Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
Oncologist. 2020 Aug;25(8):702-711. doi: 10.1634/theoncologist.2020-0088. Epub 2020 May 13.
Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib.
PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.
A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression.
Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib.
Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.
程序性死亡配体 1（PD-L1）的表达与接受酪氨酸激酶抑制剂（TKI）治疗的表皮生长因子受体（EGFR）突变型肺腺癌（ADC）的临床结局相关。然而，PD-L1 表达在间变性淋巴瘤激酶（ALK）阳性肺 ADC 中的作用尚不清楚。我们旨在评估 PD-L1 在接受克唑替尼治疗的 ALK 阳性肺 ADC 患者中的影响。
通过免疫组织化学（IHC）鉴定 PD-L1 表达。逆转录-聚合酶链反应用于 ALK 变体检测，免疫荧光多重染色用于探索肿瘤微环境中的免疫细胞。
本研究共纳入 78 例 ALK 阳性晚期 ADC 患者，其中 52 例接受了克唑替尼治疗。与 EGFR/ALK 野生型肿瘤相比，ALK 阳性 ADC 中 PD-L1 表达较低。在 32 例患者中鉴定出 ALK 融合变体，其中变体 3 和 5（短变体）的 PD-L1 表达高于其他变体。阴性 PD-L1 表达的肿瘤克唑替尼客观缓解率（ORR）和无进展生存期（PFS）更好（PD-L1 0%组的 ORR/PFS 为 60.7%/11.8 个月，1%-49%组为 38.5%/6.5 个月，50%-100%组为 36.4%/4.0 个月，p=0.007/0.022）。多变量 Cox 比例风险模型显示，PD-L1 0%（vs.≥1%）是 PFS 更长的独立因素（调整后的危险比 0.322，95%置信区间 0.160-0.650，p=0.002）。在三个病例中的多重免疫组化显示，不同 PD-L1 表达的肿瘤中有不同程度的免疫细胞浸润。
ALK 阳性肺 ADC 患者接受克唑替尼治疗时，阳性 PD-L1 表达与不良临床结局相关。
并非所有具有致敏驱动突变的肺腺癌对小分子酪氨酸激酶抑制剂（TKI）都有持久的反应。与 TKIs 治疗表皮生长因子受体突变型肿瘤中 PD-L1 的负面影响类似，本研究表明，ALK 阳性腺癌患者接受克唑替尼治疗时，PD-L1 阳性与反应率较低和无进展生存期较短有关。在不同的 ALK 融合伙伴中，短变体（V3 和 V5）的肿瘤与长变体（V1、V2 和 V6）相比，PD-L1 表达更高。在开始克唑替尼治疗 ALK 阳性肺癌之前检测 PD-L1，可以提供重要的预后信息。
