Through comprehensive treatment modalities, including nonspecific cytotoxic chemotherapy, surgery, radiotherapy, and targeted therapy, the 5-year survival rate of pediatric patients with malignancies has significantly improved, reaching 85–86% (1, 2). Unfortunately, the prognosis for children with advanced or recurrent malignancies remains poor, with a 10-year overall survival (OS) and progression free survival (PFS) of only 24.5% and 18.4%, respectively (3, 4). There is an urgent need for safe and effective novel therapeutic strategies to improve outcomes for pediatric patients with advanced or recurrent malignancies.

Over the past decade, programmed cell death-1 (PD-1) inhibitors have demonstrated durable responses and mild adverse events (AEs) in adult patients with advanced or recurrent cancers across numerous clinical trials. However, study regarding the safety and efficacy of PD-1 inhibitors in pediatric patients is limited (2, 4). Results from an interim analysis of the KEYNOTE-051 trial indicated that Pembrolizumab exhibited anti-tumor activity in pediatric patients with advanced melanoma and PD-L1-positive, advanced, relapsed, or refractory solid tumor or lymphoma (5). Sintilimab, a fully humanized immunoglobulin G4 anti-PD-1 monoclonal antibody, has demonstrated promising tolerability and anti-tumor activity in pediatric patients with advanced or recurrent malignancies in a phase I study (NCT04400851) (6). Previous studies have shown that PD-1 inhibitors are more effective in pediatric patients with lymphoma than other malignant solid tumors (7, 8). Notably, pharmacodynamic study has revealed that Sintilimab binds to human PD-1 with greater affinity, engages more PD-1 molecules on CD3⁺ T-cells, and exhibits superior T-cell activating characteristics (9). These findings highlight the potential of Sintilimab as a promising therapeutic option for pediatric malignancies.

To date, no direct comparisons of Sintilimab and Pembrolizumab in pediatric patients have been conducted. Given the limited data, we performed a retrospective study to compare the safety and efficacy of Sintilimab and Pembrolizumab, both in combination with chemotherapy, radiotherapy, or targeted therapy, in pediatric patients with advanced or recurrent malignancies in a real-world setting. Subgroup analyses were performed based on tumor type and treatment line.

Although some studies have demonstrated that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies, it remains uncertain as to whether toxicity and efficacy are comparable between these PD-1 inhibitors in the real world (5, 8, 10–14). It is crucial to emphasize the significance of different PD-1 inhibitors in meeting the requirements of pediatric patients with advanced and recurrent malignancies. A recent phase 2, randomized, controlled trial demonstrated that Sintilimab exhibited similar efficacy and safety to Pembrolizumab in patients with advanced non-small cell lung cancer, regardless of PD-L1 expression levels (9). Additionally, a real-world study in China highlighted that Sintilimab was more commonly used than Pembrolizumab, with 46.2% of patients receiving Sintilimab and 7.5% receiving Pembrolizumab among 93 pediatric patients with malignancies (8). Our study addressed a critical knowledge gap by directly comparing Sintilimab and Pembrolizumab in a heterogeneous real-world cohort, where factors such as comorbidities, prior treatment burden, and irregular monitoring may influence outcomes. Our study revealed comparable safety and efficacy profiles for Sintilimab and Pembrolizumab in pediatric patients with malignancies.

Our study highlights a novel concern regarding cardiovascular toxicity in pediatric patients receiving PD-1 inhibitors. We observed relatively high rates of cardiovascular adverse events (CVAEs) following immune checkpoint inhibitor therapy, with incidence rates of 26% in the Sintilimab group and 40% in the Pembrolizumab group, primarily manifesting as arrhythmia. This finding underscores the complexity of immune-related adverse events in pediatric populations. PD-1 inhibitors enhance anti-tumor immune responses by activating T cells but may trigger excessive immune reactions leading to immune-related adverse events (15, 16). There are significant differences between children and adults in physiology, immune system development, drug metabolism and so on. As children’s immune systems are still developing, both the incidence and severity of immune-related adverse reactions may differ. Endocrine issues such as thyroid dysfunction and pituitary abnormalities could potentially impact growth and development (17). Unfortunately, there is very limited data on immune-related adverse events in pediatric patients receiving immune checkpoint inhibitor therapies (16). Previous clinical trials reported hypothyroidism incidence of 10%-20% and colitis incidence of 5%-10% in children treated with Pembrolizumab, with type 1 diabetes and myocarditis being rare but severe immune-related adverse events (3, 5–10, 12, 13, 18–22). It has been shown that Sintilimab-associated hypothyroidism occurred in 7% of cases (NCT04400851) (6). In our study, both Sintilimab and Pembrolizumab demonstrated higher rates of thyroid dysfunction compared to corresponding clinical trial data ( Supplementary Table 1 ). However, previous clinical trials have not provided detailed reports on CVAEs following immunotherapy (3, 5–10, 12, 13, 18–22). Although immune-related cardiac adverse reactions are rare in children, they carry potentially fatal consequences. Clinicians should maintain high vigilance for non-specific symptoms such as arrhythmia and elevated cardiac enzymes.

Our study found that both sintilimab and pembrolizumab were generally well-tolerated, with hematological treatment-related adverse events (TRAEs) being the most common in both groups. The incidence of grade 3–4 hematologic TRAEs was similar between the two groups, and no severe infusion reactions or grade ≥3 non-hematologic TRAEs were observed. The incidence of non-hematologic AEs, such as fever, thyroid dysfunction, pneumonia, fatigue, increased ALT/AST, gastroenteritis, and rash showed no significant difference between Sintilimab group and Pembrolizumab group. The higher incidence of TRAEs in our study compared to clinical trials (eg, NCT04400851 for sintilimab and KEYNOTE-051 for pembrolizumab) may be attributed to the real-world setting, where patients often have more comorbidities, worse general conditions, and irregular disease monitoring ( Supplementary Table 1 ) (5).

Among patients with lymphoma in our study, an ORR of 55.6% was achieved, including CR in 5 patients and PR in 3 patients, resulting in a DCR of 88.9%. These results are comparable to those of the phase I study of sintilimab in pediatric patients (NCT04400851), where the ORR and DCR were 60.0% and 100%, respectively (6). Patients treated with Pembrolizumab had an ORR and DCR of 75.0%, with 2 patients achieving CR and one achieving PR. These findings align with the phase I/II KEYNOTE-051 study (NCT02332668), showing an ORR of 60.0% among 15 patients with relapsed or refractory Hodgkin lymphoma (5). The median follow-up time for lymphoma patients in our study was 17 months, with median PFS and OS not reached for both Sintilimab and Pembrolizumab groups. The favorable prognosis of lymphoma patients indicated the need for further follow-up and long-term monitoring of thyroid and cardiac function. Our study contributes valuable real-world data on Sintilimab and Pembrolizumab in pediatric lymphoma, highlighting their potential efficacy in this population.

Among patients with non-lymphoma malignancies in our study, the ORR was 40.5% for Sintilimab and 25.0% for Pembrolizumab, while the DCR was 50.0% for Sintilimab and 35.0% for Pembrolizumab. There were no significant differences in ORR and DCR between the two groups. Although the median PFS and OS were significantly longer in the Sintilimab group (PFS: 15.0 months vs. 3.5 months, P = 0.04; OS: not reached vs. 10.0 months, P = 0.01), this difference may be related to the earlier initiation of PD-1 inhibitor therapy in the Sintilimab group, with a median of 1 treatment line before PD-1 inhibition compared to 2 in the Pembrolizumab group. When stratified by the number of treatment lines before PD-1 inhibition, no significant differences in PFS and OS were observed between the two groups among patients with ≤2 treatment lines or >2 treatment lines (all P values > 0.05). These findings suggest that the timing of PD-1 inhibitor administration may influence treatment outcomes. In the phase I trial of Sintilimab, an ORR of 21.4% and DCR of 35.7% were observed among 14 pediatric patients with non-lymphoma malignancies, with a median PFS of 1.8 months (6). Similarly, in the KEYNOTE-051 study, which evaluated Pembrolizumab in 136 pediatric patients with non-lymphoma malignancies, the ORR was 5.9%, the DCR was 26.5%, the median PFS was 1.9 months (5). In addition to these clinical trials, several studies have explored the efficacy of other PD-1 or PD-L1 inhibitors in pediatric patients with solid tumors. For instance, in the ESMART study (NCT2813135), which evaluated Nivolumab in children with relapsed/refractory solid tumors, a DCR of 20% was reported among 13 patients, with a median PFS of 1.7 months and OS of 3.4 months (21). The CHECKMATE 908 study (NCT03130959) reported a DCR of 30.8% among 85 pediatric patients with high-grade central nervous system malignancies treated with Nivolumab, with a median PFS of 1.7 months and OS of 11.7 months (12). In the iMATRIX study, which assessed Atezolizumab in pediatric malignancies, a DCR of 12.0% was observed among 75 patients with non-lymphoma malignancies (13). Furthermore, a DCR of 20.9% with Camrelizumab was reported in 43 pediatric patients with advanced osteosarcoma, with a median PFS and OS of 6.2 months (18). Collectively, these studies indicate that PD-1 or PD-L1 inhibitors generally exhibit limited efficacy in pediatric patients with non-lymphoma malignancies, which may be attributed to factors such as low tumor mutational burden or negative PD-L1 expression in the tumor microenvironment. Further optimization of treatment strategies is needed.

There are several limitations in this study. Firstly, the sample size was relatively small. Secondly, it was a retrospective study and thus had some information bias. In addition, the follow-up time was shorter in the Sintilimab group compared with the Pembrolizumab group with a median follow-up of 7 months versus 9.5 months. The study was also limited by the lack of racial diversity because it only included Asian pediatric patients.

In this real-world retrospective study, Sintilimab and Pembrolizumab both exhibited satisfactory overall safety profiles and anti-tumor activity. Notably, better anti-tumor activity was observed in patients with lymphoma compared to those with other malignancies. However, the modest efficacy observed in non-lymphoma malignancies underscores the need for further investigation into predictive biomarkers and combination therapies to enhance treatment outcomes. Long-term follow-up and enhanced monitoring of cardiac function, endocrine function and growth development are essential for pediatric patients receiving these treatments. Further prospective studies are needed to determine the optimal treatment strategies for pediatric patients with diverse malignancies.