Treatment of LC with EGFR TKI, cytotoxic chemotherapy, or WBRT in selected patients is associated with prolong survival period. These treatment options, especially EGFR TKIs, should be studied in patients with EGFR mutation-positive NSCLC and LC.

Introduction: Osimertinib is the current recommended treatment for EGFR T790M-positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/ T790M-positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell-free DNA analysis revealed the occurrence of exon 16-skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinibresistant mechanism.Methods: We constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method.Results: We found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed to reverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells. Conclusion:HER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.

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Second-generation EGFR-TKI, afatinib, is available as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Third-generation EGFR-TKIs are under development for tumors harboring acquired EGFR T790 M.

Background: Immunotherapy that targets programmed death protein-1 (PD-1) provides improved treatment efficacy and survival in patients with metastatic non-small cell lung cancer (NSCLC), especially those with high tumor expression of PD-L1. However, data on this treatment are mostly from clinical trials enrolling highly selected patients. The real-world experience of anti-PD-1 treatment and the usefulness of tumor PD-L1 expression in prediction of treatment response are largely unknown.Methods: We retrospectively reviewed patients with stage IIIB/ IV NSCLC who received monotherapy with nivolumab or pembrolizumab, and evaluated response using RECIST 1.1 criteria. Factors associated with treatment response, progression free survival (PFS), and overall survival (OS) were determined.Results: Seventy-four NSCLC patients out of 116 examined patients were included, most of whom had adenocarcinoma (48/74, 64.9%) and received immunotherapy as a third-line or subsequent treatment (51/74, 68.9%). The median PFS and OS were 1.8 and 7.9 months, respectively. The objective response rate was 32%, but only 47 of 74 patients were evaluable. Through multivariate analysis, epidermal growth factor receptor (EGFR) mutation was independently associated with a poor treatment response. Good performance status (ECOG≤1) and smoking were independently associated with better PFS and OS. Data on tumor PD-L1 expression were available in 43 patients (58%); higher PD-L1 expression correlated with better treatment response and longer PFS. Severe treatment-related adverse events were uncommon.Conclusion: The efficacy and safety of anti-PD-1 medications for advanced NSCLC were comparable in real-world and clinical settings, except in those with poor ECOG scores. Prediction of treatment response from tumor PD-L1 expression seemed practical.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the currently recommended treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). Acquired resistance inevitably develops, with the EGFR T790M mutation comprising approximately 55% of the mechanisms of resistance following first- or second-generation EGFR-TKI therapy (e.g. gefitinib, erlotinib, afatinib, and dacomitinib). Patients without T790M are a heterogeneous group for whom platinum-based chemotherapy is currently recommended as a second-line treatment. In addition to secondary mutations in EGFR (e.g. T790M), the currently known resistance mechanisms can be classified into the following three categories: bypass pathways, downstream signaling pathways, and histologic transformations. Given the evolving knowledge and convenience of diagnosing acquired resistance mechanisms by next-generation sequencing and liquid biopsy, exploratory studies targeting these resistance mechanisms and incorporating immunotherapy into the treatment paradigm have become the mainstream of future development. This review focuses on acquired resistance mechanisms other than T790M that develop after first- or second-generation EGFR-TKI therapy. Exploratory second-line treatments targeting resistance mechanisms as well as combination immunotherapy and chemotherapy in ongoing clinical trials are reviewed here. We also highlight the recent development of next-generation sequencing and liquid biopsy in this field.

Boehringer Ingelheim Taiwan: drug supply (afatinib) and partial research funding.Merck Sharp & Dohme Corp (I.A.) LCC, Taiwan Branch: drug supply (pembrolizumab).

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