News
Local：Home-> Company Summary: EGFR monoclonal antibodies improve partial progression of non-small cell lung
Time：2020-08-17Click：
Targeted therapies based on the molecular characteristics of tumors offer new opportunities for the treatment of patients with advanced nonsmall cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) overexpression is found in 85% of NSCLC patients, and is associated with poor prognosis. Therefore, targeted therapy targeting EGFR is expected to improve the prognosis of NSCLC patients.
The most direct targeted therapy for EGFR is the blocking of EGFR by monoclonal antibodies. In addition, EGFR is a member of the transmembrane tyrosine kinase receptor family, so tyrosine kinase inhibitors can also be used to inhibit EGFR.
Egfr-specific tyrosine kinase inhibitors have been shown to work in patients with advanced NSCLS, especially those with EGFR-active mutations, and the drugs afatinib, erlotinib, and gefitinib in this class have been used as first-line treatments in patients with advanced NSCLC with EGFR-positive mutations. Inhibitors of specific mutant EGFR and wild-type EGFR are also being tested in phase III trials.
Monoclonal antibodies against EGFR bind to EGFR on tumor cell surface, leading to down-regulation of EGFR on tumor cell surface and inhibition of EGFR signaling pathway through a series of actions. In addition, monoclonal antibodies can also play a role through immunological mechanisms, such as antibody-dependent cytotoxic effects. These drugs include cetuximab, Necitumumab, Matuzumab, Panitumumab and others.
Recently, Professor Robert Pirker of the Medical University of Vienna, Austria, published in Current Opinion in Oncology, a review of the latest advances in EGFR monoclonal antibodies for non-small cell lung cancer, based on the results of some phase III trials.
Cetuximab was first introduced in this paper. Cetuximab is a human-mouse chimerical monoclonal IgG1 antibody that inhibits THE EGFR signaling pathway by binding to the external structural domain of EGFR. It may also be effective through antibody-dependent cell-mediated cytotoxicity and complex-dependent cytotoxicity.
Cetuximab combined with first-line chemotherapy has been used in phase II and III trials in advanced NSCLC, and has also been evaluated in locally advanced NSCLC with combined chemoradiotherapy. Its usage is generally used together with chemotherapy drugs, chemotherapy as a single drug continued to be used. An initial dose of 400mg/m2 was followed by weekly intravenous infusion of 250mg/m2 until disease progression or adverse effects became intolerable.
Phase II trials with different designs assessed the efficacy of cetuximab combined with different first-line chemotherapy regiments, all showing improved chemotherapy efficacy. Randomized Phase II trials found that cetuximab and chemotherapy had similar outcomes when given simultaneously or sequentially, and were designed to include the first-line ErbituX in Lung Cancer TRUAL (FLEX) trial and the Bristol-Myers Squibb (BMS) 099 trial.
The FLEX trial compared the first-line chemotherapy regimens of cisplatin and garcetuximab with the same chemotherapy regimen alone in advanced NSCLC patients expressing EGFR. EGFR expression in the inclusion criteria was determined by immunohistochemistry, and more than one EGFR positive cell in the tumor met the criteria. By tumor classification, 47% were adenocarcinoma, 34% squamous cell carcinoma, and 19% other NSCLC.
The FLEX trial showed that cetuximab combined with chemotherapy had significant benefits. Specifically, the total survival time was improved, the median survival time was increased, the 1-year survival time was increased, and all subgroups had survival benefits. There was no significant difference in progression-free survival time.
The BMS099 trial compared cetuximab plus carboplatin and a paclitaxel regimen to chemotherapy alone in randomized, progressive NSCLC patients. The results showed that there was no significant difference in progression-free survival between the two groups, but the effective rate and mortality advantage were better than that of chemotherapy combined with cetuximab.
In the above two trials, cetuximab was administered simultaneously with chemotherapy and continued monotherapy after chemotherapy was completed. The effective rate of chemotherapy combined with cetuximab was higher, indicating that cetuximab played a role during chemotherapy. However, the specific impact of continued use of cetuximab on overall survival remains to be determined.
To determine the benefits and risks of cetuximab combined with platinum-based first-line chemotherapy, a meta-analysis was conducted based on four randomized trials. The results showed that chemotherapy combined with cetuximab had survival benefits and improved median survival time and 1-year survival rate. In terms of progression-free survival, median progression-free survival, one-year progression-free survival, and effective rate, chemotherapy combined with cetuximab was beneficial.
Subgroup analysis showed that treatment effect was independent of tumor histology, age (under 65 years and ≥65 years), gender, and smoking history. The group with the greatest benefit in total survival time came from squamous cell carcinoma. The survival benefit of cetuximab was independent of the type of platinum-based chemotherapy regimen used.
In FLEX test, tumors were divided into the high expression group of EGFR and the low expression group according to the degree of membrane staining of EGFR in immunohistochemistry and the proportion of cells with different strength. There was no difference in basic characteristics between the two groups, but the high expression group showed significant benefits when cetuximab combined with chemotherapy. However, the benefit of the low expression group was not obvious. Multiple results showed that EGFR expression in immunohistochemistry could be used as a biomarker for efficacy prediction.
In the phase III trial, there are other indicators that may have prognostic value: the rash occurred within 3 weeks of cetuximab treatment, and the survival time was longer, but the prognostic significance of this feature has not been confirmed; The presence of EGFR active mutations predicted an extended survival time independent of cetuximab. EGFR copy number has prognostic significance associated with corresponding antibody.
Cetuximab may also improve the outcome of radiotherapy or chemoradiotherapy in patients with locally advanced NSCLC. A phase II randomized trial has confirmed improved survival after addition of cetuximab; An intergroup randomized phase III trial evaluation showed that the addition of cetuximab to chemoradiotherapy did not improve survival but increased toxicity. However, subgroup analysis showed that high EGFR expression may benefit from cetuximab.
Necitumumab, a recombinant human anti-EGFR monoclonal antibody similar to cetuximab, blocks the binding and receptor activity of EGF. Due to the lack of rat structure, the incidence of hypersensitivity reactions is lower than cetuximab.
There has been a phase III trial evaluating the efficacy of the drug in combination with chemotherapy: INSPIRE. In the INSPIRE trial, there was no significant difference in the number of fatal thromboembolic events, total survival and progress-free survival, and there was an increase in level 3 or more serious side effects.
The SQUIRE test assessed the efficacy of Necitumumab in squamous cell NSCLC patients: chemotherapy with or without necitumumab, with similar anticancer effects after progression; However, the total survival time was improved after the addition of the drug. Median surial, 1-year surial, and 2-year surial were all associated with benefits, as were progression-free surial, median progression-free surial, total response rate, and disease control rates, but grade 3 or more serious side effects were increased with NECitumumab and chemotherapy.
In addition to these two drugs, a human anti-EGFR monoclonal IgG1 antibody, Mattozumab, with a longer half-life, has been tested in phase I trials and in combination with permetroxide in a phase II randomized trial. Panidumab, a fully human monoclonal IgG2 antibody against EGFR, has also been used in a phase II randomized trial in egFR-positive advanced NSCLC patients who are not suitable for chemotherapy. Due to the limited efficacy of these drugs in the trials, they have not been further used in the clinic.
In conclusion, monoclonal antibodies against EGFR provide new opportunities for the treatment of NSCLC patients. Cetuximab combined with first-line chemotherapy has been shown to improve the response rate and prolong survival in patients with advanced NSCLC. The high expression of EGFR in the immunohistochemical scores indicated that self-administration of cetuximab could be beneficial. Necitumumab improves survival in patients with advanced squamous cell carcinoma.