预测性生物标志物可以更精确地使用免疫检查点抑制剂(ICI)治疗晚期癌症。鉴于HLA分子在免疫中的核心作用,HLA基因座的变异可能会差异影响对ICIs的反应。这项流行病学研究的目的是确定HLA-A*03作为预测免疫疗法反应的生物标志物的作用。
在这项流行病学研究中,我们调查了临床结果(总生存期,无进展生存期,和客观反应率)在八个患者队列中接受晚期癌症治疗后:三个观察性队列,包括各种类型的晚期肿瘤患者(可操作癌症靶标的纪念斯隆·凯特琳整合突变分析[MSK-IMPACT]队列,Dana-Farber癌症研究所[DFCI]简介队列,和癌症基因组图谱)和五项晚期膀胱癌(JAVELIN实体瘤)或肾细胞癌(CheckMate-009,CheckMate-010,CheckMate-025和JAVELINRenal101)患者的临床试验。总的来说,这些队列包括3,35例接受各种ICI药物(抗PD-1,抗PD-L1和抗CTLA-4抑制剂)治疗的患者和10,917例接受非ICI癌症定向治疗方法治疗的患者.我们最初模拟了MSK-IMPACT发现队列中HLA氨基酸变异与总生存期的关联,然后详细分析HLA-A*03与MSK-IMPACT临床结果之间的关联,在其他队列中复制(另外两个观察性队列和五个临床试验)。
在MSK-IMPACT队列中,HLA-A*03以累加方式与ICI治疗后总生存率降低相关(每个HLA-A*03等位基因的HR1·48[95%CI1·20-1·82],p=0·00022),验证DFCI概况队列(每个HLA-A*03等位基因的HR1·22,1·05-1·42;p=0·0097),在膀胱癌的JAVELIN实体瘤临床试验中(每个HLA-A*03等位基因的HR1·36,1·01-1·85;p=0·047)。在ICI药物和肿瘤类型中观察到HLA-A*03效应,但不是用替代疗法治疗的患者。在nivolumab治疗肾细胞癌的三项CheckMate临床试验中,HLA-A*03患者的无进展生存期较短(HR1·31,1·01-1·71;p=0·044),但不是在那些接受控制(依维莫司)治疗。在ICI组中的8个HLA-A*03纯合子中均未观察到客观反应(相比之下,222个HLA-A*03非携带者中的59个[26·6%]和76个HLA-A*03杂合子中的13个(17·1%))。在JAVELIN肾101肾细胞癌的随机临床试验中,HLA-A*03与接受ICI的患者的无进展生存期较短相关(avelumab加阿西替尼;每个HLA-A*03等位基因的HR1·59,1·16-2·16;p=0·0036),但不是在那些接受控制(舒尼替尼)治疗。在ICI组的八个HLA-A*03纯合子中的一个(12·5%)中记录了客观反应(相比之下,254个HLA-A*03非携带者中有162个[63·8%]和72个HLA-A*03杂合子中有40个[55·6%])。HLA-A*03与所有3335例ICI患者的荟萃分析结果受损相关,具有全基因组意义(p=2·01×10-8),无效应异质性的证据(I20%,95%CI0-0.76)解释:HLA-A*03是ICI反应不良的预测性生物标志物。在随机试验中需要进一步评估HLA-A*03。HLA-A*03携带可在癌症患者启动ICI的决定中考虑。
美国国立卫生研究院,默克KGaA,还有辉瑞.
Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy.
In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials).
HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer.
National Institutes of Health, Merck KGaA, and Pfizer.