Programmed death-ligand 1 expression in uncommon epidermal growth factor receptor mutation-positive non-small-cell lung cancer
Authors: Y. Taniguchi, M. Takeda, A. Tamiya, T. Kasai, S. Atagi
Journal: Annals of Oncology (2018)

The efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations is usually limited. Furthermore, NSCLC patients withEGFR mutations have lower programmed death-ligand 1 (PD-L1) expression compared with wild-type patients [1.Haratani K. Hayashi H. Tanaka T. et al.Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.Ann Oncol. 2017; 28: 1532-1539Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar,2.Lee C.K. Man J. Lord S. et al.Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer—a meta-analysis.J Thorac Oncol. 2017; 12: 403-407Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar]. Nevertheless, pembrolizumab, an ICI that targets PD-L1, demonstrates better efficacy compared with platinum-based chemotherapy in patients with previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells [3.Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6215) Google Scholar]. We recently reported improved outcomes in four NSCLC cases harboring both uncommonEGFR mutations (excluding del19 and L858R) and high PD-L1 expression that were treated with pembrolizumab. Thus, ICIs might be a treatment option for patients harboring uncommonEGFR mutations [4.Taniguchi Y. Tamiya A. Ishii S. et al.Effect of pembrolizumab on patients harboring uncommon epidermal growth factor receptor mutations.Ann Oncol. 2018; 29: 1331-1333Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. There are no prior reports elucidating the PD-L1 status of uncommonEGFR mutation-positive patients. Here, we examined the PD-L1 status of uncommonEGFR mutation-positive NSCLC patients. Patients who underwent biopsy and/or surgical resection for NSCLC between December 2004 and December 2017 at the National Hospital Organization Kinki-chuo Chest Medical Center, Osaka, Japan were selected consecutively. Tumor PD-L1 analysis was carried out from February 2017 to December 2017. This work was approved by our institutional review board (approval number: 634). Archived samples were newly sliced from formalin-fixed paraffin blocks and used for examination. We analyzed 411 patients in this study. Three hundred twenty-five patients were analyzed using theEGFR mutation test, PCR-Invader assay (BML, Tokyo, Japan). PD-L1 immunohistochemistry testing was carried out using the PD-L1 clone 22C3 pharmDx kit and Dako Automated Link 48 platform (Agilent Technologies/Dako, Carpinteria, CA). The PD-L1 tumor proportion score (TPS) was calculated as the percentage of at least 100 viable cancer cells with complete or partial membrane staining. Statistical analyses were carried out using the JMP statistical software program (11th version; SAS Institute, Cary, NC). Fisher's exact test was used to compare nonparametric variables. AP-value less than 0.05 was considered statistically significant. Of the 411 patients, 29 had uncommon and 78 had commonEGFR mutations. Of the 29 uncommonEGFR mutation-positive patients, 13 (44.8%) had a PD-L1 TPS of <1%, 6 (20.7%) had a PD-L1 TPS of 1%–49%, and 10 (34.5%) had a PD-L1 TPS of ≥50%. Of the 76 commonEGFR mutation-positive patients, 43 (56.6%) had a PD-L1 TPS of <1%, 27 (35.5%) had a PD-L1 TPS of 1%–49%, and 6 (7.9%) had a PD-L1 TPS of ≥50% (Table 1). The extent of PD-L1 ≥ 50% overexpression was significantly larger in uncommon compared with commonEGFR mutation-positive patients (P = 0.002).Table 1Patient baseline characteristics and PD-L1 expressionCharacteristicsAll (n = 411)CommonEGFR mutations (n = 76)UncommonEGFR mutations (n = 29)Median age (range), years70 (33-93)69 (33–87)68 (45–88)Sex: male/female270/14122/5415/14Smoking history: yes/no296/11530/4617/12Histology types: ADC/others238/17373/321/8TPS (22C3) PD-L1 < 1%137 (33.3%)43 (56.6%)13 (44.8%) 1% ≤ PD-L1 < 50%155 (37.7%)27 (35.5%)6 (20.7%) PD-L1 ≥ 50%119 (29.0%)6 (7.9%)10 (34.5%)EGFR, epidermal growth factor receptor; ADC, adenocarcinoma; TPS, tumor proportion score; PD-L1, programmed death-ligand 1. Open table in a new tab EGFR, epidermal growth factor receptor; ADC, adenocarcinoma; TPS, tumor proportion score; PD-L1, programmed death-ligand 1. This is the first report to elucidate PD-L1 expression of uncommonEGFR mutation-positive NSCLC. The characteristics of patients harboring uncommonEGFR mutations differ from those of patients with commonEGFR mutations. For example, male smokers are more prevalent among patients with uncommon mutations [5.Tu H.Y. Ke E.E. Yang J.J. et al.A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.Lung Cancer. 2017; 114: 96-102Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. In the present report, the PD-L1 TPS was significantly higher in uncommon compared with commonEGFR mutation-positive NSCLC. For NSCLC patients harboring uncommonEGFR mutations, treatment strategies considering ICIs that differ from those used for commonEGFR mutations may be needed. Further investigations are warranted. None declared.