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For a long time, although immunization and targeted therapy have made great progress in multiple tumor species, in the field of gastric cancer, many therapies based on PD-1/PD-L1 inhibitors have been fruitless, and they have failed to win the "crown" of first-line population-wide standard treatment for gastric cancer.
The results of the CheckMate-649 study were earth-shattering, dispelling questions about whether immunotherapy was clinically valuable in the first-line treatment of advanced or metastatic gastric cancer.
The dual benefits of total survival (OS) and progression-free survival (PFS) make navulisizumab combined chemotherapy the first-line immunotherapy for advanced or metastatic gastric cancer in China, bringing a new dawn to patients with advanced gastric cancer in China.
Recently, the Department of Oncology of Medical Pulse has invited Professor Li Jin, a leader in a number of cutting-edge research in the field of oncology in China and director of the Department of Oncology of Dongfang Hospital of Tongji University, to deeply interpret the latest progress of advanced gastric cancer and the trend of clinical research and development of tumor drugs in China.
Expert Profiles
Professor Li Jin
Chief physician, professor, doctoral supervisor
Director of the Department of Oncology Medicine, Oriental Hospital Affiliated to Tongji University
President of the Asian Oncology Alliance (FACO).
Former Chairman of the Chinese Society of Clinical Oncology (CSCO).
Chair of the CSCO Expert Committee on Drug Safety
Chairman of Beijing Heathco Clinical Oncology Research Foundation
Vice Chairman of colorectal Cancer Professional Committee of Chinese Medical Doctor Association
Vice Chairman of the Abdominal Tumor Committee of the Chinese Society for Continuing Medical Education
The pace is difficult, and the first-line treatment dilemma of advanced gastric cancer is difficult to solve
Previously, chemotherapy was the first-line standard treatment for advanced gastric cancer, but its survival benefits were limited and the side effects were large, making it difficult to meet the clinical needs of patients. And because the biological characteristics of the stomach are easy to cause gastric cancer to occur abdominal metastasis, obstruction, patient malnutrition, further shorten the survival time of patients.
On the other hand, gastric cancer has strong heterogeneity, making the development of targeted and immunotherapy difficult. The anti-HER2-targeted drug trastuzumab is currently the only approved first-line targeted drug, but the proportion of HER2-positive gastric cancer patients in Chinese patients is only 12-132. In addition, since no major driver genes of gastric cancer have been found, it is difficult for existing targeted drugs to curb the occurrence and development of diseases from the source.
Professor Li Jin also believes that the superposition of the above factors has led to the efficacy and survival difference of patients with advanced gastric cancer may rank in the top few of all common cancers.
"Spear" and "shield" blessing to overcome the bottleneck of ten years of first-line treatment of stomach cancer
The CheckMate-649 study is the largest randomized, global phase III study and the only global phase III study to demonstrate a significant survival benefit and a dual OS and PFS benefit in patients with untreated advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (GC/GEJ/EAC) compared with chemotherapy.
Finding 3 showed that patients with advanced or metastatic GC/GEJ/EAC with first-line treatment with navulilizumab plus chemotherapy achieved OS and PFS benefits, either at PD-L1 plus positive score (CPS) ≥1 or ≥5, or in all randomized populations compared with chemotherapy alone.
【Click to view detailed global population data】
In terms of Chinese population, CheckMate-649 included a total of 208 patients Chinese mainland, and the results of the preset Chinese subgroup analysis4 showed that the overall benefit of Chinese group receiving navuliliumab combined chemotherapy was consistent with the global population, and clinically significant benefits in key data such as OS, PFS, ORR, and DoR were observed in the whole population, and there was a trend of greater benefit.
【Click to view detailed data of China subgroup】
With the results of CheckMate-649, navulisizumab was approved by the State Drug Administration (NMPA) in August 2021 with combination chemotherapy for first-line treatment of GC/GEJ/EAC without limiting PD-L1 expression.
In this regard, Professor Li Jin commented that the road to fight against cancer is a "offensive and defensive" battle, and the combination of chemotherapy and navuliyuzumab gives patients both "spear" and "shield" - from the perspective of mechanism, the application of immune checkpoint inhibitors such as navuliyuzumab gives patients a solid "shield", reduces the damage of tumor cells to the body, and through the cytotoxic killing effect of chemotherapy, the "spear" produces synergistic sensitization, delay effect and bystander effect, and exerts a positive anti-tumor effect. In addition, patients with first-line treatment have better physical condition and stronger immune response than previously approved patients with third-line treatment indications. At this time, the application of immune checkpoint inhibitors can give full play to their effectiveness and enable patients to achieve more survival benefits.
At the same time, Professor Li Jin also pointed out that another major significance of the approval of the navulijulizumab combined chemotherapy program lies in the wide range of beneficiary populations: considering the high heterogeneity of gastric cancer, the CheckMate-649 study included patients with upper gastrointestinal tumors covering a variety of disease sites including EAC and GEJC, including more than 2,000 patients in nearly 30 countries and regions in the East and West, and the benefits of Chinese patients were consistent with the world; although the study chose PD-L1 CPS≥5 Patients were the main population analyzed, but ultimately achieved population-wide OS efficacy. Previously, navulijulizumab combined chemotherapy has been listed by the NCCN and CSCO guidelines as the recommended therapy for the first-line treatment of advanced unresectable gastric cancer for patients with HER2-negative, CPS ≥5; with this protocol approved in the United States and China successively for first-line population-wide indications, Professor Li Jin also said that the regulatory approved indications have authoritative guiding significance, and it is expected to further promote the update of the guidelines in the future.
In summary, Professor Li Jin believes that the acquisition of advanced GC/EAC/GEJC first-line population-wide indications for navulijumab is of landmark significance, which has completely changed the clinical treatment status of gastric cancer and even the entire advanced upper gastrointestinal tumor, reversed the pattern of more benefiting than only HER2-positive patients with chemotherapy alone, and will benefit more patients.
Adjuvant therapy, the next "fortress" of the "war" of stomach cancer
With the remarkable efficacy of navulijumab combined with chemotherapy in the first-line treatment of advanced gastric cancer, its application in postoperative adjuvant therapy has also aroused the thinking of researchers. Professor Li Jin said that the postoperative adjuvant treatment of upper gastrointestinal cancers such as gastric cancer and esophageal cancer is mainly based on chemotherapy, and the toxic side effects are more obvious, compared with the value of immune checkpoint inhibitors, which is that the toxic side effects are mild and controllable. In addition, the physical condition of patients receiving adjuvant therapy is better than that of patients with advanced stages, and the efficacy of immunotherapy can be more fully utilized. It is expected that PD-1 inhibitors will be able to play a big role in the postoperative adjuvant treatment of upper gastrointestinal cancer in the future.
In the field of resectable adjuvant therapy for upper gastrointestinal tumors, navuliyumab has now received the first indication for immunotherapy – in May this year, the FDA approved it as the world's first immunotherapy for adjuvant therapy for esophageal cancer. The approval was based on a phase III CheckMate -577 study showing that in patients with esophageal cancer (EC) and GEJC who had surgery after neoadjuvant chemoradiotherapy (CRT) but did not achieve complete pathological remission, navulilizumab doubled patient disease-free survival (22.4 months vs 11.0 months, P<0.001) and reduced the risk of death or disease recurrence by 31%.
Taking the interests of patients as the guideline, it guides the future exploration of oncology medicine
In September 2020, the CheckMate -649 study appeared at the ESMO conference, with significant efficacy, answered the controversy of immunocommune combination chemotherapy for the first-line treatment of advanced gastric cancer, and obtained FDA approval on April 16, 2021 after only half a year, and obtained first-line population-wide indications for gastric cancer; after a gap of 4 and a half months, it obtained NMPA approval.
At the end of the interview, Professor Li Jin said that the rapid approval of the new indications for navulijuzumab not only shows that the efficiency of China's review and approval of innovative drugs and indications has been greatly improved, but also highlights the concept of taking the interests of patients as the center, accelerating the meeting of the urgent clinical needs of patients, and the humanistic care for patients; this is consistent with the starting point of the "Guidelines for Clinical Value-oriented Clinical Research and Development of Antineoplastic Drugs (Draft)" promulgated by the National Drug Evaluation Center (CDE) in July. In the future, these reform measures to encourage innovation will greatly promote the development of innovative oncology drugs and their clinical research in China, and open a new golden age for the diagnosis and treatment of digestive tract and other high-incidence cancers.
Resources
1、Allemani, Claudia et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet (London, England) vol. 391,10125 (2018): 1023-1075.
2. Chinese Expert Consensus on Molecularly Targeted Therapy for HER2-Positive Advanced Gastric Cancer (2016 Edition) 3, Janjigian, Yelena Y et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet (London, England) vol. 398,10294 (2021): 27-40.
4、Lin Shen et al. First-line nivolumab plus chemotherapy versus chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis. AACR 2021, Presentation number CT184.
5、Kelly, Ronan J et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. The New England journal of medicine vol. 384,13 (2021): 1191-1203.