Interview With Zhang Li, Chief Expert Of Lung Cancer, Cancer Prevention And Treatment Center Of Sun Yat Sen University

In recent two years, immunotherapy has been highly concerned, and the related clinical research is a hot topic both in China and in the world. Immunosuppressive checkpoint inhibitors involved in immunotherapy achieve anti-tumor purpose by regulating the function of the autoimmune system.

Immune checkpoint is a normal regulatory point of immune function in human body, which can keep the immune system in balance. The immune system includes a pair of checkpoints: PD-1 and PD-L1, in which immune cells express PD-1 and tumor cells express PD-L1; by combining the two, tumor cells are recognized as normal cells, and immune cells of the human body will not attack the tumor, and tumor cells can escape the attack of the immune system. PD-1 inhibitors can inhibit the binding of PD-1 and PD-L1, restore the activity of human immune cells and kill tumor cells. There are several varieties of PD-1 inhibitors in the world, which have been approved in many tumor indications. With the domestic innovative drugs entering the competition with high price advantage, more indications are gradually expanding.

On August 8, at the theme forum of the 21st World Conference on lung cancer in 2020, Zhang Li, chief expert of lung cancer from cancer prevention and control center of Sun Yat sen University, announced the interim analysis results of orient-11 in the form of oral report. Orient-11 is the first randomized, double-blind, placebo-controlled phase III study of immunochemotherapy for first-line non-small-cell lung cancer in China. Studies have shown that dabetaxel combined with chemotherapy significantly reduces the risk of disease progression, and the risk ratio is even lower than that of other PD-1 inhibitors. At the same time, dabesu combined with chemotherapy can quickly achieve tumor remission.

Expansion of PD-1 indications

21st century: can you briefly introduce the clinical trials of domestic PD-1 in related cancer indications?

Tension: This clinical trial we're doing is centered on sindilimab, or dabesizumab. Dabesiu is a human monoclonal antibody against PD-1, which has been approved for marketing in China. The first indication approved is recurrent or refractory classical Hodgkin's lymphoma. This study, which is mainly aimed at advanced non-small-cell lung cancer, is also combined with chemotherapy.

Compared with the non squamous cell carcinoma, the main chemotherapy for non squamous cell carcinoma is non squamous cell carcinoma. The study was conducted in 48 centers across the country, and the study was enrolled for nearly a year. From August 2018 to July 2019, a total of 397 patients were recruited across the country.

The patients were randomly divided into two groups, one group was chemotherapy plus placebo, the other group was chemotherapy combined with dabesu, and the treatment lasted until the patients achieved disease progression. In order to ensure the scientificity of clinical trials, this study was designed as a randomized, double-blind, placebo-controlled study, that is to say, both the researchers and patients were blinded.

This clinical trial was actually announced as early as January this year, and the interim analysis reached the main end point. Although no specific data were published at that time, it was known that a positive result was obtained, that is, dabesiu combined with chemotherapy group was significantly better than that of chemotherapy alone group.

In the combined chemotherapy group, the progression free survival time was nearly 9.5 months, and the progression free survival rate of the combined chemotherapy group was nearly 9.5 months The time to remission [TTR] was 1.5m vs 2.6m, which was a very good positive result.

21st century: will we also have more research in the future, applied to other malignant tumors? In addition, how many cycles will it take for the drug administration to approve the final approval?

Tension: it depends on the final results of the study. Because I study lung cancer. As far as I know, daproshu is also a positive result in the research of lung squamous cell carcinoma, and it is also in the process of preparing for approval. The final result has not come out, but the research end point has been reached. The results of the study on squamous cell carcinoma are a little later than that of adenocarcinoma, so there is no doubt that dabashu may also get indications for squamous cell carcinoma.

In the future, there will be other different tumor types, of course, it is possible to make other tumor types are negative results.

As we all know, the average price of domestic medicine is about 560 thousand yuan for a course of treatment. Moreover, dabesiu is the only PD-1 inhibitor approved in China that has been listed in the national health insurance catalog.

In this regard, it is of great significance to expand the indications of dabashu. Its price is relatively close to the people and can benefit the people. The price of 5600 yuan per course of treatment is cheaper than that of imported immune drugs and chemotherapy drugs, which means that it can be used by the people. If the drug is positive for more tumor types and its price is cheap, it will undoubtedly benefit more people.

New drug approval accelerated

"21st century": finally approved by the State Food and drug administration, how long will it be used in patients with lung cancer?

Tension: we are still waiting for verification. After the data is handed in, the SFDA will check the data and then the production base. After these two kinds of verification are completed, the approval will be obtained in about three months after the verification is passed. Therefore, it is estimated that the national indication approval may be obtained by the end of this year or the beginning of next year.

We are still waiting for verification because of the epidemic situation and the timetable has been delayed. We are also looking forward to the approval of indications for this drug as soon as possible. However, after the release of this study, it also provides more evidence for the clinical use of drugs. In addition, after the indications are approved, there is still a need for national negotiations to enter health insurance. However, the results of this study must be helpful to the common people.

Patient in the 21st century: if there is no indication for drug use?

In fact, the so-called problem of hypertension exists in China. In fact, there are two catalogues in our country. One is the list of indications, which is approved by the State Food and drug administration, and the other is the list of medical insurance. In China, if a drug has a certain indication, but it is not included in the medical insurance, patients can use it, but it is self expense.

At this time, price is a very important factor. If you are cheap, there will be more patients willing to pay their own expenses. There is another situation where the research results are out, but the indications are still in the process of verification, which is called super indications. At present, the application of super indications is in compliance with the informed consent of patients. Drugs lag behind, but life is impossible. In this sense, with full knowledge and reliable research results, drugs can be purchased, but the indications have not been approved, and patients at their own expense can use them.

The only problem we are facing now is that there is a situation in which the drug has been included in the medical insurance list, but there is no corresponding indication. In this case, when giving drugs to patients, what is the responsibility of doctors? Now, when taking medicine, doctors need to check whether the patient can be reimbursed. If the patient is wrongly checked, the responsibility lies with the doctor. Medical insurance verification is to check whether there are items that should not be reimbursed. In this sense, there is no problem for patients to use at their own expense. Doctors must check the indications and can not check the medical insurance. But at the same time, it is very important for patients to be fully informed.

21st century: do you feel that the current national approval policy for cancer drugs is accelerating? Compared with the previous, how much speed may be accelerated?

Tension: we can really feel that the approval speed of new drugs is obviously accelerated. About five years ago, we were conservatively calculated to be 3-5 years behind the United States or European and American countries on average, and some products were 10 years behind, that is, foreign countries approved them, and then entered China 10 years later. For example, there is a drug for the treatment of osteoporosis, called dinozumab, which was approved in China only this year. In the United States, it was approved in 2004. For this drug, it is nearly 15 years behind schedule, and HPV vaccine is 10 years behind schedule.

By the end of 2018, the lung cancer indication of drug K was approved. Assuming that we can get the lung cancer indication of dabesiu by the end of this year, it is less than 2 years after the time difference of drug K. The acceleration is still obvious.

In the past, the number of people who went abroad to buy drugs, especially those adjacent to Hong Kong and Macao, is becoming less and less. In the future, it will be cheaper for patients to come to Hong Kong and Macao for negotiation. We still feel that the state has made great efforts in this field, including clinical trials. Drug approval is one aspect, and clinical trial approval is another.