Efficacy and Safety Study of Bevacizumab Plus Chemotherapy in EGFR-TKI Resistant Non-Squamous Non-Small Cell Lung Cancer

Lung, Carcinoma

chemotherapy, EGFR-TKI resistance, Bevacizumab

Epidermal growth factor receptor (EGFR) tyrosine kinase is one of most popular target molecules in the field of anticancer drug research. EGFR is highly expressed in many types of tumor cells, which could activate EGFR cytosolic kinase activity by binding to its ligand EGF, and regulates gene expression, cell proliferation, differentiation, apoptosis through different signal transduction pathways. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), competitive to specifically combined with the EGFR kinase domain, thus inhibits its kinase activity, thereby blocking cancer cell proliferation or metastasis. At present, EGFR-TKI has been widely used in clinical activity, especially in patients with EGFR mutations, which had been proved to achieved a certain effect. But with the passage of time, a drug resistance is inevitable. At present, studies have found that the cessation of treatment immediately after EGFR-TKI resistance may lead to rapid progress of cancer. Chemotherapy, as one of the most widely accepted modality in cancer treatment, might also be one of the salvage therapies of target treatment. Therefore, in patients with better physical status (PS) scores, chemotherapy is commonly applicable. In January 2010, a study published in the journal of Clinical Lung Cancer reported the application of chemotherapy as salvage treatment for advanced non-small cell lung cancer (NSCLC) patients with resistant to first-line EGFR-TKI treatment. Of the 114 patients enrolled, 67 received sequential chemotherapy, the other 47 patients received best supportive care. The results showed that, sequential chemotherapy can improve the survival time of the patients, compared with chemotherapy and supportive care groups (11.2 months vs. 3.8 months, P\< 0.01). Furthermore, in those who received sequential chemotherapy, a regimen containing paclitaxel got higher efficiency and disease control rate than those without (48.7% vs. 21.4%, 79.5% vs. 53.5% , P\< 0.05), as well as longer progression-free survival (PFS, 5.1 months vs. 1.8 months, P\< 0.01) and overall survival (OS, 12.7 months vs. 7 months, P\< 0.01). Another study in Taiwan which enrolled 195 patients treated with at least 1 cycles sequential chemotherapy after first-line gefitinib shown similar results. Generally, gefitinib as a first-line treatment had PFS for 5 months, and the second-line treatment efficiency was 14.4%. Regimens of platinum or paclitaxel had a better treatment efficiency (50.6%). A poor therapeutic effect was reported for gefitinib as second-line therapy (5.6%). In total, the median OS of second-line treatment was 12.2 months. In addition, platinum containing regimens survival better (21.7 months vs. 8.9 months, P\< 0.01); patients with mutant EGFR benefit more in a platinum-based chemotherapy (24.5 months vs. 8.5 months, P\< 0.05). Bevacizumab (trade name Avastin ®) is a kind of recombinant humanized monoclonal immunoglobulin gamma-1 (IgG1) antibody, which can selectively inhibit the combination process of vascular endothelial growth factor (VEGF) and its receptor, Flt-1 and kinase domain receptor (KDR) in endothelial cells. A reduction of tumor angiogenesis, blood supply, oxygen and other nutrients supply could be obtained after the VEGF loss of its biological activity, thus inhibit tumor growth. The drug was approved for the first-line treatment of advanced colorectal cancer in 2004 by America food and Drug Administration (FDA),thus became the first for clinical use of drugs that targeting VEGF. As the first globally approved anti-angiogenic monoclonal antibody drugs, bevacizumab has approved for advanced colorectal cancer, lung cancer, breast cancer, renal cell carcinoma and malignant glioma patients, which was used in more than 500000 cases. In the field of advanced NSCLC treatment, clinical results confirm bevacizumab combined with chemotherapy can prolong OS and PFS of patients with NSCLC, and well tolerated. The thirty-fifth annual meeting of the European Society of Medical Oncology (ESMO) conference released a meta analysis results of bevacizumab combined with platinum chemotherapy for first-line treatment of advanced non squamous NSCLC. It is confirmed that, treatment with bevacizumab based chemotherapy for advanced non squamous NSCLC patients could achieve significant survival benefit, prolong remission time, and expected safety. Therefore, the investigators design this phase II to testify the efficacy and safety of bevacizumab + chemotherapy for EGFR-TKI resistant non squamous NSCLC.

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