Immune checkpoint inhibitors in pediatric patients with melanoma: a systematic literature review

<b>Aim:</b> This study summarized the existing evidence on the outcomes and safety of anti-PD-1s, anti-PD-L1s and anti-CTLA-4s in pediatric patients with melanoma. <b>Materials &amp; methods:</b> MEDLINE^® and Embase were searched from database inception to 01-12-2023. <b>Results:</b> Of 1537 records identified, 27 studies (k) of 64 patients were included. Most studies were case reports (k = 16). All studies used anti-PD-1s (nivolumab, pembrolizumab) alone or anti-CTLA-4s (ipilimumab). Survival outcomes (k = 7), response outcomes (k = 15) and adverse events (k = 16) varied. Safety profiles of anti-PD-1s and anti-CTLA-4s were broadly similar to that seen in adults. <b>Conclusion:</b> Despite scarce, heterogenous data, this review can be a reference for clinicians. Future clinical trials should include adolescents to grow the evidence base on immune checkpoint inhibitors in pediatric melanoma. Immune checkpoint inhibitors have been well studied and documented in adult melanoma patients; however, little evidence is available for pediatric patients. In this systematic review of studies on pediatric patients (0–21 years) with melanoma who received either monotherapy or combination treatments of anti-PD-(L)1s or anti-CTLA-4s, data were scarce and heterogenous. Of 27 unique studies including a total of 64 patients, most studies were case reports. Multi-patient studies contained few pediatric patients with melanoma. Anti-PD-1s (nivolumab or pembrolizumab) alone or anti-CTLA-4s (ipilimumab) were reported in all studies, while some studies reported use of combination therapy. No study was identified on the use of anti-PD-L1s. Survival, response and adverse events were reported variably across studies, and conclusions on apparent trends on the comparative efficacy of treatments could not be realized. Anti-PD-1s and anti-CTLA-4s showed similar safety profiles in pediatric patients compared with adults; however, this limited finding is based on few studies of small sample sizes. Clinical trial data on adolescent patients with melanoma are required to further grow the evidence base on immune checkpoint inhibitors in pediatric melanoma.

**研究目的**：本研究旨在总结现有证据，分析抗PD-1单抗（anti-PD-1s）、抗PD-L1单抗（anti-PD-L1s）及抗CTLA-4单抗（anti-CTLA-4s）在黑色素瘤（melanoma）儿科患者中的疗效与安全性。**材料与方法**：本研究检索了MEDLINE^®与Embase数据库，检索时限为自建库至2023年12月1日。**研究结果**：初检共获1537条记录，最终纳入27项研究，涉及64例患者。其中多数研究为病例报告（k=16）。所有研究均采用抗PD-1单抗（anti-PD-1s，纳武利尤单抗（nivolumab）、帕博利珠单抗（pembrolizumab））单药治疗，或抗CTLA-4单抗（anti-CTLA-4s，伊匹木单抗（ipilimumab））治疗。生存结局（k=7）、应答结局（k=15）与不良事件（k=16）的报道情况存在差异。抗PD-1单抗与抗CTLA-4单抗的安全性特征与成人患者大体相似。**结论**：尽管现有数据稀缺且异质性较强，但本系统评价可为临床医师提供参考。未来临床试验应纳入青少年人群，以丰富黑色素瘤儿科患者中免疫检查点抑制剂（immune checkpoint inhibitors）的证据基础。免疫检查点抑制剂在成人黑色素瘤患者中的研究与记载已较为充分，但针对儿科患者的相关证据仍十分有限。本系统评价纳入的研究对象为0~21岁的黑色素瘤儿科患者，这些患者接受了抗PD-(L)1单抗或抗CTLA-4单抗的单药或联合治疗，整体数据稀缺且异质性较强。纳入的27项独立研究共涉及64例患者，其中多数为病例报告；多患者研究中纳入的黑色素瘤儿科患者数量均较少。所有研究均采用抗PD-1单抗（纳武利尤单抗或帕博利珠单抗）单药治疗，或抗CTLA-4单抗（伊匹木单抗）治疗，部分研究同时采用了联合治疗方案，但未检索到有关抗PD-L1单抗应用的研究。各项研究对生存、应答及不良事件的报道维度不一，无法就不同治疗方案的比较疗效得出明确趋势性结论。与成人患者相比，抗PD-1单抗与抗CTLA-4单抗在儿科患者中展现出相似的安全性特征，但该有限结论仅基于少量小样本研究。未来仍需开展针对黑色素瘤青少年患者的临床试验，以进一步扩充免疫检查点抑制剂在儿科黑色素瘤治疗中的证据基础。