Lung, Carcinoma Clinical Trial
Official title:
An Open-labeled, Single Arm, Multicenter Phase II Study to Evaluate Efficacy and Safety of Bevacizumab Plus Chemotherapy for Advanced or Recurrent Non-Squamous Non-Small Cell Lung Cancer With EGFR-TKI Resistance
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.
n/a
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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Phase 2 |