July 7, 2022

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What is the resistance mechanism of EGFR-TKIs?

What is the resistance mechanism of EGFR-TKIs?


What is the resistance mechanism of EGFR-TKIs? Is there solution for EGFR gene therapy target drug resistance?

 


What does EGFR-TKI treatment include?

Now let’s take a look at the current status and level of the treatment of these drugs in the EGFR mutation population of advanced lung cancer.

On the whole, the first-line treatment of Iressa and Tarceva of the first-generation drugs is that the progress time is basically about 12 months, and the overall survival time is about 28-30 months. They all develop resistance without exception.

The third-generation drug targets advanced lung cancer patients with positive EGFR driver genes, and the progression time is slightly prolonged, basically reaching 14-18 months, and the overall survival time is 32-35 months.

This is the current level of treatment that can be achieved for EGFR as a driving gene and therapeutic target.

Of course, this also includes the prolongation of the overall survival time after the combined treatment strategy.

 

 

What is the resistance mechanism of EGFR-TKIs?

We mentioned earlier that drug resistance will inevitably develop after treatment with either one or three generations of EGFR-TKI. Then, regarding the resistance mechanism, EGFR-TKI mainly includes four aspects:

1. The second site mutation in the EGFR gene caused further activation of the signaling pathway, making the first or third generation TKI resistant. The secondary site mutation is mainly manifested as T790M mutation in the first-generation TKI treatment, so we can use the second-generation to block such a mutation.

If it is the second mutation site where the third-generation TKI produces resistance, it is mainly C797S at present. Corresponding treatment methods are also available.

2. Mutations in the downstream nodes of the entire signal pathway of EGFR make such signals further activated. Then these site mutations are more complicated, including KRAS, BRAF mutations or mutations in which the tumor suppressor gene lacks PTEN.

3. Phosphorylation of transmembrane receptors, which we call alternative activation, includes activation of CMET or other transmembrane receptors. Of course, cMET is the most common, accounting for about 10% of the first generation of TKI resistance mechanisms.

4.  The last is the transformation of morphology, usually manifested as the transformation of adenocarcinoma to small cell lung cancer. Of course, if it is morphology transformation, we can follow the treatment of small cell lung cancer, but the treatment effect is not as good as that of newly treated small cell lung cancer. .

Of course, these four resistance mechanisms are only a small part of our understanding of the resistance mechanisms of first-generation TKI or third-generation TKI.

The resistance mechanism of the third-generation TKI is basically the same as that of the first-generation TKI, but is slightly different.

I believe that with the advancement of science and technology and a deeper understanding of tumor biology, there will be more in-depth discoveries.

 

How to solve EGFR-TKIs resistance?

1. According to the resistance mechanism to solve the resistance, this method, obviously, we have the four kinds of resistance mechanisms mentioned above, we have mature drugs, for example, for T790M, we can use the second-generation KTI, including oxitin Ninetin, including domestically produced Ametinib, is okay.

For example, if there is cMET amplification based on the resistance mechanism, we can use voritinib.

However, there is still a large part of the category where the drug resistance mechanism is not clear. We cannot use the corresponding targeted drugs, and we must adopt clinical solutions.

2. Regarding clinical solution strategies, we have three different situations to distinguish:

1). The progress is very rapid, and the patient’s body is also showing rapid deterioration, then we should adopt systemic chemotherapy or immunotherapy with Pd-1 inhibitors.

2). If the progress is only a partial progress, such as oligoprogress, then we can combine local radiotherapy and continue to use the original KTI.

3). The so-called slow treatment is manifested as the progress of the lesion is relatively slow, which means that it may take several months or half a year, and the general condition of the patient is better. In this case, the original KTI can also be retained and combined with the beat therapy .

Therefore, this approach may also adopt other combined methods, such as combined anti-vascular drugs. We call this a clinical solution strategy.

According to these three situations, we will focus on the cases below.

 

Can you elaborate on the clinical strategy of using beats to treat and reverse the drug-resistant cases of targeted therapy?

We use the following real world cases to illustrate some clinical strategies for reversing KTI resistance with beat therapy.

1. A male patient, 57 years old.

I went to our hospital on August 15, 2017 and was diagnosed with right lung cancer, mediastinal lymph nodes in both lungs, and bone metastases in the liver through various examinations. It is an advanced lung cancer. Through genetic testing, it is the 19th -EGFR exon mutation.

Lung CT showed various lesions of the right lower lung, and some mediastinal lymph node metastasis and supraclavicular lymph node metastasis were found in the pleural fluid.

The medical team started to give patients a first-generation KTI Iressa targeted therapy in 2017, and the initial state of the patient was partially relieved. Until December 2018, the disease began to slowly progress-manifested as a slight increase in pleural fluid and a slight metastasis in both lungs. Increase.

At this time, the team uses Iressa for the first-line treatment, and its progression time is 12 months, so according to the characteristics of the patient’s slow progression, the combined use of Noviben is given. Low-dose beat therapy, take oral treatment three times a week, two weeks in a row, one week of rest.

Then further review, through the intermittent monitoring and review every two months, the medical team can see that the condition is further stabilized and the patient’s general condition has improved. So far, the patient is still in a stable state, and the remission time has reached 25 months, which is nearly two years. many.

So the medical team think this reversal of resistance is a successful case.

Let’s talk about the clinical reversal strategy of the third-generation EGFR-TKI and osimertinib resistance.

 

2. A female patient, 47 years old.

Before going to our hospital, she had been diagnosed with advanced lung cancer, pleural metastasis with pleural effusion, and deletion of exon 19 was detected in the EGFR mutation.

At that time, oral Tarceva, the first-generation EGFR-TKI, was given in 2015, and the effect was not bad. It was stable for a total of 41 months, which is three and a half years.

Chest CT showed a large amount of pleural effusion and thickening of the pleura. After the first generation of EGFR-TKI Tarceva resistance appeared in our hospital, the medical team gave a biopsy of the pleura to further prove that the pleural metastatic adenocarcinoma, and the secondary mutation site T90M was also detected. So the medical team gave the third-generation drug Ositinib.

At this time, after two months of osimertinib, the condition eased slightly, but the pleural fluid increased further, and the whole lungs progressed again, so it was judged that the third-generation osimertinib resistance remained for more than two months.

Because the patient’s physical condition is not very good, and at the same time the medical team used pleural fluid tumor cells for secondary sequencing, and the medical team did not find a target that can be treated, the medical team continued to use osimertinib and the beat to treat the continuous low dose of novibe. The dose is taken orally.

This method is particularly acceptable to patients. After three months, the medical team can see that the chest radiograph has been further reduced. By July 2019, the pleural fluid has been further absorbed.

After re-examination in January 2020, after continuous testing, the pleural effusion was basically completely absorbed. In this case, it has been nearly 25 months, or more than two years, that the patient’s pleural effusion and thickening of the pleura have reached complete remission.

What is beat therapy?

Beat therapy should be said for a period of time, about 10 years ago.

In recent years, our understanding of it has increased. In general, rhythm therapy is to use vascular endothelial cells as the target of treatment. Low-dose continuous administration can inhibit the growth of tumor cells.

The mechanism of action mainly includes three aspects:

1. Inhibit the growth of vascular endothelial cells associated with tumor cells

2. It can improve or even change the immune microenvironment of tumors

3. Inhibit the proliferation signal of tumor cells

These three mechanisms make the beat therapy have its unique advantages in combination with EGFR-TKI inhibitors.

Moreover, the use of low-dose continuous administration makes it easier for more patients to accept, and does not need to be hospitalized, just take the medicine home for oral administration.

The side effects are very light, and it is suitable for older lung cancer patients, as well as for poor health or combined with other treatment methods, so it has certain advantages.

In this issue, the medical team shared with Professor Zhiyong He, the head of the Department of Thoracic Oncology of Fujian Cancer Hospital, and learned about the clinical solution strategies for using beat therapy to reverse the first or third generation of EGFR-TKI resistance.

This is only one of the clinical solutions, and there are many clinical solutions. the medical team need to communicate with the doctor continuously according to the patient’s physical condition, the spread of the patient’s tumor progression, and the treatment ideas of the patient’s family. Working together to come up with the most suitable treatment for patients, and to overcome this difficulty together, this is the ultimate goal and common aspiration of this sharing.

 

(source:internet, reference only)


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