转移性延胡索酸水合酶缺陷型肾细胞癌一线靶免联合疗效分析

Efficacy of first-line tyrosine kinase inhibitors plus immune checkpoint inhibitors in metastatic fumarate hydratase-deficient renal cell carcinoma

目的探讨一线靶免联合治疗对转移性延胡索酸水合酶缺陷型肾细胞癌(FHdeficient RCC)的临床疗效。方法回顾性分析四川大学华西医院(44例)、上海交通大学医学院附属仁济医院(27例)和中山大学肿瘤防治中心(16例)2019年3月至2022年8月收治的接受一线靶免联合治疗的转移性FH-deficient RCC患者的临床病理和基因测序资料。共87例患者,男57例,女30例,男女比例为1.9:1,中位年龄37(30,47)岁。肿瘤中位直径为7.5(5.0,10.0)cm。61例(70.1%)为FH胚系突变,26例(29.9%)为FH体系突变。49例(56.3%)为初诊转移,38例(43.7%)为异时转移。最常见的转移部位分别为淋巴结(41/87,47.1%)、骨(33/87,37.9%)、肝脏(22/87,25.3%)和肺(14/87,16.1%)。15例(17.2%)FH蛋白表达弱阳性,59例(67.8%)PD-L1表达阳性。87例采用的治疗方案分别为信迪利单抗联合阿昔替尼方案52例(59.8%),帕博利珠单抗联合卡博替尼方案6例(8.0%),替雷利珠单抗联合阿昔替尼方案6例(6.9%),帕博利珠单抗联合阿昔替尼方案5例(5.7%),特瑞普利单抗联合阿昔替尼方案4例(4.6%),其他方案13例(14.9%)。采用Kaplan-Meier生存曲线评估生存资料,并用log-rank检验比较不同治疗方案的生存差异。结果本研究87例一线靶免联合治疗的总体客观缓解率(ORR)和疾病控制率(DCR)分别为39.1%和89.7%,中位无进展生存期(PFS)和总生存期(0S)分别为16.5(11.0,22.1)个月和71.0(22.9,71.0)个月。一线信迪利单抗联合阿昔替尼方案的ORR和DCR分别为44.2%和92.3%,中位PFS为17.3(11.2,37.6)个月,中位OS未达到。一线替雷利珠单抗联合阿昔替尼方案的疗效差于其他治疗方案(PFS:4.0个月与16.6个月,P<0.01;0S:22.0个月与71.0个月,P=0.043)。亚组分析结显示,有肝转移患者的0S明显短于无肝转移患者(26.3个月与71.0个月,P=0.021),其他临床资料亚组比较的PFS和OS差异均无统计学意义(P>0.05)。结论一线靶免联合治疗对于转移性FH-deficient RCC的疗效较好,能显著延长患者的生存时间。

Objective To evaluate the efficacy of first-line tyrosine kinase inhibitors(TKI)plus immune checkpoint inhibitors(ICI)in metastatic fumarate hydratase-deficient renal cell carcinoma(FH-deficient RCC).Methods The data of 87 metastatic FH-deficient RCC patients from West China Hospital(n=44),Renji Hospital(n=27)and Sun Yat-sen University Cancer Center(n=16)from Mar 2019 to Aug 2022 were retrospectively analyzed.The median age was 37(30,47)years,the male to female ratio was 1.9:1.The median size of tumor was 7.5(5.0,10.0)cm.Sixty-one patients(70.1%)had germline FH mutations,and 26 patients(29.9%)had somatic FH mutations.Fortynine patients(56.3%)metastasis disease at initial diagnosis,and 38 patients(43.7%)had metachronous metastasis.The most common site of metastasis was lymph node(41/87,47.1%),followed by bone(33/87,37.9%),liver(22/87,25.3%),and lung(14/87,16.1%).Fifteen patients(17.2%)had weak expression of FH protein and 59 patients(67.8%)had positive PD-L1 expression.The most common treatments were sintilimab plus axitinib(52/87,59.8%),followed by pembrolizumab plus cabozantinib(7/87,8.0%),tirelizumab plus axitinib(6/87,6.9%),pembrolizumab plus axitinib(5/87,5.7%),and toripalimab plus axitinib(4/87,4.6%).Thirteen patients(13/87,14.9%)received other ICI plus TKI combination treatments.Statistical analysis was conducted using R 4.2.3 software.Kaplan Meier survival curve was used to evaluate survival data,and log-rank test was used to compare differences between treatment groups.Results The overall objective response rate(ORR)and disease control rate(DCR)of first-line TKI+ICI were 39.1%and 89.7%,respectively.The median progression-free survival(PFS)and overall survival(OS)were 16.5 months and 71.0 months,respectively.For first-line sintilimab plus axitinib,the ORR and DCR were 44.2%and 92.3%,respectively.The median PFS was 17.3 months and the median 0S was not reached for this combination treatment.The efficacy of first-line tirelizumab plus axitinib was inferior to other treatment strategies(median PFS:4.0 vs.16.6 months,P<0.001;median 0S:22.0 vs.71.0 months,P=0.043).Subgroup analyses further showed that the efficacy of ICI+TKI combination therapy was consistent in patients with different clinicopathologic and genomic features.However,patients with liver metastasis had shorter OS than those without liver metastasis(median OS:26.3 vs.71.0 months,P=0.021).Conclusion First-line TKI+ICI is effective for metastatic FH-deficient RCC and can significantly prolong the survival of the patients.