Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Weill Cornell Medical College, New York, New York.
Clin Cancer Res. 2021 May 15;27(10):2920-2927. doi: 10.1158/1078-0432.CCR-20-4650. Epub 2021 Mar 8.
exon 20 insertions (ex20ins) are an uncommon genotype in non-small cell lung cancer (NSCLC) for which targeted therapies are under development. We sought to describe treatment outcomes and genomic and immunophenotypic characteristics of these tumors.
We identified sequential patients with NSCLC with ex20ins and compared their clinical outcomes and pathologic features with other patients with NSCLC.
Among 6,290 patients with NSCLC, 106 (2%) had ex20ins. Patients with ex20ins were more likely to be Black (14% vs. 6%; < 0.001) or Asian (22% vs. 10%; < 0.001) compared with all other patients with NSCLC. Median tumor mutational burden (TMB; 3.5 vs. 5.9; < 0.001) and proportion of tumors with PD-L1 expression ≥1% (22% vs. 60%; < 0.001) were lower in ex20ins compared with other NSCLCs (TMB, = 5,851 and PD-L1 expression, = 282) and del 19/L858R (median TMB, 3.5; = 0.001 and 39% PD-L1 ≥ 1%; = 0.02). Compared with a 2:1 cohort of patients with metastatic NSCLC without targetable alterations ( = 192), ex20ins patients had longer overall survival (median 20 vs. 12 months; HR, 0.56; = 0.007) and longer time to treatment discontinuation (TTD) for platinum chemotherapy (median, 7 vs. 4 months; HR, 0.6; = 0.02) and no improvement in TTD for immune checkpoint inhibitors (ICI; HR, 1.75; = 0.05).
With better outcomes on platinum chemotherapy, patients with ex20ins NSCLC have improved prognosis, lower PD-L1 expression and TMB, and derive less benefit from ICIs compared with patients with NSCLC without targetable oncogenes. Improving molecularly targeted therapies could provide greater benefit for patients with ex20ins.
外显子 20 插入（ex20ins）是非小细胞肺癌（NSCLC）的一种罕见基因型，目前正在开发针对该基因型的靶向治疗药物。本研究旨在描述这些肿瘤的治疗结果和基因组及免疫表型特征。
我们鉴定了连续的 NSCLC 伴 ex20ins 患者，并将其临床结局和病理特征与其他 NSCLC 患者进行了比较。
在 6290 例 NSCLC 患者中，有 106 例（2%）存在 ex20ins。与所有其他 NSCLC 患者相比，ex20ins 患者更可能为黑人（14%比 6%；<0.001）或亚裔（22%比 10%；<0.001）。与其他 NSCLC 患者相比，ex20ins 患者的肿瘤突变负荷（TMB；3.5 比 5.9；<0.001）和 PD-L1 表达≥1%的肿瘤比例（22%比 60%；<0.001）更低（TMB，=5851；PD-L1 表达，=282），并且低于 del19/L858R（中位 TMB，3.5；=0.001；39%的 PD-L1≥1%；=0.02）。与无靶向治疗靶点的转移性 NSCLC 患者（=192）2:1 队列相比，ex20ins 患者的总生存期更长（中位 20 个月比 12 个月；HR，0.56；=0.007），铂类化疗的治疗停药时间（TTD）更长（中位 7 个月比 4 个月；HR，0.6；=0.02），免疫检查点抑制剂（ICI）的 TTD 无改善（HR，1.75；=0.05）。
与无靶向致癌基因的 NSCLC 患者相比，ex20ins NSCLC 患者的铂类化疗疗效更好，PD-L1 表达和 TMB 更低，对 ICI 的获益更少，但预后更好。改进针对这些肿瘤的分子靶向治疗可能会为 ex20ins 患者带来更大的获益。
