Anaplastic lymphoma kinase (ALK) fusions have been identified in approximately 5% of nonsmall cell lung cancer (NSCLC) cases. ALK-tyrosine kinase inhibitors (TKIs) are the standard firstline treatment for patients with ALK-positive (ALK+) advanced NSCLC. Along with widespread use of next-generation sequencing (NGS) for the molecular diagnosis of lung cancer, an increasing number of ALK fusion partners are being reported, with the majority being effective for ALK-TKIs. Here, we present the case of a 42-year-old female with no smoking history who was diagnosed with stage IVB lung adenocarcinoma. Two rare ALK fusions were detected simultaneously by NGS in this patient: latent transforming growth factor beta-binding protein 1 (LTBP1)-ALK and huntingtin-interacting protein 1 (HIP1)-ALK. HIP1-ALK fusion was also detected by further RNA sequencing, but LTBP1-ALK failed to give a positive signal. The patient received alectinib as first-line therapy and consequently achieved a good response. Progression-free survival (PFS) was more than 19 months, and the treatment with alectinib is ongoing currently. During treatment, clinical symptoms disappeared and no significant adverse events occurred. This is the first case report describing a patient with an NSCLC tumor harboring 2 rare ALK fusions who responded to alectinib. Our report enriches the knowledge of ALK fusion sites and provides an effective clinical basis for the screening of sensitive fusions.
Background: Recent data have demonstrated the clinical efficacy of anti-PD-1/PD-L1 checkpoint inhibitors in non-small cell lung cancer (NSCLC), and approvals by regulatory authorities in first-line and second-line settings have followed. In selected treatment scenarios, expression of PD-L1 by immunohistochemistry (IHC) is considered predictive of patient outcome. A recent comparative study using the rabbit anti-PD-L1 monoclonal antibody clone 73-10 and other commercialized IHC assays demonstrated strong intra-assay reliability in NSCLC tumor cell scoring and inter-assay differences in the number of tumor cells detected by each assay (Blueprint 2 data presented at IASLC 2017). Here we report precision around a ≥ 1% tumor cell cutoff and PD-L1 expression in 428 procured NSCLC tissues using an immunohistochemical assay developed with this antibody clone. Methods: PD-L1 expression was assessed using a standardized PD-L1 IHC assay. Scoring of tumor specimens was performed on a 0 - 3+ intensity scale, with membrane staining in ≥ 1% of tumor cells at ≥ 1+ intensity defining PD-L1 positivity. Assay precision around this cutoff was assessed in 28 specimens. PD-L1 expression was evaluated in 428 Stage IIIA, IIIB, and IV procured NSCLC tissues. Assay specificity was examined in 30 normal tissues. Results: The PD-L1 IHC 73-10 assay showed > 95% negative, positive, and overall agreement in inter-day, inter-operator, intra-run, inter-instrument, and inter-lot conditions around the ≥ 1% tumor cell cutoff. The lower bound of the 95% confidence interval was > 90% for all agreement types and precision conditions. PD-L1 protein localization in normal tissues was consistent with known patterns. The 428 procured NSCLC samples had primarily squamous cell (39.5%), adenocarcinoma (43.7%) and a mixture of other less common (16.8%) histologic subtypes; 397 (92.8%) of samples were from primary and 31 (7.2%) were from metastatic tumors. Crisp membrane staining was observed in tumor cells. Other labeled cell types included macrophages, lymphocytes, endothelial cells, and fibroblasts that exhibited membrane and/or cytoplasmic staining. Of the 428 procured specimens, 270 (63.0%) were PD-L1-positive based on the ≥ 1% cutoff. Tissues of each NSCLC stage expressed PD-L1 in the full dynamic range from 0% - 100% positive. Conclusions: These data provide insight into the prevalence of PD-L1 expression in procured NSCLC specimens when stained with PD-L1 IHC 73-10, and demonstrate that this assay is precise around a ≥ 1% tumor cell cutoff while exhibiting expected antigen specificity. PD-L1 positivity in the tumor stages examined using this assay is greater than in the literature, where prevalence using different antibodies has been reported at less than 50% in various stages. Citation Format: Darlene Krohn, Mai Nguyen, Marko Srdanov, Christina Samathanam, Peng Duan, Monika Vilardo, Alexander Prenta, Sharika Vasudevan, Landry Nicholson-Legg, Debra Hanks, Aaron R. Ellison. Characterization of a standardized immunohistochemical assay for detecting PD-L1 expression in non-small cell lung cancer using anti-PD-L1 clone 73-10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4517.
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