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Jin Zhang outlines how Chinese companies are advancing in the urgent effort to combat stomach cancer.
With an annual incidence rate of 13.86/100,000 worldwide, gastric cancer is currently ranked as the second most prevalent tumor around the globe. Its incidence rate is particularly high in China. According to the 12th International Conference on Gastric Cancer held in Beijing in April 2017, about 680,000 new cases are reported in China each year, accounting for about half of the total patient population globally. Compared to 446,500 cases in 2012, the annual growth rate has exceeded 13%.
At present, gastric cancer is the second most prevalent and the third most deadly malignant tumor in China. Its mortality rate is about four to eight times of that in developed countries. It has become one of the major threats to Chinese people’s health. What is worse is that when most patients are diagnosed, their diseases have already progressed to mid- or even late stages, making them very difficult to treat.
Gastric cancer normally starts out from the stomach tissue and develops slowly over the years. Until now, its cause has not been fully elucidated. The majority of the research indicates that Helicobacter pylori infection, nitroso compounds, and dicarbonyl compounds, as well as fungi and genetics, all play a very important role in its occurrence.
Nowadays, with the aging population and the change of diet and living environment, the incidence of gastric cancer became even higher. In China, the high-risk population is normally people who are over the age of 40. And it is especially popular in coastal cities and northwestern regions, due to their unhealthy eating and living habits.
So far, chemotherapy still dominates the market and is the most popular treatment for gastric cancer. A total of 20 different chemical drugs have been used. Among them, the most common are docetaxel series, fluorouracil derivatives, platinum, antitumor antibiotics, camptothecin derivatives, and folinic drugs. According to the China National Public Hospital's Chemical Drug Terminal Monitoring and Analysis System (HDM), the total stomach cancer chemotherapy drug market in public hospitals in China’s key cities was $940 million in 2016 (1 dollar = 6.94 yuan), amounting to a 12.24% growth compared to the same period of the previous year. Down the line, this market is expected to grow further in the future. It is estimated that its total size will reach $4 billion by 2030.
Riding on this trend, a number of new treatments have been developed to solve this pressing issue. New adjuvant chemotherapy, postoperative adjuvant chemotherapy, and palliative chemotherapy have all been proposed, in addition to the traditional concurrent chemoradiotherapy with platinum, fluorouracil, and their analogs. Furthermore, in the face of rising biologics and targeted small molecule drugs, they are also increasingly gaining attractions in the gastric cancer field in recent years.
It is well known that it is very hard to detect gastric cancer in its early stages, primarily due to its atypical symptoms, the majority of them originating from the innermost layer (mucosa) of the stomach. It is especially hard to be detected in China, because of the limited application of routine gastroscopy examination.
According to statistics, about 60% to 80% of patients in China have already reached the mid- to late stages when diagnosed. The recovery after surgery is extremely unsatisfactory and the prognosis is very poor. In addition, in the face of its high incidence in the elderly, the overall survival time, on average, is shorter than one year; its survival rate within 5 years is less than 20%.
Over the years, comprehensive treatments, including surgical removal, radiation therapy, chemical medicine, and traditional Chinese medicine, have been widely adopted as the standard in China. In particular, basic concurrent radiotherapy is highly recommended for preoperative or postoperative gastric cancer. But in fact, it has not been showing satisfactory results so far.
Understandably, treatments for gastric cancer still need improvement. The 21st century has seen some progress in this field. We have taken a big step from traditional single-agent therapies, such as fluorouracil, cisplatin, and epirubicin, and introduced the new “cocktail” approach, including oral fluorouracil carbamate, oxaliplatin, and paclitaxel altogether.
Nowadays, the anti-metabolism drug fluorouracil series is fundamental in treating stomach cancer patients with chemotherapy. It has been widely used in public hospitals in China’s key cities. The most popular products include tegafur, capecitabine, fluorouracil, doxifluridine, compound fluorouracil, uracil tegafur, etc.
Fluorouracil is the first generation of anti-metabolites synthesized in the 1960s. Currently, it is also one of the most popular anti-tumor drugs and the basics in gastric cancer chemotherapy.
According to the statistics from the HDM system, the market for fluorouracil in public hospitals in China’s key cities has exceeded $220 million in 2016, accounting for a 13.44% increase compared to the same period of last year. With more than 50% share, tegafur has become the absolute winner in this category of drug.
Tegafur, developed by Japanese Taiho Pharmaceutical, is an oral form of fluorouracil derivatives and was first approved for late stage gastric cancers in 1999. Clinical data indicates that it has been applied in more than 80% of advanced digestive system malignant tumor patients. Nowadays, it is regarded as a safe and effective anti-solid tumor cancer oral drug; its therapeutic efficiency has reached 44.6%.
According to data from HDM system, the sales of tegafur in China’s public hospitals in key cities has reached a total of $108 million in 2016, amounting to an 11.27% increase compared to the same period of the previous year. Among them, capsules accounted for 99.96% of the market, whereas tablets only represented 0.04%. In all, the overall market in China has reached $384 million.
Furthermore, with a share of 84.42%, China-produced tegafur has dominated the space there. At present, four different Chinese companies are supplying to the market. They are Shandong New Time Pharmaceutical, Qilu Pharmaceutical, Hengrui Medicine, and Fuzhou Haiwang Pharmaceutical. Shangdong New Time is leading the race. In 2016, it captured 45.35% of the market share. Right after is Hengrui Medicine, which took a 22.95% share. In the third tier, Qilu Pharmaceutical and Taiho Pharmaceutical seized 16.08% and 15.58% of the market, respectively. Worth mentioning is that data indicates that both Qilu and Hengrui are riding on an upward trend and will continue to grow in the coming years.
Capecitabine is a new generation of oral fluorouracil antitumor drugs developed by Swiss company Roche. It was approved by FDA in April 1998 under the trade name Xeloda. Currently, it is mainly used as a first-line treatment of advanced or metastatic gastric cancer that cannot be operated. Its first generic version was developed by Teva and was approved by the FDA on September 16, 2013. Three months later, its patent expired in China (December 17, 2013). Since then, a number of Chinese companies entered the race.
Riding on this wave, Hengrui Medicine became the first to notch CFDA approval in 2012. And there is more to come. In December 2013, CFDA further greenlighted the generic capecitabine from Qilu Pharmaceutical. A year later, it handed an approval to Chia Tai Tianqing. Until now, one imported and three domestically produced capecitabine treatments have dominated the market in China.
According to the data from HDM system, the total sales of capecitabine in public hospitals in China’s key cities reached $88 million in 2016, representing a 13.64% increase compared to the same period of the previous year. Among them, Roche is the leader, taking over 72.24% of market share in China in 2016. Hengrui, Qilu, and Chia Tai Tianqing captured 11.09%, 9.19%, and 7.47% respectively.
However, things are changing. Compared to 2015, Roche’s market share has reduced by about 10%. It is expected that with the increasing popularity of China’s domestic capecitabine, Roche will gradually lose its ground in China.
In recent years, targeted small molecule drugs and biologics have begun to take the center stage in the global anti-cancer market. But their applications in the gastric tumor sector is still relatively limited. So far, only a few of them have been applied in this field, including trastuzumab from Roche, Cyramza from Eli Lilly, Apatinib from Hengrui Medicine, Regorafenib, and anti-PD1/PD-L1.
HER2 is a member of the EGFR family and signals by forming heterodimers with other members of the family. The high expression of HER2 was observed in 7% to 38% of gastric and gastric esophageal cancer patients. Its expression was even higher in patients with gastric esophageal junction tumors.
In October 2010, FDA approved trastuzumab, co-developed by Roche and Medtech, in combination with fluorouracil and cisplatin or capecitabine and cisplatin, to treat patients with HER2 overexpression gastric cancers. In 2012, CFDA further approved it as the first-line treatment option for HER2-positive metastatic gastric cancers, providing more choices for the large number of advanced gastric cancer patients in China.
As with other solid tumors, angiogenesis plays a very important role in promoting the growth and metastasis of gastric cancers. And during this process, VEGF is the number one factor. Among all the known stimulus, it has the strongest angiogenic effects. It is known that tumor cells can synthesize and periodically secrete VEGF, thus boosting the tumor angiogenesis and specifically advancing endothelial cell proliferation to directly participate in vascular formation.
Studies have shown that the high expression of VEGF in gastric cancer tissues is closely related to its growth, invasion, and metastasis. In the face of these findings, an increasing number of VEGF targeted drugs began to appear in the market and show their value in treating gastric cancer patients. Currently, a total of three VEGF inhibitors have been approved.
Hengrui Medicine’s self-developed Apatinib, approved by CFDA on October 17, 2014, is the world’s first small molecule anti-angiogenic targeting drug proven to be safe and effective in advanced gastric cancers. It is also the best single-agent after the failure of the standardized treatment for advanced gastric cancers. More importantly, Apatinib, as the only oral preparation among all gastric cancer targeted drugs, can greatly improve treatment compliance among patients. According to data from the HDM system, in 2016, the sales of Apatinib to treat stomach cancer in the public hospitals in China’s key cities has reached $9.94 million, amounting to an 18.37% increase compared to the same period of the previous year.
In recent years, the checkpoint inhibitor PD-1/PDL-1 has become the rising star in the field of cancer treatment. It has been demonstrated to be effective in a wide range of tumors, including melanoma, non-small cell lung cancer, and renal cancer. Its expression was also elevated in 14-24% of gastric cancer patients.
In September 2017, the FDA approved the application of pembrolizumab in stomach tumors, based on the results of the KEYNOTE-059 clinical trial.
Jin Zhang M.D., Ph.D is editor at The Pharmaceutical Consultant.