PD-1单抗联合化疗新辅助治疗局部晚期可切除口腔鳞癌的Ⅱ期临床研究

PhaseⅡclinical trial of PD-1 inhibitor combined with chemotherapy for locally advanced resectable oral squamous cell carcinoma

目的探索程序性死亡受体1(programmed death 1,PD-1)单抗联合化疗方案新辅助治疗在局部晚期可切除口腔鳞状细胞癌(简称鳞癌)的疗效。方法本研究为前瞻性随机对照Ⅱ期研究,将天津医科大学肿瘤医院2021年7月至2023年2月招募入组的病例,按1∶1随机分为试验组(特瑞普利单抗联合白蛋白紫杉醇和顺铂)和对照组(白蛋白紫杉醇和顺铂),2组患者均进行3周期新辅助治疗,新辅助治疗结束后对患者进行评估并行后续手术治疗。根据治疗完成情况按全分析集和符合方案集进行分析,采用SPSS 20.0统计分析软件编程计算。结果入组口腔癌41例,男性26例,女性15例,年龄34~74岁。试验组23例,对照组18例,共23例依照方案完成新辅助治疗及手术。试验组与对照组相比,完全缓解率(1/19比0/17)、部分缓解率(13/19比8/17)、降期率(4/19比3/17)、完全病理缓解率(8/14比2/9)数值均增高,差异无统计学意义(P值均>0.05),达到主要病理缓解者明显增高(13/14比2/9,P=0.001)。治疗相关3~4级不良反应发生率差异无统计学意义(4/23比3/18,χ^(2)=0.13,P=0.72),试验组最常见严重不良反应为粒细胞缺乏与电解质紊乱,未出现影响后续手术治疗及导致死亡的不良反应。中位随访时间15个月。试验组1年无病生存率提高(92.86%比77.78%),但差异无统计学意义(χ^(2)=0.62,P=0.42);疾病进展或死亡风险相对下降87%(P=0.029)。对于程序性死亡受体配体1(programmed death-ligand 1,PD-L1)蛋白表达联合阳性评分≥20患者,试验组与对照组相比,达主要病理缓解者更多(5/5比0/4,P=0.03)。结论免疫联合化疗方案的新辅助治疗,可提高口腔鳞癌病理缓解率,有望提高口腔鳞癌的长期生存获益,改善患者预后。

Objective To explore the effectiveness and safety of programmed death 1(PD-1)inhibitory combined with chemotherapy as a neoadjuvant therapy for locally advanced resectable oral squamous cell carcinoma.Methods This study was a randomized controlled phaseⅡtrial.Patients recruited from Tianjin Medical University Cancer Institute and Hospital from July 2021 to February 2023 were randomly divided into two groups in a 1∶1 ratio:the experimental group(Toripalimab combined with albumin paclitaxel and cisplatin)and the control group(albumin paclitaxel and cisplatin);patients in both groups underwent three cycles of neoadjuvant therapy.After completion of neoadjuvant therapy,patients were evaluated and subsequent surgical treatment was performed.According to the completion of treatment,the analysis was conducted on both the full analysis set and the protocol set.The effectiveness and safety of treatments were evaluated.SPSS 20.0 software was used for statistical analysis.Results A total of 41 cases with oral cancer were enrolled,including 26 males and 15 females,aged between 34 and 74 years old.There were 23 cases in the experimental group and 18 cases in the control group.A total of 23 cases completed neoadjuvant therapy and surgery according to the protocol.Experimental group and control group showed respectively the complete response rates of 1/19 and 0/17,the partial response rates of 13/19 and 8/17,the stage-down rates of 4/19 and 3/17,the pathologic complete response rate of 8/14 and 2/9,with no statistically significant differences in individual rates between two groups(P>0.05).The major pathological response rate of 13/14 in experimental group was higher than that of 2/9 in control group(P<0.05).The incidence of grade 3-4 adverse reactions related to treatment was low in both groups(4/23 vs.3/18,χ^(2)=0.13,P=0.72),and the most common serious adverse reactions in the experimental group were granulocyte deficiency and electrolyte disorder.There were no adverse reactions that affected subsequent surgical treatment or caused death,and the safety and tolerability were good.The median follow-up time was 15 months,and the one-year disease-free survival rate of the experimental group was higher than that of control group(92.86%vs.77.78%,χ^(2)=0.62,P=0.42),with a relative decrease of 87%in the risk of disease progression or death(P=0.029).For patients with programmed death-ligand 1(PD-L1)protein expression combined positive score≥20,the experimental group showed higher major pathological response rate than control group(5/5 vs.0/4,P=0.03).Conclusion The neoadjuvant therapy of immunotherapy combined with chemotherapy can improve the pathological remission of oral squamous cell carcinoma and the long-term survival benefits and the prognosis of patients.