What is EGFR mutation?
Among the new targeted therapies that have been developed, the most beneficial types of cancer are probably lung cancer, leukemia and malignant melanoma. Lung cancer treatment has entered a phase of “semi-individualized” therapy, where targeted drugs with better results and fewer side effects are gradually replacing traditional chemotherapy drugs as the first-line drugs (the first drug a patient uses, which is now usually chemotherapy).
Lung cancer patients are classified into “small cell lung cancer” and “non-small cell lung cancer” based on the form of the cancer cells. About 85% of lung cancer patients have “non-small cell lung cancer”. These patients are now more or less genetically tested to see if new targeted drugs are suitable. The most common mutation in non-small cell lung cancer that has targeted drugs is the “epidermal growth factor receptor” (EGFR) mutation.
Nowadays, all good oncology hospitals in China have the ability to perform EGFR mutation testing. The reason for promoting this test is that it has been clinically proven that EGFR-targeted drugs are much better than chemotherapy if the cancer has EGFR mutation. One point in particular the authors would like to emphasize is that the comparison of anti-cancer drugs is not only about the rate of tumor shrinkage and survival time of the patient, but equally important is the quality of life. Targeted drugs and immunotherapeutic drugs have tremendous advantages over chemotherapy in improving the quality of life of patients due to their lesser side effects.
The normal EGFR gene is indispensable for controlling the growth of many kinds of cells, and as you can guess from its name (epidermal growth factor receptor), it is so important for epidermal growth that without EGFR signaling, our skin cannot heal properly after an injury. However, in general, EGFR action is short-term and tightly controlled, and it is turned off after it has performed its function (e.g., promoting wound healing).
Similar to how officials are more likely to be corrupted the higher their rank, the more important the gene is the more likely it is to be used by cancer cells. In lung cancer, EGFR is unfortunately hit, and for various reasons mutations arise, causing it not to be turned off and endlessly stimulating cell growth, which eventually leads to cancer development and even metastasis.
What patients are prone to EGFR mutations?
In lung cancer, there is a direct correlation between the rate of EGFR mutations and ethnicity, with studies in the United States finding roughly 20% in whites and 30% in Asians. However, a recent study last year, which sequenced 1,482 Asian lung cancer patients, found that as many as 51.4% of Asian non-small cell lung cancer patients had EGFR mutations!
The predominant population with EGFR mutations in lung cancer is: Asian, female, middle-aged, no history of smoking, non-small cell adenocarcinoma. Of course this is not absolute, it just means that Asians have a higher proportion than other ethnic groups, women have a higher proportion than men, young and middle-aged have a higher proportion than older, non-smokers have a higher proportion than smokers, and non-small cell adenocarcinoma has a higher proportion than other lung cancers.
Why there is such a high rate of EGFR mutations in non-smoking middle-aged Chinese women with lung cancer remains a scientific mystery, and there is no particularly convincing explanation. Some have speculated that it is related to Chinese women’s prolonged cooking in the kitchen and inhalation of fumes; others feel that it is an ethnographic factor. Regardless, it is estimated that up to about 40% of lung cancer patients in the Chinese population have EGFR mutations! This is considered a blessing among misfortunes, as more Chinese can profit from the new EGFR drug, often joking that foreign drug companies have accidentally researched a new drug for the Chinese.
What EGFR mutations can be treated by first generation targeted drugs?
EGFR mutations are not exactly the same, but there are dozens of subtypes, but there are two main ones: the first one is L858R, which means that the 858th amino acid of EGFR protein is mutated from L to R. The second one is “exon 19 deletion”, which means that the part of EGFR protein responsible for inhibiting its activity is cut off. The second is an “exon 19 deletion”, which means that the part of the EGFR protein responsible for inhibiting its activity is cut off.
These two mutations account for 90% of all EGFR mutations in lung cancer, so if a patient is diagnosed with EGFR mutated lung cancer, it will most likely be one of these two mutations (2). When you get the test results, if you see an EGFR mutation, please pay attention to which type of mutation it is, because if it is not one of these two types of mutations, the targeted drugs described below may not be effective.
But in case it is one of those rare mutations in the 10% (e.g. exon 18 or exon 20 mutations), don’t despair, there are other drugs that can be used.
If a patient is indeed diagnosed with these two mainstream EGFR mutations, that is the best candidate for a first-generation EGFR-targeting drug. The best known first-generation targeted drugs for EGFR are Iressa (Iressa) and Tarceva (Trocheva). These two drugs function very similarly, both are effective against the two main EGFR mutations, and there is no question of which is better. Iressa is much used in China, in large part because it was first marketed in China.
Currently, ERSA is used more in Asia and Europe, and Trocaire is used more in the United States. The clinical side effects of both drugs are also very similar, mainly rash, diarrhea and lack of appetite. The underlying cause of these side effects are both because the drugs inhibit not only the mutated EGFR protein in lung cancer, but also inhibit the EGFR function in normal cells. As I mentioned earlier, normal EGFR is important for epidermal growth, so a rash after EGFR drug use is to be expected. This is not necessarily all bad, as the appearance of a rash is the easiest and most direct sign clinicians use to confirm that the drug has worked.
What if resistance develops?
Although first-generation targeted drugs are highly effective, most patients will develop resistance and tumors may start to rebound after about 1 to 2 years of using the drugs, whether it is Erythromycin, Troche or Kemena.
The reason why each patient develops resistance to the first generation drugs varies, but more than half of them are due to another new mutation in the EGFR gene: T790M, which is the change of amino acid 790 of the EGFR protein from T to M. This mutation directly leads to the failure of the first generation drugs (4).
Scientists then developed second-generation EGFR inhibitors, represented by avatinib, which not only inhibits the two mainstream EGFR mutations as the first-generation drugs, but also inhibits the new T790M mutation. Unfortunately, the second-generation drug has had disappointing results in the clinic, mainly because although the second-generation drug has a stronger ability to inhibit new protein mutations, it also inhibits normal EGFR more strongly than the first-generation drug, and therefore develops more severe side effects, which directly affects the dose and frequency of administration to patients.
Since the dose is lower than ideal, the tumor suppression is limited. This is what I mentioned in my previous article about the low Therapeutic Index of drugs: the goodness of an anti-cancer drug depends not only on its ability to kill cancer cells, but also on its ability to affect normal cells, the greater the difference between these two characteristics, the better. Health care products are both low, so they are not ideal.
Failure is the mother of success, drug companies did not give up, because we realized in the process, to develop better EGFR-targeted drugs, it is necessary to find inhibitors that can inhibit the new T790M mutation and do not affect normal EGFR. Once the goal was clearly defined, the race to develop third-generation EGFR by big pharma began with a bang.
At present, third-generation EGFR-targeting drugs have not been approved for marketing by the FDA, but several are already in phase 3 clinical trials, represented by Clovis’ CO1686, AstraZeneca’s AZD9291 and Novartis’ EGF816 (drugs are generally only codenames, not names, before they are marketed). These third-generation drugs have shown good clinical efficacy in lung cancer patients who are resistant to first-generation drugs due to T790M mutations, and because third-generation drugs no longer affect normal EGFR gene function, side effects such as rash and diarrhea are greatly reduced, further improving patients’ quality of life.
For these reasons, third-generation EGFR inhibitors should be approved by the FDA this year for patients who have developed resistance to drugs such as Erythroxel. In addition, because third-generation drugs are as capable of suppressing mainstream EGFR mutations (L858R and exon 19 deletions) as first-generation drugs, it is possible that third-generation drugs will replace ERSA as the first-line drug for EGFR-mutated lung cancer in the long run. Clinical trials are currently comparing which works better: direct use of a third-generation drug, or the use of a first-generation drug followed by a third-generation drug.
Compared to 20 years ago, targeted anti-cancer drugs such as Gleevec and Erysal have not only significantly prolonged the lives of many cancer patients, but have also significantly changed the quality of life of patients due to the low side effects and the fact that they can be taken orally. Cancer is difficult to cure because it keeps evolving and developing resistance to targeted drugs. Scientists are trying very hard to understand this evolution and trying to find its weaknesses to develop new drugs.
Although there are many setbacks in the development of new anti-cancer drugs, the field as a whole is clearly progressing, and new targeted and immune drugs are giving us great hope. If you are unfortunate enough to have cancer, please don’t be discouraged, and don’t give up if you become resistant to drugs, not only because optimism is a powerful tool to strengthen your immune system to fight cancer, but also because the next drug we are fighting for may be able to cure you!