Targeted therapy (eGFR) in the treatment of metastatic non-small cell lung cancer

Article written by BS. Nong Ngoc Son - Doctor of Chemotherapy and Palliative Treatment, Oncology Center - Vinmec Central Park International General Hospital.

This method uses drugs capable of killing strong proliferative cells (regardless of cancer cells or normal cells), thereby prolonging the average survival time about 8-9 months and helping more One-third of patients with metastatic lung cancer are likely to live for 1 year from diagnosis and initiation of treatment.

Lung cancer is a malignant disease of the lungs. About 85%-90% of cases are related to smoking status (active or passive). According to cancer data in 2018, there were more than 2 million new cases of lung cancer worldwide, more than 1.7 million deaths, making lung cancer a common cancer and has the second highest mortality rate (after liver cancer) in our country.
Non-small cell lung cancer accounts for more than 80% of cases, including adenocarcinoma, squamous cell carcinoma and a small number of large cell cancers. Silent progression and poor prognosis are important features of this disease. Patients may come to the doctor because of a prolonged cough, coughing up blood, difficulty breathing, chest pain, bone pain...
But then, more than 50% of the cases were in the metastatic stage, ie the cancer cells. has spread to the lungs and other organs of the body and the prognosis for 5-year survival of these cases is very low, only about 6%.

Treatment goals for metastatic lung cancer are to relieve symptoms, improve quality of life, slow tumor progression and prolong survival. Prior to the advent of targeted therapy, chemotherapy was the only specific treatment for metastatic disease.

Over the past 30 years, research on genetic profiles in cancer pathology, especially lung cancer, has really "exploded". One of the achievements is the detection of important gene mutations that affect cancer, or "Driver mutations". Since then, scientists have researched a form of drug capable of inhibiting the activity of these gene mutations, preventing cancer cells from growing, and promoting the natural process of cell death.
Treatment using drugs with the above mechanism of action, targeting molecular targets is called targeted therapy.

For lung cancer, mutations in the EGFR (Epideral growth factor receptor) gene were the first approved therapeutic target and are still being studied to this day.
This is the most common type of gene mutation in lung cancer patients, especially in the Asian population, female patients, non-smokers and lung cancer cells of adenocarcinoma origin. According to a study in Vietnam, for every 100 lung cancer patients, 32 people carry mutations in the EGFR gene.
In 1986, researchers Stanley Cohen and Rita Levi-Montalcini were awarded the Nobel Prize in medicine for their discovery of growth factors, including EGF (epidermal growth factor). Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor located across the cell membrane. The outer part of the cell membrane is the place for the EGFs to attach to form a complex, thereby activating a series of intracellular signaling pathways to help cells grow and multiply. There are many types of EGFR mutations detected, but about 90% of cases are deletion mutations on exon 19 and point mutations on exon 21-L858R.
When mutations in the EGFR gene occur, these tyrosine kinase receptors by themselves are able to activate the intracellular pathway without the need for EGF binding, leading to disorganized proliferation of cells. cancer.

Drugs that target EGFR are EGFR tyrosine kinase inhibitors (EGFR-TKI), which help prevent tumor growth. Currently, 3 generations of EGFR-TKI are being used for patients with advanced or metastatic non-small cell lung cancer, specifically as follows:
1st generation drugs include erlotinib and gefitinib. Both drugs have similar therapeutic effect, helping to improve quality of life, increase tumor response rate, prolong disease progression-free time by 5-6 months compared to chemotherapy. According to the IPASS study, with more than 1200 non-small cell lung cancer patients, cases with EGFR sensitive gene mutations treated with Gefitinib brought some benefits such as: 70% tumor reduction, 50% reduced risk of disease progression, and 22% reduced risk of death compared with chemotherapy. The advantage of this group of drugs is safety, few side effects, mainly skin rash if erlotinib is used or liver enzymes increase if gefitinib is used. 2nd generation drugs include Afatinib and Dacomitinib. The ability to inhibit the activity of EGFR mutations in a sustainable, irreversible way is the advantage of this group of drugs. According to the study, both drugs, especially dacomitinib, help prolong disease progression better than erlotinib and gefitinib. In addition, Afatinib has also been shown to be effective in treating not only cases of common EGFR-sensitive gene mutations (such as exon 19 point mutations and exon 21-L858R deletion mutations) but also for rare gene mutations such as L861Q, G719X and S768I. In addition to the strengths mentioned, cases of use of 2nd generation drugs often suffer from more toxicity (such as diarrhea, skin rash, enteritis, dermatitis) and those toxicities are usually of high level. more severe than the 1st generation drugs.
3rd generation drugs include osimertinib. Similar to the 2nd generation drugs, osimertinib also has the ability to inhibit the activity of EGFR mutations in a sustainable, irreversible way. In particular, it can also inhibit mutations in the T790M gene. This is a type of gene mutation that increases the likelihood of treatment failure. It occurs in about 50%-60% of cases of non-small cell lung cancer patients treated with drugs targeting 1st or 2nd generation EGFR after 9-12 months. However, this type of gene mutation can also be present in the absence of treatment, but is very rare, only about 1-2%. And the presence of T790M in the first place is a signal of poor tumor response to 1st and 2nd generation EGFR-TKI drugs.
In addition, osimertinib has also been shown to have a good effect on other drugs. brain metastases and above all, the drug can help 50% of patients have a survival time of up to 38 months – something that chemotherapy drugs or other targeted drugs cannot achieve.
Although Osimertinib brings amazing effectiveness, the drug has high safety, even fewer serious side effects than the 1st generation EGFR-TKI drugs.

* UTP: lung cancer, NSCLC: non-small cell lung cancer
a: Step 1 treatment is the first step of treatment when the disease is detected, b: Step 2 treatment is the next step after heart failure. fail with step 1 treatment

The doctor will decide the dose of medicine that the patient needs to use. The EGFR-TKIs listed above are all oral tablets and should be taken once a day, at a certain time. Erlotinib, Afatinib should be taken on an empty stomach, 1 hour before a meal or 2 hours after a meal. The remaining drugs Gefitinib, Dacomitinib, Osimertinib can be taken on an empty stomach or full. When you miss a dose of the day, depending on the type of medicine and the specific time the patient remembers, whether to take the medicine or not. In case of using Dacomitinib, Osimertinib should not make up, wait for the next appointment and take the usual dose. Never take a double dose. In case of using Gefitinib, Afatinib: if the time from remembering to taking the next dose is more than 12 hours, it can be taken immediately, but should not be taken if it is less than 12 hours, wait until Send your next medication and take your usual dose. Never take a double dose. When it is difficult to swallow tablets, gefitinib and osimertinib can be stirred in water until completely dissolved. Avoid crushing the pill. After drinking the dissolved drug solution, it is recommended to pour a little more water into the glass to rinse and drink more of that water to ensure the full dose of the medicine. All medications should be stored at room temperature of 25oC, in a dry place. If the patient is using other drugs for medical treatment, the doctor should be informed for further advice to avoid interactions between drugs, to avoid reducing the effectiveness or increasing the unwanted effects of the drug. . If you are pregnant or want to become pregnant, discuss it with your doctor because the medicine may harm your unborn baby. The duration of drug treatment is often prolonged until the disease worsens because the drug is no longer effective or when many unwanted effects are severe.

An important note is that not all lung cancers can be treated with drugs that target EGFR. Only when the tumor cell sample or the patient's blood sample is tested for the presence of EGFR mutations, the use of this class of drugs is effective.
And although we know the pros and cons of the three classes of EGFR-TKI drugs, the choice of which drug to treat depends on the discussion between the patient and the doctor on a case-by-case basis.
The duration of drug treatment usually lasts until the disease progresses or when the patient suffers from many serious side effects.
For those who do not carry EGFR mutations, we can search for other types of gene mutations such as ALK, ROS1, BRAF, MET, RET. If these gene mutations are present, the patient can use targeted drugs depending on the type of mutation.
Specifically, Dabrafenib in combination with trametinib is for lung cancer tumors with the BRAF V600E mutation. Crizotinib, ceritinib, or alectinib are used for patients with ALK rearrangement and crizotinib for tumors with ROS1 rearrangement.
If the above gene mutations are not present, immunotherapy or chemotherapy can be used, where immunotherapy is a new step today and has also been shown to bring spectacular results to patients. patients with metastatic lung cancer.