The era of precision in cancer treatment

  China News Weekly reporter/Li Mingzi

  Issued in the 994th issue of China News Weekly on May 2021.5.3

  In July 2018, 66-year-old Liu Jianguo was diagnosed with colon cancer. Lymph node, liver, lung, and bone metastases had already occurred at the time of discovery.

After undergoing chemotherapy for one month, he lost 20 pounds in weight, and was eventually pronounced the "death sentence."

"The doctor told me that there are still two months left," Liu Jianguo said, "I thought about my will at the time."

  The family does not want to give up. If a new medicine can be found, there is still hope of survival.

  Two months later, Liu Jianguo waited until a new generation of targeted drugs was launched in the United States-not yet introduced to China.

In November of that year, the first re-examination after medication showed that the tumors on the colon were significantly reduced, the tumors with liver metastases were reduced by more than 90%, and the tumor marker index decreased significantly.

  The international journal Nature Review analyzed in detail 45 targeted cancer drugs approved by the U.S. Food and Drug Administration (FDA) at the end of 2016. As of the outbreak of the new crown epidemic, targeted drugs and immunosuppressants approved for marketing in the United States The number has tripled, and there are more than 140 kinds. According to statistics from Shengnuo, a medical service agency abroad, about one-third of them have been listed in China.

  New drugs bring hope

  Liu Jianguo used targeted drugs in domestic treatment.

  The treatment plan at that time was "FOLFOX combined with bevacizumab".

FOLFOX is the recommended chemotherapy regimen for stage III colon cancer in the National Comprehensive Cancer Network's oncology clinical practice guidelines. Bevacizumab is a targeted drug approved in the United States for the treatment of metastatic colorectal cancer in February 2004. It will be available in China six years later. Listed.

  Due to multiple metastases, surgery is not possible and only chemotherapy is available. For Liu Jianguo, the pain has just begun.

In addition to taking 16 capsules of oral medicine daily, chemotherapy is given every two weeks for three consecutive days: the infusion starts at 8:30 in the morning, and a total of 8 bottles, large and small, until six in the evening, sometimes lasting more than three in the morning, long Up to 18 hours.

  Four days after the first chemotherapy ended, side effects such as abdominal pain, hiccups, cold sweats, decreased appetite, and decreased sleep quality began to occur, but they could only be hardened.

In order to get better treatment, Liu Jianguo also followed the doctor's suggestion, and took more than 8,000 yuan a shot at his own expense to boost immunity.

More than 600,000 yuan was spent on hospitalization, treatment, and examination.

  After the domestic treatment failed, Liu Jianguo planned to go to the United States to try under the arrangement of his son.

At the Dana-Farber Cancer Institute in Boston, he did gene sequencing and found mutations in the BRAF gene.

In response to this situation, doctors adjusted the chemotherapy regimen to "three-drug combination", including the targeted drug cetuximab for intravenous injection, and two oral targeted drugs, Cornefinib capsules and bemetinib tablets. , The latter two drugs have just been approved by the FDA for combined use at the end of June 2018 to treat BRAF V600E or BRAF V600K mutations, which have not yet been approved for marketing in China.

  "I didn't expect that chemotherapy can be so easy." Liu Jianguo told China News Weekly. In Dana-Farber, chemotherapy is also once every half a month, but it only takes 1 hour each time, walking back and forth, no hospitalization, daily diet. There are basically no taboos, and I take 10 pills of oral medicine every day. "Such a small medicine costs 600 yuan." Liu Jianguo said.

  According to the definition of the National Cancer Institute of the United States, targeted molecular therapy is a drug therapy that interferes with specific molecules needed for cancerous transformation or tumor growth to prevent the growth of cancer cells.

  "Targeted drugs target specific targets on cancer cells, such as a specific gene mutation. Although the purpose of chemotherapy is to directly kill as many cancer cells as possible, they are more selective than chemotherapy. It is stronger and can effectively inhibit cancer cells, but will not cause significant damage to normal cells." Former senior researcher of Novartis Pharmaceuticals (U.S.) Cancer New Drug Development Department and Doctor of Cancer Biology at Duke University, Li Zhizhong wrote in his popular science book "Cancer·New Knowledge" "Wrote.

  The life-saving drug prototype "Gleevec" in the movie "I'm Not the God of Medicine" was approved by the US FDA in 2001. It is one of the first targeted drugs with the best long-term therapeutic effects.

It has made the 10-year survival rate of patients with chronic myelogenous leukemia jumped from less than 50% to about 90%. By 2011, it has been used to treat ten different cancers such as chronic myelogenous leukemia.

  Nowadays, targeted drugs are no longer a new term. Its emergence has opened a new era of cancer precision medicine.

In 2004, Dana-Farber and Japanese researchers jointly discovered that lung cancer patients with dysfunction of the epidermal growth factor receptor (EGFR) on cancer cells showed a significant response to a specific targeted drug. This result was subsequently followed by more than 6000 studies. Cited.

  "This study in 2004 is the first proof of the success of precision medicine in lung cancer patients," said Pasi Jann, chief physician of the Dana-Fabero's Thoracic Tumor Center. "Precision medicine brings a new understanding. Not all lung cancers are the same. According to the molecular abnormalities behind them, different subtypes can be classified and targeted for treatment."

  Studies have shown that before the advent of targeted therapy, only 20%-40% of advanced lung cancer patients respond to standard chemotherapy. The remission period usually lasts four to six months, and the average survival period is about one year.

After EGFR mutation patients receive targeted therapy, the remission period can reach one year, with an average survival period of two to three years, and some people can even survive for five years or longer.

For cancer patients, the more new drugs and the faster the research and development, the greater the hope of survival.

  Drug resistance and new drug iteration

  Before returning to China during the Spring Festival in 2019, Liu Jianguo prepared enough oral medications. There was no chemotherapy in Guangzhou. He went to Hong Kong to get cetuximab every two weeks. When the first injection on the fifteenth day of the first month, he already felt a vague backache. At that time, he thought it was. The exercise was twisted, and I didn't think much about it.

  As the pain became more frequent, Liu Jianguo performed an MRI at a local tertiary hospital, and the results showed that there was bone metastasis again.

What he was worried about still happened—resistance appeared.

  This seems to be the fate of patients using targeted drugs.

Because targeted drugs are highly targeted, they usually take effect within a few weeks, and gratifying progress such as tumor shrinkage and tumor marker reduction will occur soon or even within a few days.

However, the tumor itself is also evolving, and drug resistance will inevitably appear after a period of time.

  Take Liu Jianguo's BRAF gene mutation as an example. The information transmission is abnormal, and the "rapid growth" error message is constantly sent to cancer cells, causing the tumor to grow uncontrollably. Targeted drugs can accurately block the information transmission path of the mutant gene.

However, after a period of struggle, new mutations often occur in genes to find another way, reconnect with tumor cells, and again send the error message of "rapid growth", causing the originally controlled tumor to get out of control again.

  For some gene mutations, there are second-generation targeted drugs or third-generation targeted drugs for patients to use, but this only accounts for a small proportion.

Li Zhizhong concluded in "Cancer·New Knowledge" that of the 18 genes that are frequently mutated in cancer, only four mutations of BRAF, EGFR, MET, PIK3CA have direct targeted drugs, and the other four mutations have indirect targeted drugs. The remaining ten major mutations are completely drug-free.

  Taking the common gene mutation EGFR in lung cancer as an example, the first-generation drugs include gefitinib (also called Iressa), erlotinib and icotinib.

According to Jin Mingli, deputy chief physician of General Surgery of the First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, in "Interpretation of AME | Progress in Targeted Lung Cancer Drugs", nearly 80% of lung cancer patients who use a first-generation targeted drug after EGFR mutation are in 9~ After 14 months of effective treatment, about 50% of the population experienced disease progression and drug resistance recurrence.

  At this time, the patient needs to undergo genetic testing again and use the corresponding targeted drugs for the new mutation.

The second-generation targeted drug afatinib has a stronger ability to inhibit EGFR than the first-generation drug.

In 2017, the third-generation EGFR inhibitor osimertinib was approved by the FDA and the European Union for the treatment of non-small cell lung cancer.

  In the article "EGFR and ALK Targeted Therapy: Present and Future", the European Journal of Oncology Medicine "Oncology Newsletter Special Issue" mentioned that half of the cases of drug resistance using a first-generation EGFR-targeted drug are due to the T790M mutation. However, the second-generation drug did not solve this problem well, but the third-generation drug osimertinib solved it.

  The new generation of drugs can often effectively solve the problems left by the older generation of drugs, including drug resistance or greater toxic side effects, thereby ensuring the therapeutic effect.

But it is not to say that with new drugs, the previous generation of targeted drugs will be eliminated.

  Combination drugs are more beneficial to the overall survival of patients than the most advanced targeted drugs alone.

The statistics of "EGFR and ALK Targeted Therapy: Now and in the Future" have also verified this point. Using the third-generation targeted drug osimertinib alone, the median survival time of patients without tumor progression is 18.9 months, while using The median survival time of osimertinib after the first generation of EGFR-targeted drugs appears to be resistant is 19.6 to 23.2 months—nearly 2 years.

  "Our goal is to give each patient adequate treatment and extend their lives as much as possible." Dana-Farber Cancer Institute Senior Vice President of Medical Affairs, Director of the Center for Breast Cancer Medicine, and Professor of Medicine at Harvard Medical School. Ke Wenner told China News Weekly that, under normal circumstances, new drugs will be used in a targeted manner only after the use of the older generation of targeted drugs has developed resistance.

  Clinical trials, when is the "little white mouse"?

  In March 2019, Liu Jianguo once again embarked on a journey to the United States to treat cancer.

In order to use the latest generation of targeted drugs that have not yet been on the market to solve his drug resistance problem, he can only enter a clinical trial and give it another try.

  Boston, the capital of Massachusetts in the northeastern United States, is famous for its higher education institutions. It has gathered more than 100 universities such as Harvard and MIT. The eight teaching affiliated hospitals of Harvard Medical School are scattered in various places in the city. Bo Cancer Institute is located in the city center.

In preparation for future clinical trials, he and his wife rented a high-rise apartment of about 80 square meters near the hospital. It only takes 5 minutes to walk to the hospital from here.

  After many communications and inspections, Liu Jianguo was approved by the hospital to enter the experimental group in mid-May of that year.

Even though he was told that the new drug had many risks affecting vision, liver function, and nerves, he did not hesitate to sign the consent form.

Clinical trials are mainly used to evaluate the safety and effectiveness of new cancer treatments. Because new drugs against drug resistance may be used in trials, they are often regarded as the last life-saving straw for advanced patients.

  "There will always be new drugs in the United States, and there is hope when there are new drugs." When Liu Jianguo said this, his mood was not high.

  Liu Jianguo said that he has spent more than 6 million yuan on anti-cancer, and every day of the advanced stage of cancer is exchanged for real money. Even if the drugs and various treatments that enter the experimental group are free, he has already spent no money. Philippine, besides, there are still great uncertainties in the treatment prospects.

After many attempts, in the end, Liu Jianguo's life span was extended by nearly a year.

  Search for the keyword "cancer" in the clinical research database supported by the National Library of Medicine. By April 27, 2021, the United States will apply for 38,590 "cancer"-related clinical studies, accounting for approximately the total number of cancer clinical studies in the world. Half of that is nearly 5 times that of mainland China (8068 items).

  Taking breast cancer as an example, “Massachusetts General Hospital has more than 50 clinical trials open to breast cancer patients at any time,” Leif Allison, director of the breast cancer medical program at the hospital, told China News Weekly, of course However, not all patients can participate in the trial, and the restriction conditions are another matter, which are closely related to the purpose of the research.

  While providing adequate treatment, there are also some clinical trials dedicated to finding the most suitable drug dosage to avoid the side effects caused by over-treatment.

In Dana-Farber's about 50 clinical trials for breast cancer each year, the dose test is less than 10%, but it is "the most important clinical trial known to the public."

Emphasized by Eric Wenner, senior vice president of medical affairs at the Dana-Farber Cancer Institute, director of the Center for Breast Cancer Medicine, and professor of medicine at Harvard Medical School.

  The most common question about clinical trials is that if they were assigned to the control group, wouldn't they become mice?

  The patients participating in the trial are all selected and need to have certain conditions.

For example, patients are required to have developed a certain drug resistance and be checked before being admitted to the group to ensure their physical condition; secondly, although the control group did not use new drugs, it is standard treatment and will not be worse than conventional treatment.

In addition, in the Phase II clinical trials of new tumor drugs, multiple tumor types, multiple doses or usages are often explored to eliminate invalid doses and screen sensitive tumor types. "One-arm studies" are often used, that is, there is no control group. It is the experimental group, that is, all patients will use the new drug.

  Regulatory agencies will also conduct rigorous review of clinical trials to ensure the safety of patients and the effectiveness of trials.

Taking the clinical trial of chimeric antigen receptor T cells (CAR-T) as an example of the cutting-edge cancer treatment method, the FDA will have clear requirements on the top-level design of the laboratory and the treatment effect, and the technology of the trial. The review board (IRB) supervises.

All professional medical centers, institutions, and academic centers participating in the trial have their own technical review committees, which are fully responsible for the trial plan, including each data and record, even if the patient's infusion time is extended by half an hour, it needs to be reported in time.

  For CAR-T clinical trials, the International Society for Cell Therapy and the American Society of Blood and Bone Marrow Transplantation have also jointly established the Cell Therapy Certification and Examination Committee (FACT), a professional association. "The association is composed of industry experts and scholars and regularly visits various stem cell transplants in the United States. The center evaluates and reviews cell therapy treatment, safety, and whether it meets the standards. If there are deficiencies, we will give suggestions for improvement.” said Sarah Nikiforo, director of Dana-Farber immune effect cell therapy technology. She is also a member of the Cell Therapy Certification Inspection Committee.

  In the 1970s, there were frequent violations of clinical trial data such as falsification of clinical trial data in the United States. Subsequently, a series of laws and regulations were established, especially the Food, Drugs and Cosmetics Act, which clearly stipulated the responsibility of researchers to maintain accurate trial records, save and retain trial records, etc. , To implement the legal responsibility of clinical trial fraud to the individual investigator.

  According to a notice on the official website of the Federal Bureau of Investigation (FBI), in 2009, Maria Carmen Palazzo, a doctor in the New Orleans area, failed to carry out clinical trials as planned and submitted a fraud report. He was eventually charged with 39 medical fraud charges. The local judge sentenced him to 87 months in prison.

  The road to new drugs

  The long-awaited third-generation EGDR targeted drug osimertinib for lung cancer patients took only two and a half years from the start of clinical trials to the approval of the market in the United States, while the general anti-cancer drugs have gone from the trial to the market in the United States. It takes about ten years.

  The movie "Dallas Club" once criticized the US FDA's slow approval of drugs so that patients could not take them in time. In fact, this is the current status of AIDS treatment in the United States in the 1980s.

The public's condemnation prompted the FDA to launch a series of reforms in 1987 to speed up the approval of new drugs, especially "drugs for serious or fatal diseases."

  In 1992, the FDA created two procedures for standard review and priority review. The approval cycles were 10 months and 6 months, respectively.

Gleevec was given priority review and passed the review two and a half months after the review, making it the fastest drug to market at the time. From the beginning of clinical trials in 1998 to the listing in 2001, it only took 3 years.

  Ten years later, "Breakthrough Therapy Designation" was proposed in the "Food and Drug Administration Safety and Innovation Act", aimed at accelerating the development and approval of drugs for the treatment of serious diseases.

Later, the FDA gradually established fast-track and accelerated approval mechanisms.

Osimertinib, which is currently the fastest on the market, passed the accelerated approval channel in November 2015, and it took only two and a half years to complete the process from clinical trials to marketing.

  The rapid listing of osimertinib does not stop in the United States.

In February 2016, the European Medicines Agency approved osimertinib, making osimertinib the first new drug under the EU's accelerated approval process.

In September 2016, the State Food and Drug Administration of China also included osimertinib on the priority review list. It was approved in March of the following year, setting a new record for the approval of new cancer drugs imported into China.

  Cai Qiang, chairman of Shengnuo, an overseas medical consulting and service agency, said that patients going abroad for medical treatment is a comprehensive choice. What attracts them is that in addition to the more accurate diagnosis and treatment services of the multidisciplinary team, humanized medical services, etc., the search has not yet been listed in the country. The new drug is one of the most important factors.

  China's drug review was once criticized for its slow speed and high backlog.

From 2001 to 2016, there were only more than 100 new drugs on the market in China with more than 400 new drugs listed overseas, and the time to market was on average 5 to 7 years later than in Europe and the United States.

According to the public disclosure of the State Food and Drug Administration, the backlog of registration applications in the Drug Evaluation Center has reached a maximum of more than 32,000.

  In August 2015, the reform of drug review and approval, which has been brewing for many years, was launched, and the speed of drug review was doubled.

In 2016, the China Food and Drug Administration handled more than 8,000 backlogs at twice the review speed of 2015, and released 8 batches of drug priority review catalogs.

In 2018, China approved 48 new drugs for the market, 38 of which are imported drugs. Anti-cancer drugs cover multiple myeloma, non-small cell lung cancer, breast cancer, melanoma, liver cancer, rectal cancer, leukemia, etc. .

  Also in 2018, "I'm Not the God of Medicine" caused a sensation. The movie was based on "the first person to buy anti-cancer drugs in India" and Lu Yong, a chronic leukemia patient.

In reality, the "Gleevec" purchased by Lu Yong purchased a box of 23,500 yuan in China. Each box was only enough to eat for 10-15 days. Many patients ran out of family assets to continue their lives. At that time, the Indian generic drugs only had one box per box. It takes hundreds of dollars. In order to survive, they can only take risks and purchase drugs from abroad.

The price of Gleevec in the United States is about 6000 yuan lower than that in China. The difference is the tariff and value-added tax.

  Perhaps it is the social concern caused by the movie that has played a role. From May 1, 2019, all common drugs including anti-cancer drugs, alkaloid drugs with anti-cancer effects and actual imported Chinese patent medicines have been reduced in import tariffs. To zero.

At the same time, the Ministry of Finance and other four departments issued specific measures to reduce the after-value added tax in the production and import of anti-cancer drugs, including 103 anti-cancer drugs that have been on the market.

The government will implement centralized price negotiation and procurement of anti-cancer drugs that have been included in medical insurance.

Negotiations on medical insurance access will be implemented for anti-cancer drugs that are not covered by medical insurance.

  The longer-term strategy for reducing the cost of new drugs is to encourage domestic pharmaceutical companies to innovate in research and development.

In 2020, the China Food and Drug Administration approved a total of 48 new drugs under the pressure of the epidemic. From the perspective of the treatment field, these approved new drugs can be described as "tumor is king"-the approved anti-tumor drugs accounted for 34% (16/48) ).

  "Foreign advanced equipment, technology, clinical trials of new drugs, and targeted drugs are now available in China. China is a large country with a population of 1.4 billion. The current incidence of lung cancer in China accounts for 40% of the world’s total, and the incidence of liver cancer accounts for more than 50% of the world. Nasal cancer accounts for a higher proportion. Therefore, it is impossible for clinical trials of new drug development in various countries not to consider launching in China." Zhi Xiuyi, chairman of the Lung Cancer Medical Education Committee of the China Medical Education Association and director of the Lung Cancer Center of Capital Medical University, commented on China News Weekly "Said, "The gap in new drugs is further narrowing."

  (At the request of the interviewee, Liu Jianguo is a pseudonym in the text)

  China News Weekly, Issue 16, 2021

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