[Efficacy of adjuvant programmed cell death 1 (PD-1) monoclonal antibody immunotherapy in Chinese patients with resected stage Ⅱ-Ⅲ melanoma].

Objective: To explore the efficacy of adjuvant programmed cell death 1 (PD-1) monoclonal antibody immunotherapy in Chinese patients with resected stage Ⅱ-Ⅲ melanoma. Methods: A total of 296 patients who underwent radical surgery for stage Ⅱ-Ⅲ cutaneous orlimb melanoma at Fudan University Shanghai Cancer Center and Shanghai Electric Power Hospital between 2017 and 2021 and received adjuvant PD-1 monoclonal antibody immunotherapy, low-dose interferon (IFN), or observational follow-up were enrolled in this study. Patients were divided into the PD-1 monoclonal antibody group (164 cases) and the IFN or observation group (IFN/OBS group, 132 cases) based on postoperative adjuvant treatment methods. Patients' disease recurrence and survival were observed. Results: Among the 296 patients, 77 had cutaneous melanoma and 219 had limb melanoma; 110 were stage Ⅱ and 186 were stage Ⅲ. Among stage Ⅱ patients, the median recurrence-free survival (RFS) in the PD-1 monoclonal antibody group (46 cases) did not reach, while the median RFS in the IFN/OBS group (64 cases) was 36 months. The 1-year RFS rates were 85.3% and 92.1% and the 2-year RFS rates were 71.9% and 63.7% in the PD-1 monoclonal antibody group and the IFN/OBS group, respectively, with no statistically significant difference (P=0.394). Among stage Ⅲ patients, the median RFS rates in the PD-1 monoclonal antibody group (118 cases) and the IFN/OBS group (68 cases) were 23 and 13 months, respectively. The 1-year RFS rates were 70.0% and 51.8% and the 2-year RFS rates were 51.8% and 35.1%in the PD-1 monoclonal antibody group and the IFN/OBS group, respectively, with a statistically significant difference (P=0.010). Stratified analysis showed that the advantage of PD-1 monoclonal antibody adjuvant therapy in improving RFS persisted in the subgroups of primary ulceration (HR=0.558, 95% CI: 0.348-0.893), lymph node macroscopic metastasis (HR=0.486, 95% CI: 0.285-0.828), stage ⅢC (HR=0.389, 95% CI: 0.24-0.63), and the subgroup without BRAF/c-Kit/NRAS gene mutations (HR=0.347, 95% CI: 0.171-0.706). In terms of recurrence patterns, in stage Ⅱ patients, the recurrence and metastasis rate was 15.2% (7/46) in the PD-1 monoclonal antibody group, significantly lower than the IFN/OBS group [43.8% (28/64), P=0.002]. In stage Ⅲ melanoma patients, the recurrence and metastasis rate was 42.4% (50/118) in the PD-1 monoclonal antibody group, also lower than the IFN/OBS group [63.2% (43/68), P=0.006]. Conclusions: In real-world settings, compared with patients receiving low-dose IFN adjuvant therapy or observational follow-up, PD-1 monoclonal antibody immunotherapy can reduce the recurrence and metastasis rate of cutaneous and limb melanoma, and prolong the postoperative RFS of stage Ⅲ cutaneous and limb melanoma patients. Patients with a heavier tumor burden benefit more from immunotherapy.目的： 探究中国Ⅱ~Ⅲ期黑色素瘤术后接受程序性死亡蛋白1(PD-1)单抗免疫辅助治疗的疗效。 方法： 收集2017—2021年复旦大学附属肿瘤医院和上海电力医院接受根治性手术且经病理诊断为Ⅱ~Ⅲ期皮肤和肢端型黑色素瘤、术后接受PD-1单抗、中低剂量干扰素(IFN)辅助治疗或单纯观察随访的296例患者，根据术后辅助治疗方法将患者分为PD-1单抗组(164例)、中低剂量IFN辅助治疗或单纯接受随访观察组(IFN/OBS组，132例)，观察患者的疾病复发和生存情况。 结果： 296例患者中，皮肤型77例，肢端型219例；Ⅱ期110例，Ⅲ期186例。Ⅱ期患者中，PD-1单抗组(46例)中位无复发生存时间(RFS)未达到，IFN/OBS组(64例)中位RFS为36个月，两组的1年无复发生存率分别为85.3%和92.1%，2年无复发生存率分别为71.9%和63.7%，差异无统计学意义(P＝0.394)。Ⅲ期患者中，PD-1单抗组(118例)和IFN/OBS组(68例)的中位RFS分别为23和13个月，1年无复发生存率分别为70.0%和51.8%，2年无复发生存率分别为51.8%、35.1%，差异有统计学意义(P＝0.010)。分层分析显示，PD-1单抗辅助治疗RFS获益的优势在原发灶溃疡亚组(HR＝0.558，95%CI：0.348~0.893)、淋巴结大体转移亚组(HR＝0.486，95%CI：0.285~0.828)、ⅢC期亚组(HR＝0.389，95%CI：0.24~0.63)及无鼠类肉瘤滤过性毒菌致癌同源体B1/c-Kit/神经母细胞瘤Ras病毒致癌基因同源物基因突变亚组(HR＝0.347，95%CI：0.171~0.706)中持续存在。从复发模式来看，在Ⅱ期患者中，PD-1单抗组复发转移率为15.2%(7/46)，比IFN/OBS组[43.8%(28/64)]显著降低(P＝0.002)。在Ⅲ期黑色素瘤患者中，PD-1单抗组复发转移率为42.4%(50/118)，也低于IFN/OBS组[63.2%(43/68)，P＝0.006]。 结论： 在真实世界中，与中低剂量IFN辅助治疗及单纯观察随访患者相比，PD-1单抗免疫辅助治疗能降低皮肤型和肢端型黑色素瘤的复发转移率，延长Ⅲ期皮肤型和肢端型黑色素瘤患者的术后RFS，其中肿瘤负荷较重的患者从免疫辅助治疗中获益更多。.