In-depth: Analysis report on the current status of treatment drugs for advanced liver cancer in China

1.
Silent killer-stars who died of liver cancer

On February 3, 2021, Zhao Yingjun, the famous musician who wrote the swan song "Send You A Little Red Flower" written with his life, died at the age of 43
.
On February 27 of the same year, our Uncle Da, a famous Hong Kong movie star Wu Mengda, died of liver cancer at the age of 68.

While sighing for these stars, we are thinking about this question, what is liver cancer? And is it late as soon as it is discovered? What is the status of the existing treatment drugs?

2.
Epidemiology and treatment of liver cancer

1 Epidemiology

Primary liver cancer (primary liver cancer, PLC) is abbreviated as liver cancer, which refers to a common malignant tumor of the digestive system that originates in liver cells or intrahepatic bile duct epithelial cells worldwide
.
The global and China incidence of liver cancer is shown in Table 2-1

2 Causes of liver cancer

The exact cause of liver cancer is still unclear.
Possible risk factors include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, long-term alcoholism (alcoholic liver disease), non-alcoholic steatohepatitis, People who eat aflatoxin-contaminated food, schistosomiasis and other causes of liver cirrhosis, and people with a family history of liver cancer
.
The main causes of liver cancer in China are chronic hepatitis caused by hepatitis B virus infection, and liver cirrhosis caused by drinking or non-alcoholic steatohepatitis

3 Treatment strategies for liver cancer

Since Sorafenib was approved by the US Food and Drug Administration for the treatment of advanced liver cancer in November 2007, drugs for the indications of liver cancer have been approved internationally, including first-line treatment of sorafenib and lenvatinib ; Second-line treatment of regorafenib, ramucirumumab, carbotinib, apatinib, pembrolizumab, nivolizumab, carrelizumab
.
Except for ramucirumumab, pembrolizumab, nivolizumab, karelizumab, other targeted drugs are all small-molecule multi-target oral tyrosine kinase inhibitors (tyrosinekinaseinhibitor, TKI).

3.
Analysis of domestic approved single-drug therapy for liver cancer and its current status

Targeted therapies approved for liver cancer indications in China include sorafenib, lenvatinib, regorafenib, apatinib, and carrelizumab
.
Only sorafenib and lenvatinib are used for first-line treatment, and the other three are second-line drugs

Although Sorafenib is an old drug for the treatment of liver cancer, its objective remission rate is only 2%
.

Regorafenib became the first liver cancer drug approved 10 years after the market of sorafenib.
Compared with placebo, it can significantly prolong the overall survival of patients with OS.
Patients with advanced liver cancer received sorafenib as the first-line treatment.
With regorafenib, the patient's overall survival can be extended to 26 months
.

       Lenvatinib is particularly effective in the treatment of liver cancer induced by hepatitis B.
In the HBV population, the lenvatinib group has an OS of 14.
9 months.
For Chinese patients with hepatitis B as the main cause of liver cancer, it provides a new treatment option for patients with advanced liver cancer in China
.

       Apatinib OS and PFS are equivalent to sorafenib, but the objective response rate is 10 times that of sorafenib
.

       Carrelizumab is China’s first self-developed anti-PD-(L)1 liver cancer drug.
It is not compatible with other second-line therapies (nivolizumab, pembrolizumab, regorafenib, etc.
).
It has comparable efficacy and good safety
.

       4.
Analysis of the market situation of approved liver cancer treatment drugs in China

       1 Analysis of market access

       (1) Medical insurance

       For the more expensive liver cancer drugs, inclusion in the medical insurance catalogue is of great significance to the accessibility of patients and increasing drug income.
At present, all five drugs approved for liver cancer indications in China have been included in the medical insurance, which can greatly improve the accessibility of patients It can reduce the economic burden of patients and accelerate the popularization and application of drugs
.

       (2) Bid winning situation

       At present, the lowest price of the five drugs is apatinib at 174.
32 yuan/tablet, and the highest price is Carrelizumab injection at 19,585 yuan/bottle.
The winning price of sorafenib has been approved and included in other liver cancer drugs.
After medical insurance, there is a clear downward trend
.

       (3) Centralized procurement

       Jiangxi Shanxiang Pharmaceutical and Chongqing Yaoyou’s sorafenib entered the fourth batch of centralized procurement.
The winning bids were 1,369 and 798 yuan respectively.
This will give the other two companies that have not entered the centralized procurement (Beijing Yabao, CSPC Ouyi) ) Will bring a serious blow and may cause a serious decline in market share
.
Other drugs have not yet entered the centralized procurement list, see Table 4-3 for details

       (4) Consistency evaluation

       Sorafenib: 4 companies have passed the consistency evaluation (including deemed equivalent), 4 companies (Jiangxi Shanxiang Pharmaceutical, Chongqing Yaoyou, Beijing Yabao Biology, CSPC Ouyi) are deemed to have passed the consistency evaluation, and the other 2 Home (Hangzhou Sino-American East China, Shanghai Chuangnuo Pharmaceutical) is currently in the application stage
.

       2 Sales in the domestic market

       In 2020, China’s approved liver cancer indication drugs (multi-kinase inhibitors and immune checkpoint inhibitors) sales reached 605 million U.
S.
dollars, showing an upward trend in the past five years, with a five-year compound growth rate of 106%.
The sales of Rafinil and Rigofinil were US$12 million, US$105 million, and US$399 million, respectively, and both showed an upward trend year by year
.
Apatinib was approved in December 2020, and there is no relevant sales data

       The proportion of sorafenib sales has been declining year by year, from 100% to 17.
35%, and the market share of regorafenib has increased year by year, from 5.
87% to 65.
92%
.
Carrelizumab has a market share of 14.

       V.
China registration and acceptance of liver cancer therapeutics

       1 Registration and acceptance of drugs that have been marketed for liver cancer in China

       At present, domestic registration applications are still concentrated in sorafenib, 18 companies are applying for listing (Qilu, CSPC, Kelun, Hausen, etc.
), and 8 companies are applying for clinical trials (China East China, Jiayi, Kaifeng Pharmaceutical) Etc.
); 10 lenvatinib companies (Hengrui, Orsay, Huadong Medicine, etc.
) are applying for listing, 4 companies (Yangzijiang, Shanxiang Pharmaceutical, Zhengda Weatherqing, etc.
) are applying for clinical trials, and Regorafenib has 18 companies (Kelun, CP Tianqing, CSPC, etc.
) are applying for clinical trials
.

       2 Acceptance of other drugs for liver cancer indications on the market abroad

       Cabozantinib is ready to go on the domestic market.
3 companies (Jiangsu Orsay, Jiangsu Hausen, Simcere) are applying for listing, and 6 companies (China Chia Tai Tianqing, Shanghai Huilun, Shenzhen Wanle, etc.
) have been approved Clinical
.

       It is worth mentioning that donafenib is a multi-target, multi-kinase inhibitor by Suzhou Zejing Biotechnology, based on an open-label, randomized, parallel-controlled phase II/III registered clinical trial ZGDH3 study As a result, compared with sorafenib, donafenib can significantly prolong the OS of patients with advanced liver cancer (12.
1 months VS 10.
3 months), and has better safety and tolerability, and the diagnosis and treatment of primary liver cancer In the 2020 version of the guidelines, Donafenib is recommended as the first-line treatment for advanced liver cancer patients with liver function Child-Pugh A or better B (≤ 7 points) (level I expert recommendation, 1A evidence)
.
In March 2020, the sponsor has submitted a listing application to the NMPA and listed it as a priority for review and approval.
At present, the listing application of Donafinil is still in the review and approval stage
.

       6.
The status of domestic clinical research drugs

       The currently ongoing domestic trials on targeted therapy for liver cancer are mainly combined therapy.
Innovent's IBI310 combined with Sintilimab Phase III clinical trials are underway, and Jiangsu Hengrui is undergoing three phase II clinical trials: PD-1 antibody combined with apatinib, carrelizumab combined with apatinib, apatinib mesylate tablets combined with TACE
.
See Table 6.
1
.

       Seven, summary

       Hepatocellular carcinoma mainly occurs in patients with chronic hepatitis (type B or C) or cirrhosis caused by alcohol abuse, and hepatocellular carcinoma patients in China account for almost half of the global cases
.
Currently approved domestic liver cancer treatment drugs include sorafenib and lenvatinib for first-line treatment; regorafenib, apatinib and carrelizumab for second-line treatment
.
Except for carrelizumab, other targeted drugs are small molecule multi-target TKIs
.

       All five liver cancer treatment drugs are included in medical insurance, which can accelerate the popularization and application of drugs
.
All five drugs are included in the national medical insurance 2020 medical insurance, and the price of drugs has a downward trend, which can improve the accessibility of patients and reduce the economic burden of patients, and accelerate the popularization and application of drugs
.

       The overall sales of liver cancer treatment drugs in China are increasing year by year, and the market share of second-line treatment drugs is increasing year by year
.
In 2020, China’s approved liver cancer indication drugs (multi-kinase inhibitors and immune checkpoint inhibitors) sales reached 605 million U.
S.
dollars, showing an upward trend in the past five years, with a five-year compound growth rate of 106%.
The sales of Rafinil and Rigofinil were US$12 million, US$105 million, and US$399 million, respectively, and both showed an upward trend year by year
.
Apatinib was approved in December 2020, and there is no relevant sales data
.
Carrelizumab, an indication for liver cancer, was approved in March 2020.
The sales of Carrelizumab in the 10 months of 2020 will still reach US$89 million
.
Among them, the market share of second-line treatment drug regorafenib has increased year by year, rising from 5.
87% to 65.
92%
.
Carrelizumab has a market share of 14.
66% in 2020
.
Both drugs have greater growth potential
.

       At present, domestic small-molecule targeted therapy drugs are fiercely competitive, sorafenib, 18 companies are applying for listing (Qilu, CSPC, Kelun, Hausen, etc.
), and 8 companies are applying for clinical trials (China East China, Jiayi, etc.
) , Kaifeng Pharmaceutical, etc.
); 10 lenvatinib companies (Hengrui, Orsay, Huadong Medicine, etc.
) are applying for listing, and 4 companies (Yangtze River, Xiangshan Pharmaceutical, Zhengda Weatherqing, etc.
) are applying for clinical trials.
Feni has 18 companies (Kelun, CP Tianqing, CSPC, etc.
) that are applying for clinical trials
.

       In the future, domestic liver cancer drug treatments may be targeted by small molecule targets and turn to biological drugs
.
Ramulizumab, pembrolizumab, and nivolizumab are actively applying
.

       8.
References:

       [1] Chinese Society of Clinical Oncology (CSCO), Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2020).

       [2] Multidisciplinary Collaborative Group of Gastrointestinal Tumors, Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College, Expert consensus on targeted therapy of liver cancer (draft).
"Electronic Journal of Liver Cancer" 2020, 7(2): 2-11.