.¹ In China, the majority of patients with NSCLC are diagnosed at middle to advanced stages due to the absence of early symptoms and regular physical examinations, resulting in poor prognoses. Therefore, it is of paramount importance to explore effective therapeutic strategies for patients with advanced NSCLC.

The past decade has witnessed remarkable advancement in immunotherapeutic strategies, culminating in their establishment as first-line interventions for diverse malignancies ranging from NSCLC to various solid tumors.² Immune checkpoint inhibitors (ICIs) function through blockade of immunosuppressive mechanisms mediated by the immune checkpoint pathway in the tumor microenvironment, thereby enhancing host antitumor immune responses. For advanced non–oncogene-addicted NSCLC, a combination of platinum-based doublet chemotherapy plus PD-1/PD-L1 inhibitors becomes the standard treatment approach for patients with an eligible performance status according to the European Society for Medical Oncology. Although ICIs targeting the PD-1/PD-L1 axis, such as pembrolizumab, nivolumab, and atezolizumab, have revolutionized treatment paradigms for advanced NSCLC, their high cost restricts accessibility in resource-limited settings.³ To address this, domestically developed PD-1 inhibitors were approved in China as cost-efficient alternatives, significantly improving treatment affordability. Tislelizumab, sintilimab, and camrelizumab, the
3 most commonly used modified PD-1 inhibitors, have exhibited great efficacy and manageable toxicities in clinical practice for treating NSCLC. However, variations in molecular structure (eg, Fc receptor–binding modifications in tislelizumab) and pharmacokinetic profiles may influence clinical outcome. Despite the advances in pharmacy engineering, direct comparisons of efficacy and safety among the 3 modified PD-1 inhibitors remain limited because most studies have focused on comparing the modified PD-1 inhibitors with imported counterparts.

This study represents the first comprehensive comparison of tislelizumab, sintilimab, and camrelizumab, combined with chemotherapy in patients with inoperable wild-type advanced NSCLC. By analyzing efficacy end points (progression-free survival [PFS] and overall survival [OS]) and safety metrics, this study aims to elucidate differences attributable to their unique pharmacological properties. The findings offer evidence-based guidance for clinicians to tailor immunotherapy regimens, ultimately enhancing treatment precision and accessibility in real-world practice.

Materials and Methods

Patient Eligibility

We retrospectively analyzed the clinical data of patients with locally advanced or metastatic NSCLC (stage IIIA-IV) at Qingdao Municipal Hospital from June 30, 2020, to June 30, 2023. The inclusion criteria were as follows: patients with ECOG performance status scores of 0 to 2; patients with pathologically confirmed diagnosis of NSCLC; patients who received 2 or more cycles of chemotherapy combined with 1 of 3 modified PD-1 inhibitors (tislelizumab, sintilimab, or camrelizumab); patients who had posttreatment response evaluation documented within 4 months of the initiation of immunotherapy; and patients with negative driver genes, including EGFR, ALK, and ROS1 gene mutations. The exclusion criteria were as follows: patients who received targeted therapy or radiotherapy during the observation; patients diagnosed with other malignant neoplasms; patients with autoimmune diseases or interstitial pneumonia; and patients whose data were incomplete. The tumors were classified according to the American Joint Committee on Cancer staging manual (eighth edition) and relevant imaging. This study protocol was approved by the Ethics Committee of Qingdao Municipal Hospital (No.2024-LW-125). Individual consent was waived because of the retrospective nature of the research. The procedures conducted in this study were in accordance with the Declaration of Helsinki (as revised in 2013).

Data Collection

Patient baseline demographics (eg, age, sex, and smoking history) and clinical characteristics (eg, cancer TNM [tumor, node, metastasis] stage, ECOG performance status, histologic type, site of distant metastasis, PD-L1 expression, line of therapy, chemotherapeutic protocols, time to death and progression, and adverse events [AEs]) were collected. Chest and abdomen CT scans and cranial MRI were routinely performed, and the therapeutic response was evaluated according to the RECIST version 1.1.⁴ ECOG performance status was assessed prior to treatment initiation. All patients were followed up through structured telephone interviews or electronic medical record review, and the last follow-up date was July 31, 2024.

Outcome Assessment

The primary end point was OS, which was defined as the time interval from initial treatment with tislelizumab, sintilimab, or camrelizumab administration to death from any cause or the last follow-up. PFS was defined as the period from the start of immunotherapy to the first documented disease progression. For patients who did not experience death events or disease progression, data were censored at the last follow-up. Objective response rate (ORR) was calculated as the combination of complete response (CR) or partial response (PR), whereas disease control rate (DCR) was determined by the proportion of patients with CR, PR, and stable disease (SD). Immune-related AEs (irAEs) were defined as AEs with a likely immunological etiology that occurred during PD-1 inhibitor treatment. Attribution was determined based on the following: temporal association with drug administration; exclusion of alternative causes (eg, infection, disease progression, or conventional chemotherapy toxicity); clinical features typical of immune-mediated phenomena (eg, rash, colitis, hepatitis, pneumonitis, endocrinopathies); and response to immunosuppressive therapy (eg, corticosteroids) where applicable. All irAEs and treatment-related AEs (TRAEs) were graded according to the Common Terminology Criteria for Adverse Events version 5.0.⁵ The primary objectives were to compare PFS, OS, and ORR among the 3 groups. The secondary objective was to compare AEs among the 3 groups.

Statistical Analysis

Categorical variables were presented as frequencies and percentages and compared using the χ² test or Fishers exact test, as appropriate. Time-to-event end points, including PFS and OS, were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. For subgroup analysis, OS and PFS were estimated via the same method after classifying patients by PD-L1 expression, chemotherapeutic protocol, histologic type, line of therapy, and tumor TNM stage, respectively. Univariate and multivariate Cox proportional hazards models were used to identify factors associated with PFS and OS. Factors with a P value less than .1 in the univariate model were then adjusted to identify independent risk factors in the multivariate regression model. All analyses were performed using SPSS version 22.0 (IBM Corp, Armonk, New York, US) and GraphPad Prism version 7.0 (GraphPad Software, San Diego, California, US). All statistical tests were 2-sided, and a P value less than .05 was considered statistically significant.

Results

Baseline Characteristics

A total of 812 patients with inoperable NSCLC were screened, and 161 patients were ultimately enrolled in this study (Figure 1). Table 1 displays the baseline characteristics of the patients. The cohort comprised predominantly men (82.6%) and current/former smokers (57.8%), with a median age of 59 years (range, 31-88). Tumoral PD-L1 expression data were available in 50.9% (tislelizumab), 55.0% (sintilimab), and 64.3% (camrelizumab) of patients. Lung adenocarcinoma was present in 111 cases (68.9%), followed by 49 patients with squamous cancer (30.4%), and the remaining patient had another rare pathologic type of NSCLC.

Short-Term Therapeutic Response

In the tislelizumab, sintilimab, and camrelizumab groups, CR rates were uniformly low (1.7% to 2.4%); PRs were present in 27 (45.8%), 21 (35%), and 22 (52.4%) of patients; SD was achieved in 29 (49.2%), 32 (53.3%), and 17 (40.5%) patients; and PD was documented in 2 (3.4%), 6 (10%), and 2 (4.7%) patients, respectively (Table 2). The ORRs were 47.5%, 36.7%, and 54.8% for the tislelizumab, sintilimab, and camrelizumab groups, respectively (P = .17), with DCRs of 96.6%, 90.0%, and 95.2% (P = .296).

Long-Term Survival Outcomes

The median PFS was 11.7 months with tislelizumab, 7.3 months with sintilimab, and 8.6 months with camrelizumab, with no significant intergroup differences (P = .535; Figure 2A). Similarly, the median OS did not differ statistically, being 17.3, 17.6, and 22.2 months, respectively (P = .841; Figure 2B). Because PD-L1 expression remains the most critical biomarker for predicting the immune response, we conducted a subgroup analysis based on PD-L1 expression. In patients who were PD-L1 positive (tumor proportion score [TPS] ≥ 1%), the median PFS was 11.8 months in the tislelizumab group compared with 7.6 months in the camrelizumab group (HR, 0.441; 95% CI, 0.203-0.957; P = .038; Figure 2D). The median PFS of 10.4 months in the sintilimab group was also significantly longer than that in the camrelizumab group (HR, 0.423; 95% CI, 0.194-0.924; P = .031; Figure 2E). These results suggest that PD-L1–positive subgroups may derive greater benefit from tislelizumab or sintilimab. Given the high rate of missing PD-L1 data (overall 44.1%), we performed a worst-case scenario sensitivity analysis to assess the robustness of these findings. Under the assumption that all missing PD-L1 data in the tislelizumab and sintilimab groups were PD-L1 positive and all missing data in the camrelizumab group were PD-L1 negative, the PFS advantage of tislelizumab over camrelizumab remained significant (HR, 0.4785; 95% CI, 0.24-0.954; P = .036), whereas that of sintilimab was no longer statistically significant (HR, 0.525; 95% CI, 0.264-1.041; P = .065). No significant survival differences were observed across other subgroups stratified by chemotherapy regimens, histology type, number of treatment cycles, or tumor stage (Figure 3).

Correlations Between Clinicopathological Characteristics and Survival Outcomes

We evaluated the impact of different factors on patient prognosis using the Cox proportional hazards regression model. Based on the results from the univariate analyses of PFS, we selected gender, ECOG performance status, and treatment line as factors for further multivariable analyses. After multivariable analyses were performed, only ECOG performance status (2 vs 0) and treatment line (second or later line vs first line) remained as the independent risk factors for PFS outcomes, suggesting that patients with poor physical status and later-line treatment were at a higher risk of disease progression (Table 3). Moreover, the multivariate analysis of OS showed that the HR for higher ECOG performance status (2 vs 0) was 5.43 (95% CI, 1.152-25.597), indicating that ECOG performance status is an independent risk factor for OS (Table 4).

Safety and Adverse Events

TRAEs of any grade occurred in 74.6% of patients with tislelizumab, 73.3% with sintilimab, and 81.0% with camrelizumab, with grade 3 to 4 TRAEs observed in 16.9%, 21.7%, and 15%, respectively. The most common TRAEs in all groups were anemia and decreased white blood cell count. Thrombocytopenia occurred more frequently in the camrelizumab group than in the other 2 groups (P = .042; Table 5). Although the distribution of chemotherapy regimens was not significantly different among the groups, the specific contribution of the PD-1 inhibitor vs the chemotherapy backbone to this hematological AE remains unclear and warrants further investigation. irAEs occurred in 20.3% to 31.0% of patients, predominantly ICI-related pneumonitis (4.8% to 10%). No statistically significant differences were observed in any grade of TRAEs (P = .652) or irAEs (P = .461).

Discussion

With the fast development of pharmaceutical technology, Chinese biopharmaceutical enterprises have made great progress in innovative drugs, especially in the field of tumor immunotherapy. The costs of domestic PD-1/PD-L1 inhibitors such as tislelizumab, sintilimab, and camrelizumab are approximately $300 per cycle, and the costs could even be as low as $60 after they have been included in the China National Essential Medicare Formulary, which offers substantial cost advantages over imported PD-1 inhibitors such as pembrolizumab and nivolumab.⁶ Most recent studies focused on comparing the modified PD-1 inhibitors with imported ones, and some have demonstrated that modified PD-1 inhibitors showed comparable survival outcomes and manageable safety profiles to those of pembrolizumab in NSCLC, indicating no significant differences between domestic PD-1 inhibitors and imported ones.^7,8 However, there are currently limited data available from previous clinical research that could directly compare the domestic PD-1 inhibitors themselves. Although these modified PD-1 inhibitors have passed bioequivalence evaluations in China, structural modifications altering stability, binding specificity, and functional activity may lead to different efficacy and safety profiles in tumor immunotherapy. Therefore, we conducted this retrospective study to establish superiority or inferiority in a real-world setting, intending to provide guidance for the choice of different modified drugs.

Tislelizumab, a humanized immunoglobulin (Ig) G4-variant monoclonal antibody, features an engineered Fc domain to attenuate the binding capacity of the FC-γ receptor on the surface of macrophages. This modification reduces the antibody-dependent cellular phagocytosis, thus avoiding the consumption of T cells and enhancing the effectiveness of immune cells.^9,10 In a phase 3 trial, although the ORR (57.4%) for tislelizumab plus chemotherapy was higher than our study (47.5%), its median PFS (9.7 months) was shorter than the present study (11.7 months).¹¹ As for sintilimab, it could attenuate PD-1 activation by sustainably occupying greater than or equal to 95% PD-1 molecules on T cells with an extremely high binding affinity. It displays higher levels of PD-1 occupancy than pembrolizumab and nivolumab with slow dissociation kinetics.¹² Regarding safety, sintilimab exhibits weak affinity to Fc receptors for IgG (FcgR), indicating that sintilimab could not induce complement or antibody-dependent cytotoxic responses.¹³ Sintilimab also displays a weak immunogenicity as revealed by low detection rates of antidrug and neutralizing antibodies, making the toxicity more tolerable.¹³ The phase 2 CTONG1901 study (NCT04252365) led by Wu Yilong directly compared sintilimab vs camrelizumab in combination with chemotherapy as first-line treatment in patients with advanced NSCLC, and demonstrated that sintilimab had similar efficacy and safety to pembrolizumab.¹⁴ In our study, the combination of sintilimab and chemotherapy was shown to result in a median PFS of 7.3 months in locally advanced or metastatic NSCLC, which appeared to be noninferior to the ORIENT-11 (NCT03607539) and ORIENT-12 (NCT03629925) studies.^15,16 Camrelizumab, a humanized IgG4-k monoclonal antibody, was the first to receive marketing authorization for the treatment of patients with NSCLC.¹⁷ The therapeutic efficacy of camrelizumab depends on its ability to block the PD-1/PD-L1 interaction, and the binding affinity uniquely relies on the glycosylation of asparagine 58 (N58) in PD-1 protein. Camrelizumab mainly employs its heavy chain to bind to PD-1, whereas the light chain sterically suppresses the binding of PD-L1 to PD-1.¹⁸ Regarding safety, one aspect deserving special mention during camrelizumab treatment is the characteristic reactive cutaneous capillary endothelial proliferation (RCCEP). As a unique cutaneous AE related to camrelizumab, the occurrence of RCCEP indicates that the special binding epitope of camrelizumab might result in a difference in regulating the immune system compared with other PD-1 inhibitors.¹⁹ In a phase 3 study, the PFS was 11.3 months for camrelizumab plus chemotherapy as a first-line treatment option for patients with advanced nonsquamous NSCLC, which is consistent with our study.¹⁶ The ORR (54.8%) observed in our cohort fell between that of the CTONG2004-ADV study (40.2%) and other trials (60.5% and 64.8% for nonsquamous and squamous NSCLC, respectively), indicating the reliability of our study.^17,19,20 Although all 3 PD-1 inhibitors developed in China demonstrated comparable overall efficacy within our cohort, their distinct structural attributes and safety profiles necessitate distinct clinical management strategies. For instance, the management of camrelizumab-associated RCCEP requires specific patient counseling and monitoring protocols. The Fc engineering of tislelizumab and sintilimab, although theoretically advantageous in mitigating specific off-target effects, warrants further investigation in diverse clinical scenarios. Although all 3 inhibitors share broad approvals in NSCLC, subtle differences in their approved indications (eg, specific histological subtypes or lines of therapy) and their distinct safety profiles inevitably influence therapeutic selection in practice. Furthermore, beyond approved indications and biomarker profiles, patient tolerance represents a crucial practical consideration in selecting among PD-1 inhibitors. Tolerance not only encompasses the management of irAEs but also influences treatment adherence and quality of life, and the feasibility of long-term therapy, all of which are essential in the long-term management of advanced NSCLC. For instance, the distinct safety profiles of these agents, such as camrelizumab-associated RCCEP, may affect patient acceptance and persistence with therapy. Therefore, individualized treatment strategies should integrate tolerance assessment alongside biomarker-driven selection to optimize both clinical outcomes and patient experience. Within our institution, the choice of PD-1 inhibitors is determined by multifactorial considerations, integrating emerging evidence (eg, the CTONG1901 study) and practical considerations such as drug accessibility, particularly the health insurance policy.

In the present study, our results demonstrated no significant differences in median OS or PFS among the 3 groups. To exclude the possible influence of confounding factors on efficacy, the median PFS was compared among the 3 inhibitors across various subgroups, including PD-L1 expression, pathological type, treatment line, and strategy, etc. Subgroup analysis revealed a PFS advantage for tislelizumab and sintilimab over camrelizumab in patients who were PD-L1 positive, which might be attributable to the distinct mechanisms of action and binding characteristics discussed above, suggesting that biomarker status could interact with specific drug properties. Because PD-L1 expression remains the most validated biomarker for predicting the response to immunotherapy in patients with advanced NSCLC, these results offer novel insights into biomarker-driven therapeutic selection for domestic PD-1 inhibitors, reinforcing its role as a predictive biomarker.^21,22

The results of the multivariate Cox analysis indicated that ECOG performance status is an independent risk factor for both the PFS and OS in patients with advanced NSCLC. We observed that patients with an ECOG performance status of 2 had significantly shorter median PFS (7.8 months vs 10.85 months) and OS (13.6 months vs 19.3 months) than those with a performance status of 0, which is consistent with the study by Friedlaender et al.²³ As a validated scale quantifying disease-related functional impairment, ECOG performance status serves as both a functional assessment tool and a prognostic indicator. Notably, stringent eligibility criteria in randomized controlled trials often exclude patients with an ECOG performance status of 2 or higher, particularly in frontline ICI investigations. To our knowledge, most of the clinical studies predominantly stratify patients into performance status 0 to 1 cohorts. Therefore, our study provided a more realistic clinical setting in NSCLC therapy. Because a meta-analysis demonstrated that immune-based monotherapy or combination therapy is associated with improved survival outcomes irrespective of ECOG performance status (0 or 1), we focused on the comparisons between performance status 2 and performance status 0 to 1 populations.²⁴ Our results align with a pooled analysis of trials showing ECOG performance status of 2 or higher remains an important prognostic factor in patients treated with ICIs in advanced NSCLC, indicating that patients with better ECOG performance status may gain survival benefits from immunotherapy.²⁵ Another risk factor identified to be significantly associated with median PFS in the multivariate Cox analysis is the treatment line. Patients receiving second- or later-line treatment had a shorter PFS (7.4 months vs 10.6 months) than those with first line, indicating that the increased line of combination therapy independently correlated with a deteriorated tumor response. This finding is consistent with a study that also showed the efficacy of second-line therapy is inferior to that of first-line therapy.²⁶ The prognostic impact of ECOG performance status and treatment line highlights the importance of patient stratification in clinical decision-making. Additionally, because emerging biomarkers, including neutrophil-eosinophil ratio and serum albumin, have recently gained recognition as predictive biomarkers in immunotherapy response profiling, comprehensive exploration of novel prognostic determinants remains imperative to optimize risk stratification frameworks.^27,28

With the widespread use of immunotherapy, irAE management has emerged as a critical concern because some AEs (eg, myocarditis and pneumonitis) are clinically occult yet potentially fatal. In clinical practice, it is challenging to distinguish some irAEs from the AEs of chemotherapy. Some irAEs lack specific diagnostic criteria, which may result in bias in data analysis. For instance, the occurrence of some hematological AEs (eg, thrombocytopenia) could potentially be attributed to chemotherapy or immunology. Furthermore, rare toxicities such as hearing loss, which was reported in other ICI-treated populations, were not documented in our cohort, possibly due to underreporting or ethnic differences.²⁹ It should be noticed that the actual incidence of AEs in practice may be higher than the reported medical records, as the recording of low-grade AEs may not be rigorous in the real world. Future prospective studies with standardized AE monitoring and detailed attribution analyses are warranted to further elucidate the distinct safety profiles of these agents.

This study has several limitations that warrant consideration. Firstly, the single-center design and exclusive inclusion of Chinese participants may restrict the generalizability of findings across diverse populations. Secondly, the retrospective nature inherently restricts the standardization of chemotherapy regimens and dosing protocols compared with prospective trials. Thirdly, incomplete biomarker documentation was noted, particularly regarding PD-L1 immunohistochemical data in a subset of cases. The high proportion of missing PD-L1 expression data (overall 44.1%) may compromise the statistical power and validity of the corresponding subgroup analyses. Therefore, the observed PFS advantage of tislelizumab and sintilimab over camrelizumab in patients who are PD-L1 positive should be interpreted with caution. Future prospective studies with comprehensive and systematic biomarker profiling are warranted to validate these findings. Furthermore, our study lacked data on emerging biomarkers (eg, TMB, STK11 mutations) and tumor microenvironment features (eg, CD8+ T-cell density), which may refine prognostic stratification.³⁰ Finally, insufficient follow-up duration limited long-term survival assessment, which may influence the robustness of the results. These limitations highlight critical directions for subsequent prospective multicenter investigations with extended observation periods and standardized biomarker profiling.

In conclusion, tislelizumab, sintilimab, and camrelizumab demonstrated comparable efficacy and safety in advanced NSCLC. However, the superior PFS observed with tislelizumab and sintilimab in PD-L1–positive subgroups implies potential mechanistic differences in PD-1/PD-L1 axis modulation and highlights the importance of biomarker-driven selection among domestic PD-1 inhibitors. These findings underscore the need for personalized immunotherapy strategies where cost-effective domestic alternatives are utilized. In the next 5 years, we anticipate increased adoption of domestic PD-1 inhibitors globally, driven by cost-effectiveness and biosimilar development. Personalized regimens leveraging emerging biomarkers (eg, circulating tumor DNA) and artificial intelligence–guided selection of therapeutic strategies may further optimize outcomes.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contributions

All authors contributed to the study’s conception and design. Dapeng Wu and Juanjuan Cui collected and analyzed the data. Dapeng Wu and Wenjing Zhu wrote the manuscript. Tao Qin and Hanlin Xu revised the manuscript.

Corresponding Author

Tao Qin; Email: 313263788@qq.com

Hanlin Xu; Email: 18661807795@163.com

Funding

This work was supported by grants from the Natural Science Foundation of Qingdao Municipality (No.25-1-1-229-zyyd-jch) to Dapeng Wu. This study was supported by grants from the Natural Science Foundation of Shandong Province (No. ZR2022QH055) to Tao Qin. This work was also supported by Natural Science Foundation of Shandong Province (No. ZR202111120048), 2022 Shinan District Science and Technology Plan Project (No. 2023-2-015-YY) to Wenjing Zhu.

Data Availability Statement

The data are available on request from the corresponding author.

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