PD-1 treatment of esophageal cancer surprises again and again "Chinese characteristic tumor" treatment sees new hope

In July this year, the US FDA approved the treatment of esophageal cancer with drug K (keytruda, pabolizumab)The specific indication is PD-L1 positive recurrent locally advanced or metastatic esophageal squamous cell carcinomaThis is the first time in 50 years that esophageal cancer treatment has seen a new light of hope< br / > according to the progress of clinical studies, both drug K (pabolizumab) and domestic carrilezumab have published the data of esophageal cancer treatment in Chinese population, while drug o (navulizumab) has also published the data of Asian patientsThe era of immunotherapy for esophageal cancer has come< br / > next, let's see if these three drugs can achieve "two hands, two hands should be hard" in the most important efficacy and safety of patients' friends< br / > esophageal cancer can be divided into squamous cell carcinoma, adenocarcinoma, small cell carcinoma, mucinous cell carcinoma and other cancersThe sensitivity of different subtypes of esophageal cancer to the treatment of PD-1 antibody is differentThe majority of esophageal cancer patients in China are squamous cell carcinoma, and the majority of esophageal cancer patients in western countries are adenocarcinomaTherefore, Chinese patients should pay more attention to the therapeutic effect of PD-1 antibody on Chinese esophageal cancer patients, that is to say, the Chinese population data of each clinical trial will have more reference significance for patients< br / > clinical efficacy index: < br / > in terms of efficacy, we should pay special attention to the gold standard of total survival time (OS)The longer OS is, the longer patients liveSpecifically, OS data can be evaluated from three aspects: < br / > 1The median of the total survival time (MOS) of patients after treatment: also known as the median total survival time, which is the most direct parameter of OS dataWith the extension of the tracking time, the survival data of the patients also came out one after another, and the survival time of the middle patient was counted, that is, MOSIf we calculate the mean of all patients' survival data, it is easy to be biased by extreme data, and the median can better reflect the middle level of the whole group of dataMOS is the most important index in clinical trials, and it is the gold standard to measure the specific survival benefit of new therapy compared with standard therapy For example, in keynote-181, the MOS of Chinese esophageal cancer treated with K drug was 8.4 months, while that of chemotherapy was only 5.6 months, with significant difference in survival HR: hazard ratio: it is an important index to measure the survival benefit of new therapy compared with standard therapy Compared with the disease death risk of standard therapy, the reduced disease death risk of new therapy = 100% - HR, that is, the lower HR, the higher the reduced disease death risk, which means the better the effect of new therapy For example, in keynote-181, the HR of esophageal cancer in China is 55%, which means that compared with chemotherapy, drug K can reduce the risk of disease death by 100% - 55% = 45% Halving the risk of death indicates that the new therapy has a great improvement in survival compared with the traditional therapy, and is also a condition for accelerated approval of various breakthrough therapies < br / > 3 One year (12 months) survival rate: This is a very intuitive data, which specifically shows how many patients are still "living" after one year of treatment For example, in keynote-181, 36.3% and 16.7% of Chinese esophageal cancer patients used K medicine and chemotherapy respectively, which means that less than 20% of the patients lived for one year before, and the number of people who lived for one year after using K medicine doubled, nearly 40% < br / > at present, the clinical data comparison of three PD-1 antibody drugs in esophageal cancer < br / > k drug: < br / > keynote-181 is a global large-scale clinical study It is the first phase III randomized controlled study in which the head-to-head comparative immunotherapy and standard chemotherapy are used in the treatment of esophageal cancer in the world The success has broken the deadlock in the treatment of esophageal cancer in the past 50 years, proving that in the treatment of esophageal cancer, Single drug K is more effective than chemotherapy < br / > 628 patients (including 123 Chinese patients) were included in the clinical study, and the data of Chinese patients were analyzed by default The results were published in this year's ESMO annual meeting [5]: < br / > in terms of the total survival time: the MOS of K drug and chemotherapy were 8.4 months and 5.6 months, respectively, extending the survival time by 2.8 months, The one-year survival rate of K drug and chemotherapy was 36.3% and 16.7%, respectively, with an increase of nearly 20% < br / > in the past 50 years of clinical research on esophageal cancer treatment, there has never been any precedent, showing that the survival rate of the experimental drug group is more than 2 times higher than that of the standard treatment group! Therefore, the keynote-181 study is a milestone in the treatment of esophageal cancer < br / > carrelizumab: < br / > the clinical trial of carrelizumab in the treatment of esophageal cancer is the escort study All the patients in the group are patients with advanced or metastatic esophageal cancer in China, with a total of 457 cases The results were published at this year's world esophageal Congress (oeso): < br / > total survival time: the MOS of carrelizumab and chemotherapy were 8.3 months and 6.2 months respectively, In terms of the one-year survival rate, the one-year survival rate of carrizumab and chemotherapy was 33.7% and 22.3%, respectively, 11 percentage points higher < br / > drug o: < br / > drug o has no data from China, but can only refer to Asian data The related clinical study is action-3 The patients are non resectable locally advanced and metastatic esophageal squamous cancer or squamous adenocarcinoma There are 419 patients in total, most of them (401 cases) are from Asia, accounting for 96% The research results are also published in the ESMO annual meeting [6]: < br / > in terms of the total survival time: the MOS of drug O and chemotherapy are 10.9 months and 8.4 months, respectively, extending the survival time of 2.5 months, The one-year survival rate of drug O and chemotherapy was 47.0% and 34%, respectively, increasing by 13% < br / > figure: compared with chemotherapy, different PD-1 antibody drugs reduce the risk of death (Note: the treatment population includes all esophageal squamous cell carcinoma, drug K and caribou are Chinese patient data, and drug o is Asian patient data According to the data, drug K reduces the most risk of death in Chinese population and Chinese population with high expression of PL-1) < br / > it is worth mentioning that for patients with PD-L1 positive esophageal cancer, no matter for patients with PD-L1 CPS ≥ 10 in keynote-181 study, As for the patients with PD-L1 ≥ 1% in the escort study, both drug K and carrizumab can bring more significant survival benefits, reducing the risk of disease death by 66% and 42% respectively < br / > in the past few decades, chemotherapy has been the standard treatment for esophageal cancer, and a series of serious or relatively serious side effects, such as leukopenia, neutropenia, poor blood, decreased appetite, fatigue, vomiting, hair loss and so on, have been "unbearable pain" for cancer patients, There are also many patients who are afraid of the side effects of chemotherapy and choose to give up the treatment, so they are helpless for the coming of death < br / > the appearance of immunotherapy makes the treatment pattern of esophageal cancer change Compared with chemotherapy, the side effect of PD-1 McAb is milder and the incidence is lower < br / > looking at the side effects (treatment-related AE) of the three PD-1 monoclonal antibodies in clinical trials, the side effects of carrizole were found in 94.3% of the patients, 75.8% of the patients with drug K and 65% of the patients with drug o But this includes all side effects If only serious side effects (treatment-related AE above level 3) are compared after treatment, the proportion of chemotherapy is more than 40%, while the proportion of three PD-1 monoclonal antibodies is only half of that of chemotherapy < br / > however, PD-1 mAb has some unique immune-related adverse reactions, the most common of which are thyroid function damage and immune inflammation With the popularization of PD-1 monoclonal antibody and the accumulation of clinical experience, doctors have more experience in controlling the adverse reactions of PD-1 monoclonal antibody and using immunotherapy safely For example, it is suggested that medical staff and family members of patients should monitor the whole process during and after treatment, improve their vigilance, find out abnormal situations as early as possible and intervene in time, gradually establish a complete system management system for adverse reactions related to tumor immunotherapy, pay close attention to safety, and provide tumor patients with a comprehensive and reliable immunotherapy "protection network" < br / > although most of the adverse reactions of PD-1 antibody have been well known by the medical staff, and they are relatively mild and easy to manage However, unlike other PD-1 antibodies, caribou had a special side effect: reactive capillary endothelial hyperplasia (rccep), which reached 79.8% in the escort study This side effect also appeared in the treatment of other tumors by carrizumab In the clinical study of second-line treatment of HCC by carrizumab published at the ESMO conference in 2018, the overall incidence of rccep in the treatment group was 66.8% (q2w, 63.3%, q3w 70.4%) < br / > in January this year, the British Journal mAb published a research article, pointing out that it may be because of the "Miss target" of Carrelli bead to activate the signal pathway of vascular endothelial growth factor receptor (VEGFR2), which leads to capillary proliferation and high incidence of hemangioma [7] Therefore, the side effect of rccep is specific to caribou, not common to PD-L1 antibody < br / > as early as 2017, the patients who took part in the clinical trial of carrizumab responded in succession, with many hemangioma symptoms, even in the face seriously affecting the beauty and interfering with normal life, many patients withdrew from the group, and many media also reported the event "withdrawal of patients in the clinical trial of Hengrui PD-1" < br / > the occurrence of this special adverse reaction has sounded the alarm for the application of immunotherapy, and put forward higher requirements for strengthening the supervision of immunotherapy related adverse reactions After all, in practice, it is a basic medical ethical principle to try to protect patients from unnecessary medical harm < br / > the new hope of esophageal cancer patients is to grasp both efficacy and safety < br / > frankly speaking, PD-1 monoclonal antibody is not a magic drug, and not every patient can benefit from the treatment < br / > however, from the current clinical research results of PD-1 antibody in the treatment of esophageal cancer, PD-1 antibody will bring light to the majority of patients, especially some patients with high expression of PD-L1, which is expected to obtain long-term therapeutic effect from immunotherapy < br / > immunotherapy will bring revolutionary progress to the treatment of esophageal cancer, and it is also expected to become a powerful tool for the treatment of esophageal cancer < br / > it is reported that drug K is the first one of the indications for esophageal cancer in China to submit an application for listing, which has also been included in the priority review list and is expected to be approved Next to that is carrelizumab, which is expected to be approved next year At present, no application for indication of esophageal cancer has been seen for drug o, and no results of phase III clinical trials of esophageal cancer have been published for other domestic monoclonal antibodies such as Junshi / Xinda / Baiji < br / > when we are optimistic about the efficacy of immunotherapy, patients should not be blinded by the efficacy, but also pay attention to the safety of PD-1 monoclonal antibody, both efficacy and safety < br / > References: < br / > 1 National health and Health Commission Esophageal cancer diagnosis and treatment specifications (2018 Edition) [J / CD] Chinese Journal of Gastroenterology and imaging (Electronic Edition), 2019,9 (4): 158-192 Doi: 10.3877/cma.j.issn.2095-2015.2019.04.005 < br / > 2 Meng Yachao, Wang Feng, Meng Xiangrui, et al Research progress of esophageal cancer immunosuppressant [J] Chinese Journal of practical medicine, 2019, 46(3):122-126 3 Hou H, Meng Z, Zhao X, Ding G, Sun M, et al (2019) Survival of Esophageal Cancer in China: A Pooled Analysis on Hospital-Based Studies From 2000 to 2018 Frontiers in Oncology 9:548 4 Freddie B , Jacques F , Isabelle S , et al Global Cancer