What are the new treatments for lung cancer? How to use it?

Pineapple said

The last time I did a live broadcast of lung cancer science with Professor Lu Shun, it was really full of dry goods (see the main text). More than two years have passed, what are the new advances in targeted and immunotherapy? How to consider the order of use of drugs? Tomorrow (April 21st) evening, I have the honor to invite Professor Lu Shun and Professor Li Ziming again to share with you the "Precision Medicine for Advanced Lung Cancer".

Pineapple: Can you tell us about the essential difference between targeted therapy and traditional chemotherapy? What are its advantages?

Professor Lu: Targeted therapy must have a target, traditional chemotherapy is mainly the use of drugs on cancer cells toxic effects, targeted therapy is a drug for cell stability. For example, the Americans used two kinds of bombs in the Iraq War, one was a precision-guided missile, which hit Iraqi television stations, and the bungalows 20 meters nearby were not damaged; the other was a cluster bomb, which blew up two kilometers and was completely destroyed five meters underground. Chemotherapy is a cluster bomb, and targeted therapy is a precision-guided missile.

Therefore, the essential difference between chemotherapy and targeted therapy: targeted therapy must be an attack on tumors with certain specificities in tumor genes or protein expression; chemotherapy attacks the core components of cells such as DNA damage systems in vivo.

Pineapple: Patients have found that some treatments require genetic testing, but some do not, please explain the classification of targeted drugs.

Professor Lu: In 2018, the National Health Commission formulated the rational use of new drugs, especially pointing out that only anti-angiogenesis drugs do not require genetic testing. Because for anti-angiogenic drugs, it is currently known in principle that it acts on blood vessels, but there is no corresponding marker. Other types of targeted therapies require detection of the corresponding target.

Pineapple: In terms of lung cancer, what kind of people are suitable for targeted drugs and need to do genetic testing, and which patients are not suitable for targeted drugs?

Professor Lu: At present, there is a consensus at home and abroad that there is no targeted treatment for small cell lung cancer and does not need to be tested.

For squamous cell carcinoma, genetic testing is not recommended by international guidelines because it has fewer types of mutations available for the drug. However, in the East Asian population, a certain proportion of squamous cell carcinoma patients without a history of smoking have EGFR gene mutations, and genetic testing is recommended, and 4-5% of squamous cell carcinoma patients with a history of smoking also have EGFR mutations.

For adenocarcinoma, genetic testing is highly recommended in all countries and regions. Therefore, we advocate that non-small cell lung cancer patients in China receive genetic testing as much as possible.

Pineapple: EGFR mutations currently have 1, 2, 3 generations of drugs, each generation can choose more drugs, for patients, how to choose drugs, is it used in order?

Professor Lu: Targeted drugs for EGFR mutations, 1st and 2nd generation drugs are mainly aimed at sensitive mutations, second-generation TKI will be effective for patients with rare mutations, and third-generation TKI is also effective for 790 patients with positive mutations who have failed to use first-generation second-generation drugs in addition to sensitive protrusions.

At present, studies have proved that the total survival time of the first 3 or 2 generation drugs is longer than that of the first generation of drugs. Scientifically speaking, it is advocated to use three generations of drugs first. However, the issue of access to medicines and costs must also be considered. At present, when clinically recommended use, it will take into account the scientific nature, drug accessibility and the patient's ability to pay.

Pineapple: Some patients with mutations use targeted drugs very well, but may have heard that immunotherapy also works well, so patients can consider immunotherapy or targeted therapy in combination with immunotherapy?

Professor Lu: What we know at present is that mutant patients can not benefit from choosing immunotherapy in the first place. If targeted therapy is used first and then immunotherapy is used after failure, small sample studies have shown that at least a subset of patients are beneficial.

There are currently two large ongoing randomized controlled international studies in this area, Checkmate-722 and KEYNOTE-789, and I am the national study leader of KEYNOTE-789. The study was conducted in a random comparison of the efficacy of chemotherapy and chemotherapy plus K drugs in patients who failed a second-generation TKI and did not have a T7900 positive, or who had failed with three generations of drugs.

I also undertook a registered study of a domestic innovative drug, Delizumab, comparing the efficacy of chemotherapy, chemotherapy + PD-1, chemotherapy + PD-1 + anti-angiogenesis drugs, hoping to give a final conclusion.

Pineapple: So if there are sensitive mutations, it is recommended to use targeted therapy first; if drug resistance occurs, it is possible to benefit from the backline of immunotherapy in the future.

Professor Lu: Yes, there are some people who can definitely benefit, and at present we must first find this part of the people.

Pineapple: At present, domestic enterprises are also doing research and development of targeted drugs, how do you evaluate domestic and imported targeted drugs?

Professor Lu: Targeted drug research in China is mainly small molecule drugs. Compared with similar drugs abroad, there is no obvious difference in efficacy; there are also some comparative studies that are being carried out smoothly. At present, there are so-called "four generations of drugs", such as research on third-generation drug resistance, and drug research and development for the more difficult EGFR secondary insertion mutations. EGFR mutations are very common in Chinese patients, so domestic small molecule drug research in this area is believed to soon compete with international multinational companies.

Pineapple: Patients may choose to change the dressing for different reasons, whether it is domestic for import, or import for domestic production, how do you generally look at this problem?

Professor Lu: There must be a clear and reasonable reason for changing the medicine. For example, when using a generation of drugs, the use of gefitinib in some patients will lead to liver function damage, while the toxicity of ektinib liver function damage is relatively low, and there is indeed a patient change of dressing; and the side effects of gefitinib's rash are more mild. Therefore, when the efficacy is comparable, the rationale for substitution of similar drugs is based on toxicity and tolerability, and there is no need to replace an effective and tolerable therapeutic agent.

Pineapple: If you can't buy medicine during the epidemic, can you temporarily change the same kind of medicine for treatment for a period of time?

Professor Lu: There is not much of a problem with this. As long as it is a similar drug approved by the State Food and Drug Administration, it can be. Powders (APIs) are unsafe and not recommended.

Pineapple: If the side effects are a bit serious when using targeted drugs, can I reduce the dose?

Professor Lu: If a drug has different dosage or dosage form settings, it can be adjusted. However, some drugs only have a single dosage form, and it is more difficult to reduce the amount of a single drug. For example, Troquet has two dosage forms, 100mg and 150mg, so 150mg cannot be tolerated and 100mg is exchanged. Gefitinib is only 250 mg, and it is more difficult to adjust this type of drug.

Pineapple: Some people say that the stronger the side effects, the better the effect, so some patients are very happy to see that they have a rash. Is this statement reliable?

Professor Lu: In the early years, there was some small sample evidence for this statement, but later it was found that this evidence was not scientific enough. Clinically, it is not advocated to predict efficacy with toxicity. It is true that anti-angiogenesis drugs are used in patients who cause hypertension, which may indicate good efficacy, but this is not a good criterion.

Pineapple: Clinically, you will also see cases where the side effects are relatively mild, but the effect is still very good, right?

Professor Lu: Many patients with EGFR mutations have almost no toxic reactions when they are treated, and some people say that they do not have a rash, which is definitely ineffective, in fact, there is no need to worry about it.

Pineapple: In addition to EGFR and ALK, what other targeted lung cancer drugs are worth knowing and looking forward to?

Professor Lu: In the past five years, there has been great progress in this regard. Studies have proved that 75-80% of adenocarcinoma patients in Chinese patients can find the corresponding target and receive targeted therapy with corresponding commercial drugs. Another 20% of genetic mutations are called rare mutations.

China has approved drugs against ROS-1 mutations, accounting for 1-2% of adenocarcinoma patients.

The drug with the c-MET 14 mutation has been approved in China. NTRK, two mutations of RET, NRG1, etc., have clinical trials or scientific research to support the application of some drugs, and the Chinese registration research of LOXO292 for RET fusion and entratinib for NTRK and ROS1 fusion for NTRK and ROS1 fusion is underway. But other targets need more confirmatory clinical trials to prove it.

In general, in addition to the common sites of EGFR and ALK, lung cancer has a large number of sites in the process of being discovered. For EGFR, some sites that originally did not have drugs are now under development, such as the Exon20 insertion mutation.

There is also a KRAS mutation that has not been found for many years, and some drugs have been seen in early clinical trials at the G12C site, showing very encouraging results, and will soon be registered in China.

For lung adenocarcinoma, in the future, it is hoped that 80-85% of patients can find the corresponding driver gene for targeted therapy.

Pineapple: Drug resistance will occur with targeted drugs, how should the mentality of patients be adjusted?

Professor Lu: This is a problem of "one foot high and one foot high", chemotherapy and immunotherapy will have drug resistance, just because the short-term effect of targeted therapy is particularly good, once drug resistance is developed, patients are not psychologically easy to accept.

I appreciate the phrase: If you want to beat cancer, you must think like cancer.

My understanding is that cancer is a part of yourself, and you have to destroy it to achieve immortality, and you have to live forever. This is a philosophical paradox.

While fighting tumors will eventually lead to drug resistance, if one drug tube is 10 months and 10 drugs are administered for 100 months, our goal is to chronicize advanced tumors. When patients achieve decades of survival by taking drugs, cancer will become chronic diseases like high blood pressure and diabetes. Hypertension and diabetes are not cured, and patients are not afraid, mainly because there are few fatal cases. Through continuous drug research and development, we continue to prolong the survival time, and patients will not be afraid of drug resistance, because drug resistance can be changed. The five-year survival rate mentioned in the national 2030 health goals is to be expected.

Pineapple: Are there currently clinical ways to delay drug resistance?

Professor Lu: Depending on the different genetic characteristics of the tumor, we use different methods. One is through a combination therapy regimen, chemotherapy + targeted drugs, or chemotherapy + targeted drugs + anti-tumor vascular combination therapy. In addition, through noninvasive means, especially blood testing, if genetic changes are found, treatment can be switched early through intervention and replacement therapy. In short, through continuous dynamic monitoring and combination therapy, the emergence of drug resistance is delayed and the overall survival time is prolonged.

Pineapple: You recently did a study that used liquid biopsies to monitor the outcome of a patient's treatment. When no problem is found on the image, consider changing the dressing or considering a new treatment plan in advance. Can you tell us what this research means for patients?

Professor Lu: CtDNA testing is noninvasive, while biopsies of tissue are difficult and invasive. Blood testing is to provide this noninvasive dynamic observation: for example, after EGFR targeted drug resistance, measured met amplification, plus MET inhibitors, continue to use this drug, a quarter of people can get good relief, progression-free survival significantly prolonged. Therefore, through liquid biopsy, it is possible to understand what changes have occurred in the patient's genes during targeted therapy, and it is possible to change or add drugs for this change, hoping to improve the survival of the patient and improve his quality of life.

Pineapple: Why do people have a particularly long resistance to drugs and some people have a particularly short resistance time?

Professor Lu: Mainly genetically. It has been shown that targeted therapy for this target works well in patients with mutations in a single driver gene. However, many patients are accompanied by changes in other genes, especially TP53 mutations; patients with coexisting mutations are generally less effective.

In terms of clonal evolution, if the patient's genetic mutation is a master clone change, the treatment effect will be better. If it is a subclonal, the effect of the treatment will be a little worse. The dynamic observation of tumor evolution in the future will be an important theoretical basis for understanding tumor biology and proposing treatments.

Pineapple: Some people will consider taking some health supplements during treatment. In China, Traditional Chinese medicine is a common option. As a clinician, you generally recommend how your patients are, especially during the process of taking targeted drugs.

Professor Lu: My logic is that the integration of traditional Chinese medicine and Western medicine needs to be well coordinated, and patients should tell the doctor what treatment they have received or are receiving. Chinese medicine is divided into the so-called attack and defense, one is to attack the poison, and the other is to correct. I combined with my TCM partner, when Western medicine attacked, he straightened it out; when Western medicine did not attack, TCM attack poison can also be done, and the overall toxicity of patients cannot be increased. We are also doing a lot of research and see that the combination of Chinese and Western medicine brings good benefits to patients. It is recommended to receive good treatment in the hospital of traditional Chinese medicine, some patients believe in folk remedies, I do not rule out the effectiveness of this home remedies, but only say that more clinical verification is needed, especially to verify its scientific nature.

Pineapple: Is there now evidence that targeted plus chemotherapy is better than targeted alone?

Professor Lu: The Japanese NEJ009 study has proved that in the head-to-head comparison of gefitinib combined with chemotherapy, the combination treatment has brought about an extension of total survival, and this combined effect has also been demonstrated by indian studies. But the problem it brings is that patients need to go to the hospital every three weeks to receive chemotherapy, which may be less convenient for patients, which has pros and cons, and the total survival is prolonged in terms of advantages.

Pineapple: The patient asked, non-small cell lung cancer, targeted drugs eaten for half a month, how long to eat to see the effect? When should I go back to review?

Professor Lu: Targeted drugs start to work relatively quickly, my patients have to do chest CT in a month to detect the effect, and 90% of patients can take effect in one month.

Pineapple: Does this test have to go back to the original hospital, or is it okay in the local hospital?

Professor Lu: The first review, preferably in the treated hospital, is more reliable to compare under the same CT conditions. If you have received the first treatment in a large hospital, it is best to let the doctor see the effect during the review, determine the effect and take the program home, after which you can check it in the local hospital.

Pineapple: Some people say he's used it for three generations, osimtinib has already used it, if resistance can go back to the first and second generations?

Professor Lu: First use three generations of drug resistance, and then come back to use a second generation of drugs, which is a few in ten thousand probabilities. After three generations of drugs have been used, there is a simple 797S mutation, and at this time, the use of gefitinib is moderately sensitive and theoretically effective, but it is generally not recommended that patients use it this way, and the effect is not very good.

Pineapple: Is there a one-generation plus three-generation or two-generation-three-generation, a mixed-use method?

Professor Lu: Clinical trials of alternating use are underway. If you put it together and eat it together, it will be very toxic, especially bad for the liver. In order to overcome drug resistance, the United States designed a study: eat two months of one generation, and then eat two months of three generations, because the resistance mechanism is different, hoping to prolong progression-free survival through this method. However, research is still ongoing and is not currently recommended.

Pineapple: The sensitive mutations in EGFR are generally 19 and 21, but there are also 18 and 20, what recent progress has been made in this regard?

Professor Lu: No. 18 is still relatively sensitive to the existing TKI. 20 Insertion mutations have made some progress in the last year or two, and some Chinese research and development companies are also doing it. For now, the 20 insertion mutation has not yet become a standard treatment in China, but I believe some drugs have seen the light and are currently doing clinical trials.

Pineapple: Some people say that one generation of targeted medicinal use is very good, should those three generations be replaced as soon as possible, or must it be used until after the progress?

Professor Lu: If a drug is effective, it is not recommended to change the medicine. However, it can be observed through dynamic genetic testing, and drug change can be considered when drug resistance appears. Effective non-change of dressing is a basic principle of medical oncology.

Pineapple: There are different options for ALK second-generation targeted drugs, and when someone is using a second-generation drug, the doctor says that they can switch to another second-generation drug. This is different from EGFR, what is the difference?

Professor Lu: This is a very academic question. EGFR can be called "stupid cancer" and ALK is called "smart cancer". EGFR mutations are commonly T790, accounting for about 50%-60% of EGFR resistance mutations, so after a generation of failure, it is basically ineffective to switch to a generation or this site of drug resistance. But ALK is different, and the types of mutations in ALK are mixed. There is a certain second-generation drug resistance, with another second-generation effective case, and this probability is not low, so in the ALK pathway may be used alternately with the same drug. The third generation of ALK has been listed in Hong Kong called loratinib, if loratinib is listed in China, it will be easier to choose, because loratinib basically covers all the drug resistance sites of the first and second generations, so the future second generation failure and then use another second generation may be relatively small, but the reality of this application has its rationality.

Pineapple: The next question may be that everyone is more concerned, what to do after oscitinib runs out?

Professor Lu: The standard treatment is chemotherapy. But after the failure of osimitinib, if it is the amplification of MET, plus a MET inhibitor such as volitinib, there are also clinical trials. Of course, immunotherapy can also be considered. Standard treatment is still chemotherapy, but the strategy of osimertinib+ is still being explored and clinical trials are underway. After the failure of three generations of drugs on the front line, patients will be encouraged to join the current clinical trials.

Pineapple: The three generations of drugs in domestic clinical trials have also been approved for marketing, in your opinion, can its efficacy be said to be comparable to that of imports, and everyone can choose according to their own situation?

Professor Lu: The current approved indication is T790 positive, that is, after a generation of TKI resistance, there are more such patients in China. The approval is based on a single-arm clinical phase II, the efficacy is encouraging, the response rate can reach 68.8%, and the progression-free survival of PFS exceeds 12 months. Since there is no head-to-head comparison with three generations of osimtinib, it can only be numerically said that the effect is not inferior to that of osimtinib, and may even be better numerically, but it cannot be concluded that the two drugs are equivalent.

Pineapple: This is really scientifically rigorous, but at least it gives patients a new option.

Professor Lu: Yes, numerically it does not lose to osimtinib at all. Both in remission and progression-free survival, it is even higher in numerical value than osimtinib reported. But not head-to-head experiments, patients are not the same, we can not compare, can only say that the two choices are not good and who is bad.

Pineapple: Must the effect of targeted drugs in patients with brain metastases be worse than in patients without metastases?

Professor Lu: The brain penetration of the three generations of drugs is already very good, whether it is osimertinib or ametinib, the brain penetration is very good. Now brain metastases are not a major problem, and the effect of TKI may be slightly lower in patients with relatively extensive bone metastases, so local radiotherapy is added to this part of the patient.

Pineapple: Are there any questions that you are often asked clinically that you can clarify here?

Professor Lu: Many people say that clinical trials are about treating patients as guinea pigs, and I would like to take this opportunity to explain. Our clinical trials are based on a scientific, ethical basis and have a rigorous review process. First of all, it must be approved by the State Food and Drug Administration, and it must also be approved by the ethics committee; it is well guaranteed in science, and there are good pre-clinical data, and even some phase III clinical, as well as clinical phase I and PHASE II data. And there are data that show that patients who participate in clinical trials end up surviving better than patients who do not participate in clinical trials.

Lung cancer is not an easy disease to treat, so we must constantly explore new treatments, and these means must be proven through rigorously designed clinical trials. Only drugs or treatments proven through clinical trials are truly effective treatments. We encourage patients with advanced lung cancer to actively participate in clinical trials, not only for you, but also for future lung cancer patients. Fighting cancer is our common goal, and we definitely don't treat patients like guinea pigs. We fully respect the interests of our patients, who will always be in our highest interests, which is also in line with the Helsinki Declaration.

Pineapple: In clinical studies of cancer treatment, the control group is usually not a placebo but a standard of care, right?

Professor Lu: As long as there is standard treatment, our control group must be standard treatment. Only when standard treatment is uncertain, we use a so-called placebo control, and the use of placebo must be fully considered.

Pineapple: I remember studies that said that standard treatment in the control group was better than chemotherapy in general, and there would be more follow-up and attention to patients.

Professor Lu: Yes, after entering the clinical trial, it meets a complete set of follow-up and observation indicators, which is better than the treatment effect of the same kind for patients in general clinical practice.

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*This article aims to popularize the science behind cancer treatment, not drug promotional materials, and it is not a treatment plan recommendation. For guidance on treatment options, visit a regular hospital.

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