New data highlighting the efficacy and safety outcomes of third‐generation EGFR‐TKI in NSCLC patients with rare EGFR mutations

Lung cancer is the most common primary cancer of the lung and is responsible for the ever increasing number of cancer-related deaths worldwide. Especially in China, the burden of lung cancer has been rising rapidly due to its large and growing population. Histologically, approximately 85% of lung cancers are non-small-cell lung cancer (NSCLC). Molecular targeted therapy has been shown to dramatically improve the quality of life and survival outcomes of NSCLC patients. One of the most important targeted drugs in NSCLC has been the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). In 2009, the IPASS study demonstrated that metastatic NSCLC patients with sensitizing EGFR mutations who received gefitinib treatment had better outcomes than patients with standard chemotherapy. Subsequent phase III clinical trials of the firstand second-generation EGFRTKIs, such as gefitinib, erlotinib, afatinib, dacomitinib, have also confirmed that these drugs could effectively improve the objective response rate and prolong progression-free survival. Likewise, the ongoing ACTIVE study has also preliminary demonstrated that apatinib plus gefitinib could be used as first-line treatment for patients with EGFRmutant advanced NSCLC. Osimertinib is a third-generation EGFR-TKI that can selectively inhibit sensitizing mutations and Thr790Met mutation. At present, it is approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR Thr790Met mutations and specific Leu858Arg mutation. A previous study found that osimertinib possessed greater central nervous system (CNS) activity compared to the first-generation of EGFR-TKIs and standard chemotherapy. In NSCLC, approximately 25%–20% of EGFR mutations are rare mutations that consist of a group of highly heterogeneous molecular alterations. Several previous studies have shown that NSCLC patients harboring rare EGFR mutations have inconsistent responses to firstor second-generation EGFR-TKIs. However, whether third-generation EGFR-TKIs, such as osimertinib, can be used to treat NSCLC patients with rare EGFR mutations is still unknown. In a recent study published in the Journal of Clinical Oncology entitled “Osimertinib for Patients with Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09)”, the authors provided the first evidence about the efficacy of osimertinib in treating patients with NSCLC harboring rare EGFR mutations. They recruited 37 metastatic or recurrent NSCLC patients from seven institutes in Korea between March 2016 and October 2017. A total of 36 patients were included in the safety and efficacy analyses. They were over 19 years old (median age: 60 years old) and histologically diagnosed as carrying rare EGFR mutations (19 [53%] Gly719Xaa, nine [25%] Leu861Gln, eight [22%] Ser768Ile, and four [11%] others). Among them, 22 (61%) patients received osimertinib treatment as first-line therapy. Their objective response rate was 50% (95% confidence interval [CI]: 33%–67%), median progression-free survival was 8.2 months (95% CI, 5.9–10.5 months) and median duration of response was 11.2 months (95% CI: 7.7– 14.7 months). A total of 11 (31%) patients developed rash, nine (25%) pruritus, nine (25%) decreased appetite, eight (22%) diarrhea, and eight (22%) dyspnea. However, all adverse events were manageable. These results demonstrated that osimertinib was effective in the treatment of NSCLC patients with rare EGFR mutations and that the toxicities caused by the treatment were acceptable. Because of the high heterogeneity and low incidence of rare mutations in EGFR, it has been difficult to evaluate the efficacy of EGFR-TKIs in the treatment of NSCLC with rare EGFR mutations. Preliminary studies have observed inconsistent responses with firstor secondgeneration EGFR-TKIs in NSCLC patients with common and rare EGFR mutations, respectively. Given that thirdgeneration EGFR-TKIs have more advantages than the firstand second-generation EGFR-TKIs, it is therefore necessary to explore the therapeutic effects of the thirdgeneration of EGFR-TKIs in NSCLC patients harboring rare EGFR mutations. Yang et al. analyzed the data from the LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 clinical trials and found that afatinib-treated NSCLC patients with some rare EGFR mutations had an objective response rate of 71% and a progression-free survival of 11 months. Only the patients with Thr790Met or exon 20 insertion mutations had an objective response rate of 9%–14% and a progression-free survival of less than three months. Based on these data, the U.S. Food and Drug Administration expanded the indications of afatinib to make it available as