Targeted Therapies for Lung Cancer 肺癌的標靶治療(英文)
Targeted Therapies for Lung Cancer 肺癌的標靶治療(英文)
Non-small cell lung cancer (NSCLC) includes "adenocarcinoma," "squamous cell carcinoma," "large cell carcinoma," and "bronchoalveolar carcinoma." NSCLC often produces excessive levels of the epidermal growth factor receptor (EGFR), which contributes to the rapid growth, metastasis and drug resistance of cancer, resulting in sharp deterioration of the patient's condition.
"Iressa" (AstraZeneca, ZD1839 or gefitinib) is an EGFR inhibitor. The main “target” of attack is excessive EGFR levels in lung cancer cells, which make it lose the ability for malignant transformation, stimulate the growth, metastasis and drug resistance of cancer cells and achieve therapeutic effect. However, Iressa cannot kill cancer cells completely.
Iressa is an active tyrosinase inhibitor (TKI). Because the EGFR itself is a receptor, as well as an active tyrosinase. Iressa can antagonize the tyrosinase ATP binding region on the EGFR, cause the growth message of cancer cell membranes not to be transmitted to the cancer cell (nucleus), so as to "inhibit" or "mitigate" the growth of cancer cells.
The EGFR is mainly found in tumor cells. Without too many of such receptors, the body's normal cells are virtually immune to attack, so Iressa has fewer side effects than conventional chemotherapy drugs (white blood cells and platelets are not easily weakened, nor are the patients prone to anemia, vomiting or hair loss). Therefore, the use of Iressa will have a more "targeted" effect.
Almost all EGFR mutations occur in adenocarcinoma, and the mutation rate is as high as 55%. Lung adenocarcinoma is the most common form of lung cancer in Taiwan (40 to 50% of men and nearly 70% of women), and studies have shown that lung adenocarcinoma is not associated with smoking.
Iressa is effective for people those who are East Asians, women, non-small-cell lung adenocarcinoma patients and non-smokers. Further studies found that Iressa is more effective in patients with EGFR mutations. However, less than 10% of patients with NSCLC have EGFR mutation in Western countries. About one-third of East Asians have EGFR mutation. Therefore, Iressa will be more effective than westerners.
Generally speaking, NSCLC patients with "EGFR mutation" have a better overall survival (OS) rate, whether they receive Iressa targeted therapy or carboplatin or paclitaxel chemotherapy, than those who have no EGFR mutation.
Some patients experience rapid "remission" of their symptoms, It may occur one week later after using Iressa. More than 40% of patients, cancer-related symptoms typically improve within two weeks of taking the drug. Symptoms like poor appetite, cough, dyspnea, pain or physical condition will improve significantly whthin a few days. As a first-line treatment, Iressa has better tolerance, and patients can obtain better quality of life and prolong the progression-free survival (PFS).
Most studies have shown that patients who develop a rash within a few weeks of taking Iressa appear to have a better response rate (the chance that the tumor shrinks by more than half), and that the more severe the rash, the better the response and the longer the patient is likely to survive.
However, if the X-ray and computed tomography (CT) images of the chest or other parts of the body fail to show a decrease in the shadow of the tumors after the administration of Iressa for one month, that means the drug is very likely to be ineffective. It is suggested that the drug be discontinued and the next stage of treatment be considered.
The incidence of side effects is very low . The common symptoms include rash (nearly 50%), diarrhea (40%), dry and itchy skin (30%), abnormal liver function (20%) and nausea (10%), but most of them are mild. Only about 3% of patients have to reduce their dosage or stop taking them due to side effects.
Most patients with advanced NSCLC often exhibit significant symptoms. For advanced lung cancer patients who have previously received first-line or second-line chemotherapy regimens but with a significantly higher toxicity, more effective and well-tolerated treatment is needed. At this point, Iressa-targeted therapy is also a preferred method.
In the treatment of advanced lung cancer with Iressa, the treatment and prognosis of some patients may be similar to that of general chemotherapy, which has no advantage.
Drug Resistance of Iressa
If disease dose not deteriate, patients can take Iressa for months or even years. There are still many patients who have developed drug resistance after about half a year. At this time, the tumors are growing and getting worse. The clinical effects of Iressa or erlotinb are limited by acquired drug resistance, such as gate keeper T790 residue (T790M) or MET oncogene mutation. T790M is present in half of all patients with clinical resistance.
As with bacterial resistance, whether it's chemotherapy (agents, monoclonal antibodies) or radiotherapy, tumor cells will develop resistance sooner or later, and cells that survive the treatment may become more malignant.
New Targeted Therapy Drug for Lung Cancer
An international clinical trial of Afatinib, a new targeted drug for lung cancer, found that it is far more effective than chemotherapy, and will be available in Taiwan soon. The results showed that patients treated with "first-line therapy" - Afatinib - have a progression-free survival (PFS) of 13.6 months, compared with 6.9 months for those treated with folic acid combined with platinum-based chemotherapy.
Afatinib is also a targeted drug for EGFR mutations in lung cancer cells. The target of Afatinib occlusion gene mutation is more accurate than other lung cancer targeted drugs. Afatinib, a new targeted drug for lung cancer, has been approved and marketed to serve as another choice for patients.
Studies have clearly shown that the EGFR plays an important role in cancer. Research in cancer therapy suggests that blocking the action of receptors and substrates on the surface of these cells, or inhibiting their activity as tyrosine kinases, by using monoclonal antibodies or small molecule inhibitors, may slow or even inhibit the growth of cancer cells.
The presence or absence of EGFR mutations in patients does not justify the preferred choice of chemotherapy or targeted therapy. However, there is no doubt that compared with chemotherapy, Iressa is an oral drug with more acceptable drug tolerance, which can provide better quality of life and better therapeutic effect.