LRP1b Loss Predicts Sensitivity to Immunotherapy in Patients with NSCLC: An Analysis of the Phase III CheckMate-026 Randomized Trial.

experimental_design

LRP1b alterations were determined by whole-exome sequencing and associated with PFS and objective response rates in patients with non-small cell lung cancer (NSCLC) in a post hoc analysis of the randomized controlled phase III CheckMate-026 (CM026) trial (NCT02041533) examining chemotherapy compared with nivolumab, adjusting for tumor mutational burden (TMB) and clinical features.

通过全外显子组测序确定的LRP1b改变与非小细胞肺癌（NSCLC）患者的无进展生存期（PFS）和客观反应率相关，在对随机对照的III期CheckMate-026（CM026）试验的事后分析中，该试验（NCT02041533）比较了化疗与纳武利尤单抗的疗效，同时调整了肿瘤突变负荷（TMB）和临床特征。

We separately evaluated a deidentified nationwide (US-based) NSCLC clinico-genomic database for associations of LRP1b alterations and PFS with anti-PD-1 immunotherapy.

我们分别评估了一个去标识的全国性（基于美国）非小细胞肺癌（NSCLC）临床基因组数据库，以研究LRP1b变异与无进展生存期（PFS）和抗PD-1免疫治疗之间的关联。

Results

In the clinico-genomic database cohort of patients with NSCLC (N = 18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n = 1,569; adjusted HR, 0.86; P = 0.014).

在该非小细胞肺癌患者临床基因组数据库队列中（N = 18,369），LRP1b突变与TP53/KRAS变异呈正相关，与EGFR/RET/MET/ERBB2变异呈负相关，并且在PD-1抑制治疗下显著改善了无进展生存期（PFS）（n = 1,569；调整后的风险比（HR），0.86；P = 0.014）。

In CheckMate-026, patients with LRP1b alterations had a statistically significant improvement in objective response rateto nivolumab versus LRP1b wild-type patients (OR 3.5; 95% confidence interval, 1.71-7.13; P = 0.0006) but not with chemotherapy (OR 0.63; 95% confidence interval, 0.32-1.26; P = 0.19), adjusting for TMB, age, gender, histology, smoking, and performance status.

在CheckMate-026研究中，与LRP1b野生型患者相比，LRP1b变异的患者对纳武利尤单抗的客观缓解率有统计学显著性改善（OR 3.5；95%置信区间，1.71-7.13；P = 0.0006），但与化疗相比没有显著性差异（OR 0.63；95%置信区间，0.32-1.26；P = 0.19），在校正肿瘤突变负荷（TMB）、年龄、性别、组织学类型、吸烟史和体能状态后。

LRP1b mutations were associated with improved PFS with nivolumab (HR, 0.66; P = 0.04) but not chemotherapy (HR, 1.26; P = 0.25), also maintained in multivariate and TMB-adjusted analyses.

LRP1b突变与纳武利尤单抗治疗的无进展生存期（PFS）改善相关（HR, 0.66；P = 0.04），但与化疗无关（HR, 1.26；P = 0.25），这一结果在多变量和校正肿瘤突变负荷（TMB）的分析中也得到维持。

Conclusions

LRP1b mutations are a candidate predictive biomarker for immune checkpoint inhibition versus chemotherapy in NSCLC.

LRP1b突变是NSCLC中免疫检查点抑制与化疗比较的候选预测生物标志物。

Further mechanistic characterization of LRP1b and prospective validation are warranted and might enable future clinical use.

需要进一步对LRP1b进行机制特征描述和前瞻性验证，这可能会促进其未来在临床中的应用。