Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama.
Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki.
Ann Oncol. 2017 Jul 1;28(7):1532-1539. doi: 10.1093/annonc/mdx183.
The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
程序性死亡-1 阻断在表皮生长因子受体基因（EGFR）突变阳性的非小细胞肺癌（NSCLC）患者中具有不同获得性 EGFR 酪氨酸激酶抑制剂（TKI）耐药机制的疗效尚不清楚。我们根据 EGFR 的 T790M 耐药突变状态，回顾性评估了此类患者接受纳武利尤单抗治疗的疗效和免疫相关因素。
我们确定了 25 例 EGFR 突变阳性 NSCLC 患者，这些患者在 EGFR-TKI 治疗期间疾病进展后接受纳武利尤单抗治疗（队列 A）。通过免疫组织化学检测获得 EGFR-TKI 耐药后肿瘤标本中程序性死亡配体 1（PD-L1）的表达和肿瘤浸润淋巴细胞（TIL）密度。对肿瘤 DNA 进行全外显子组测序以鉴定基因改变。还在 60 例患者的独立队列（队列 B）中检查了 T790M 状态与 PD-L1 表达或 TIL 密度的关系。
在队列 A 中，T790M 阴性和 T790M 阳性患者的中位无进展生存期（PFS）分别为 2.1 和 1.3 个月（P=0.099；95%置信区间的风险比为 0.48，0.20-1.24）。PD-L1 表达水平≥1%和<1%的患者的中位 PFS 分别为 2.1 和 1.3 个月（P=0.084；风险比为 0.37，95%置信区间为 0.10-1.21）。随着截断值≥10%和≥50%，PD-L1 表达水平升高时 PFS 有增加的趋势。T790M 阴性患者的 PD-L1 水平≥10%或≥50%的肿瘤比例高于队列 A 和 B 的 T790M 阳性患者。纳武利尤单抗应答者的 CD8+TIL 密度和非同义突变负担明显更高。
与 T790M 阳性患者相比，EGFR 突变阳性 NSCLC 患者在接受 EGFR-TKI 治疗后，T790M 阴性患者更有可能从纳武利尤单抗治疗中获益，这可能是由于 PD-L1 表达水平更高所致。
