Background Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients. Methods We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab (n = 44) or pembrolizumab (n = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated. Results The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11 (9%), ERBB4 (6%), EGFR (6%), BRAF (6%), and MET (6%). We confirmed that KRAS mut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRAS wt patients. In addition, we observed that patients with ERBB-family mutations, including EGFR, ERBB2, and ERBB4 all failed to respond to PD-1 antibodies, independently of KRAS status. Conclusions This study suggests that the analysis of KRAS and ERBB-family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors.

中文翻译：

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KRAS 和 ERBB 家族基因改变影响转移性非鳞状 NSCLC 对 PD-1 抑制剂的反应。

背景 程序性细胞死亡 1 (PD-1) 和 PD-配体 1 (PD-L1) 抑制剂代表了晚期非小细胞肺癌 (NSCLC) 的新治疗选择。然而，大约 50% 的患者没有从治疗中受益并且经历快速的疾病进展。PD-L1 表达是唯一获批的对抗 PD-1/PD-L1 治疗有益的生物标志物。然而，它的弱点已在许多研究中得到证实。最近，肿瘤突变负荷 (TMB) 已被证明是一种合适的生物标志物，但很难为所有患者获得其计算结果。方法 我们测试了特定的 NSCLC 基因改变作为潜在的免疫治疗生物标志物。从接受抗 PD-1 单克隆抗体 nivolumab (n = 44) 或 pembrolizumab (n = 3) 治疗的晚期 NSCLC 患者中获得肿瘤 DNA。通过靶向二代测序评估了 22 个基因的突变状态，并在单变量和多变量模型中测试了与生存的关联。还研究了基因突变与临床益处之间的关联。结果最常见的突变基因是TP53（49%）、KRAS（43%）、ERBB2（13%）、SMAD4（13%）、DDR2（13%）、STK11（9%）、ERBB4（6%）、EGFR (6%)、BRAF (6%) 和 MET (6%)。我们证实，KRAS mut 患者对 PD-1 抑制剂的反应更好，显示出比 KRAS wt 患者更长的无进展生存期 (PFS) 和总生存期 (OS)。此外，我们观察到具有 ERBB 家族突变（包括 EGFR、ERBB2 和 ERBB4）的患者对 PD-1 抗体均无反应，与 KRAS 状态无关。