Major breakthrough in first-line treatment of liver cancer! Is this immune combination therapy expected to change the treatment mode?

Roche announced that tecentriq (atezolizumab, atzumab), a blockbuster PD-L1 inhibitor, combined with Avastin (bevacizumab), an anti VEGF antibody, reached two common primary endpoints in phase 3 clinical trials for patients with unresectable HCC Compared with the standard therapy sorafenib, it brings statistically significant and clinically significant improvement in patients' PFS and OS This progress is a major breakthrough in the first-line treatment of liver cancer, and also shows a broad prospect of the combination of anti angiogenic drugs and immunotherapy Since sorafenib was approved as the standard treatment for advanced liver cancer in 2007, the treatment of liver cancer has stagnated in the past 10 years However, since 2017, the field of liver cancer treatment has obtained one after another innovative therapies Today, the content team of Wuxi apptec will review the latest breakthroughs in liver cancer treatment in recent years, and interpret the synergistic effect between VEGF signaling pathway and immunotherapy Why is HCC difficult to treat? HCC is one of the main causes of cancer death in the world According to statistics, more than 750000 people suffer from HCC every year in the world, most of them in Asia and almost half in China The main causes of HCC are chronic hepatitis caused by hepatitis B or C virus infection, and cirrhosis caused by drinking or non-alcoholic fatty hepatitis One of the important reasons for the high mortality rate of HCC is that the early symptoms of HCC are not obvious, leading to 70% of patients diagnosed with advanced cancer The prognosis of unresectable HCC is poor Usually, the average survival time of patients is less than one year, and the 5-year survival rate is only 14.1% Another reason why HCC is difficult to treat is the heterogeneity of HCC HCC belongs to the cancer type with high heterogeneity Its heterogeneity is manifested in different levels Not only different tumors in the body will have significant differences in histology, but also different cancer cells in the same tumor have different molecular biology and epigenetic characteristics This is a major challenge to develop effective therapies Progress of small molecule targeted drugs since 2017, a total of three multi protein kinase inhibitors (MKI) have been approved by the FDA for the treatment of HCC Among them, stivarga and cabometryx were approved as second-line therapy to treat patients with HCC whose disease continued to progress after sorafenib treatment Lenvima, developed jointly by Eisai and MSD, was approved as a first-line treatment for patients with advanced HCC The common feature of MKI is that it can inhibit the activity of many receptor protein kinases related to angiogenesis, including VEGFR, PDGFR and FGFR Due to the abnormal angiogenesis is one of the important characteristics of HCC, the development of innovative therapies targeting the abnormal angiogenesis is one of the major directions of HCC treatment Another innovative treatment brought about by this research and development direction is cyramza of Lilly This is a humanized VEGFR2 monoclonal antibody This year, it was approved by FDA After the second-line treatment of sorafenib, the disease continued to progress in patients with HCC AFP levels in these patients were higher than 400 ng / ml AFP is an important index to reflect the prognosis of patients, especially in patients with elevated levels The birth of immunocheckpoint inhibitors has changed the treatment mode of cancer In the treatment of HCC, immunosuppressive checkpoint inhibitors have also made some progress In 2017, opdivo (nivolumab) of Bristol Myers Squibb Company became the first PD-1 / PD-L1 therapy approved for the treatment of HCC, which is used for the second-line treatment of patients with advanced HCC after sorafenib treatment Subsequently, keysruda (pembrolizumab), the PD-1 inhibitor of MSD, was approved in November 2018 to treat the same type of HCC patients with second-line treatment However, PD-1 / PD-L1 inhibitors, as a first-line single drug therapy, did not show better therapeutic effect than sorafenib Since angiogenesis inhibitors and immunotherapy can produce curative effects in the treatment of HCC, can the combination of angiogenesis inhibitors and immunotherapy produce better results? The synergistic effect of angiogenesis inhibitors and immunotherapy angiogenesis inhibitors have a long history as anticancer therapy At first, it was thought that the way of action of angiogenesis inhibitors was to inhibit the proliferation of blood vessels that dominate the tumor, thus cutting off the channels of nutrition and oxygen delivery for the tumor, so as to "starve" the tumor This is just one of the ways that angiogenesis inhibitors work Recent studies have shown that tumor angiogenesis plays an important role in helping to form tumor microenvironment with immunosuppressive characteristics It turns out that although there are more blood vessels in tumors, their function is different from that of normal blood vessels The abnormal blood vessels of these functions and structures will cause hypoxia and low pH environment in the tumor The release of cytokines stimulated by this environment can not only inhibit the function of immune cells in tumor microenvironment, but also produce systemic immunosuppression through blood circulation The anti angiogenesis drugs, such as VEGFR inhibitors, can restore the balance of angiogenesis, change the tumor microenvironment and improve the effect of immunotherapy Therefore, there are many clinical trials that combine angiogenesis inhibitors with immunocheckpoint inhibitors to treat a variety of solid tumor types, including glioblastoma, non-small cell lung cancer, melanoma, renal cell carcinoma and so on In terms of the treatment of HCC, Roche's tecentriq / Avastin combination and mosadon / Weicai's keytruda / lenvima combination have both obtained the breakthrough treatment recognized by FDA, and have made positive early clinical trial results in the treatment of advanced HCC According to the results of phase 1 trial published by Roche at this year's ESMO annual meeting, the combination of Avastin and tecentriq can reduce the risk of disease progression or death by 45% compared with the single drug tecentriq The positive results obtained by Roche tecentriq / Avastin combination in phase 3 clinical trials yesterday are the first in phase 3 clinical trials to prove the synergistic effect of this combination in the treatment of HCC Roche said it would quickly submit regulatory applications to regulators around the world, including the U.S FDA, the European Drug Administration (EMA) and China's National Drug Administration (nmpa), bringing new treatments to patients with limited choice of liver cancer We hope that the combination of antiangiogenic drugs and immunosuppressive agents will not only bring breakthroughs in the first-line treatment of HCC, but also benefit other solid tumor patients Recommended conference of editor in chief: 2019 Wuxi International Biomedical forum and the 9th International Conference on cell death & Disease - new drug research and development: http://meeting.bioon.com/bcdd? __token=liaodefeng