Editor's note: The 2022 Chinese Society of Clinical Oncology (CSCO) Guidelines Conference will be held on April 23-24. In accordance with the requirements for epidemic prevention and control, this meeting was held online. Experts and scholars from various oncology fields across the country gathered together to exchange academic research results, discuss future development directions, and witness the updates of multiple guidelines. At this meeting, Professor Wang Fenghua from Sun Yat-sen University Cancer Center gave a wonderful interpretation of the 2022 version of the CSCO gastric cancer guideline update for the diagnosis and treatment of advanced metastatic gastric cancer. The general principles of medical treatment of advanced metastatic gastric cancer in the
2022 version of the guideline emphasize that for patients with no chance of radical surgical cure or metastatic gastric cancer, it is currently recognized that comprehensive treatment based on systemic anti-tumor drugs should be adopted. Anti-tumor drugs mainly include: chemical drugs, molecular targeted drugs, and immune checkpoint inhibitors. In recent years, the field of gastric cancer diagnosis and treatment has developed rapidly. The rapid development of immunotherapy, , and targeted therapy has injected new power into the field of gastric cancer treatment. In particular, the emergence of immunotherapy drugs has made breakthrough progress in the treatment of advanced gastric cancer. The immune checkpoint inhibitor PD-1 monoclonal antibody has been approved as a third-line treatment for advanced gastric cancer. Although immunotherapy alone has poor efficacy, PD-1 monoclonal antibody combined with chemotherapy has It has become the new standard of first-line treatment for advanced metastatic gastric cancer. Professor Wang Fenghua elaborated on the drug treatment options for advanced metastatic gastric cancer at the conference.
Immunotherapy
Update 1: The first-line treatment recommendation is to add XELOX combined with sintilimab (Class 1A evidence and Level I recommendation)
Source of evidence:
National multi-center, double-blind , randomized controlled trial ORIENT-16 phase III clinical results It shows that XELOX combined with sintilimab achieved clinical benefit in terms of OS, PFS and ORR in all randomized populations and the CPS ≥5 population. As the evidence of immunotherapy continues to be refreshed, immunotherapy combined with chemotherapy has established a first-line treatment status and a new standard.
Update 2: First-line recommendations for immune combination chemotherapy: PD-L1 CPS scores are different, and the recommendation levels are different (CPS ≥ 5 people, class IA evidence/level I recommendation; the whole population, class IB evidence/level II recommendation)
Source of evidence
① Reference from NCCN guidelines
② The subgroup analysis results of a series of phase III studies found that there are differences between different ethnic groups: Asians, especially Chinese people, benefit more from chemotherapy combined with immunotherapy; differences between immunotherapy and different chemotherapy regimens: Recommended A two-drug combination regimen of fluorouracil drugs combined with oxaliplatin; differences in efficacy depending on PDL1 expression: increased PD-L1 expression means greater clinical benefit, whereas low PD-L1 expression means small or unclear clinical benefit.
③ Three studies (CM649, KN062 and KN590) were included. KMSubtraction was used to reorganize the undisclosed subgroup data in these studies and found that in patients with low PD-L1 expression, immune combination chemotherapy failed to provide better survival benefits. Although the
④Orient-16 study and Checkmate-649 study achieved a statistically significant survival benefit in the entire population, neither published a survival benefit for patients with PD-L1 CPS 5 points. Two meta analyzes showed that for PD-L1 expression The use of immunotherapy in patients with negative or low-expression advanced gastric cancer does not improve the survival time of the patients.
In summary, combined with my country's clinical practice, it is recommended that PD-L1 CPS5 or detection cannot be performed in a timely manner if the patient has a large tumor burden, is in good physical condition, needs to reduce the tumor burden as soon as possible to relieve symptoms, or has limited follow-up second-line treatment options and the patient does not have immunity. When checkpoint inhibitors are contraindicated, XELOX/FOLFOX combined with nivolumab or XELOX combined with sintilimab may also be considered.
Update 3: New first-line immunotherapy recommendations for Her2-positive (IHC 3+ or 2+ and FISH+) gastric cancer patients: pembrolizumab + trastuzumab + XELOX/PF regimen (Class IB evidence and III Level recommendation)
Research evidence:
Based on the interim analysis results of the KEYNOTE-811 study, in May 2021, the FDA accelerated approval of pembrolizumab combined with trastuzumab and fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of unresectable or metastatic patients. Patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma. The shortcoming of the study is that the immune combination regimen was only approved in the United States based on the FDA's Real-time Oncology Review (RTOR) pilot.Although consistent with expectations, the ORR was 74%, which was lower than the 91% ORR previously reported in the ISR trial; the DoR (10.6 months) was comparable to the previously reported data (9.4 months) in the ISR trial. We also need data on the primary endpoints of PFS and OS.
Update 4: New first-line immunotherapy recommendations for dMMR population
Level II recommendation: pembrolizumab alone (Category 2B);
Level III recommendation: nivolumab combined with ipilimumab (Category 2B); Na Vulumab combined with FOLFOX/ microsatellite highly unstable (MSI-H) gastric cancer accounts for about 6% of advanced gastric cancer. Its molecular classification characteristics, biological behavior, drug sensitivity, tumor microenvironment, treatment mode and prognosis are significantly different from those of pMMR/MSS patients. , the main characteristics are good prognosis, insensitivity to chemotherapy and obvious benefit from immunotherapy, so this update will classify it separately and manage it throughout the process.
② In October 2016, the FDA approved pembrolizumab for non-colorectal, MSI-H/dMMR tumors based on 5 clinical studies (KN-012, 028, 016, 158, and 164).
③ A summary analysis of KN-059 third-line/061 second-line/062 first-line studies shows that patients with MSI-H gastric cancer can achieve good results regardless of the number of lines of treatment.
④ The MSI-H subgroup analysis results of the prospective phase III RCT Checkmate 649 first-line treatment study also show that nivolumab combined with Ipilimumab and chemotherapy combined with Nivolumab are better than chemotherapy alone, and can be tried with caution in clinical practice.
Update 5: New dMMR population, second-line immunotherapy recommended
Source of evidence:
① Based on the results of the multi-center, single-arm KN035-CN-006 phase II study in China, envolimab was approved by NMPA on 2021.11.25 for dMMR/MSIH Indications.
②Based on the results of a Chinese multi-center single-arm phase II study, slulimumab was approved by NMPA for dMMR/MSIH indications on March 24, 2022).
Update 6: Recommendations for third-line and late-line immunotherapy for gastric cancer
①Add a note "If you have not been treated with PD1/PDL1 monoclonal antibody before", nivolumab monotherapy can be considered as a third-line treatment, but attention should be paid to assessing the patient's physical condition , and assessment of potential hyperprogression risks and adverse reactions.
② Delete pembrolizumab recommendation from the table: Merck announced the voluntary withdrawal of an accelerated approval of Keytruda indication in the United States for the treatment of PD-L1-positive locally advanced or metastatic disease that has progressed after second-line and subsequent lines of therapy. Adenocarcinoma of the stomach and gastroesophageal junction.
③Annotation content added CLDN18.2 CAR-T third-line immunotherapy data.
Update 7: Third-line immunotherapy adds CLDN18.2 in annotated form CAR-T cell immunotherapy
Source of evidence: Based on CT041 research results
Claudin18.2 is a pan-cancer target and is widely expressed in a variety of epithelial cell tumors. , especially moderately or highly expressed in approximately 40-80% of gastric cancer patients, making it an ideal target for the development of immunotherapy for solid tumors. In a phase I study initiated by an investigator, 28 patients with Claudin18.2-positive gastric cancer received CART cell therapy , and the ORR reached 57.1%. Among 18 gastric cancer patients who failed previous second-line treatment, the ORR was as high as 61.1%, and the median PFS and OS were 5.4 months and 9.5 months respectively, which was significantly improved compared with existing second-line treatments. Currently, there are monoclonal antibodies, bispecific antibodies, ADCs and CAR-T drugs deployed for Claudin18.2 advanced gastric cancer, and patients are encouraged to participate in clinical studies.
Anti-angiogenic therapy
Update 8: Ramucirumab combined with paclitaxel is added to the second-line treatment of gastric cancer (Class 1A evidence and Level I recommendation)
Source of evidence:
① Based on the results of the REGARD study and the RAINBOW study, ramucirumab in 2014 Approved by FDA as second-line treatment for advanced gastric cancer.
②Based on the results of the RAINBOW-Asia trial, ramucizumab was approved by NPMA as a second-line treatment for advanced gastric cancer in March 2022. The study found that ramucizumab + paclitaxel is a second-line treatment for patients with advanced gastric cancer who are mainly Chinese people. There is a significant PFS benefit, and the OS benefit is consistent with that of the global population.
Anti-Her2 treatment increases the selection of ADC drugs
Update 9: Recommendation for third-line and later-line treatment of Her2-positive gastric cancer Vedicitomab (Class 2A evidence and level II recommendation in the table)
Evidence source:
Based on RC48-C008 As a result of the study, in June 2021, the NMPA approved it for the treatment of HER2-positive (Her2-positive IHC 3+ or 2+) locally advanced or metastatic gastric cancer that has received at least 2 types of systemic chemotherapy.
Update 10: T-DXd is recommended for third-line and later-line treatment of Her2-positive gastric cancer (explained in the comments)
Research evidence:
Prospective randomized controlled DESTINY-Gastric01 study results showed that the primary endpoint ORR T-DXd was significantly better than the clinician's choice Chemotherapy. Based on this data, in January 2021, the FDA approved its use for patients with locally advanced or metastatic HER2-positive gastric cancer who have previously received trastuzumab. T-DXd is not yet available in China.
Summary
Based on the 2021 Gastric Cancer Guidelines, the 2022 Gastric Cancer Guidelines incorporate the latest clinical research progress at home and abroad. Among them, my country's independent research and development and research data based on the Chinese population have been successful and approved for indications. The treatment progress of molecular targeted drugs is remarkable. Anti-Her-2 ADC drugs have redefined the Her-2-positive population and opened up a new treatment landscape. The first-line treatment of advanced gastric cancer has fully entered the era of immunotherapy combination therapy. The treatment is constantly being optimized, and it also faces certain thinking and challenges: such as the selection of different PD-1 monoclonal antibodies and different chemotherapy regimens, the rational layout of immunotherapy under full management, and immunotherapy combination. Management of adverse reactions related to chemotherapy, etc. The efficacy of immunotherapy needs to be further improved and benefit more effective people. We look forward to more exploration in clinical research, including precision immunotherapy and new immunotherapy strategies after PD-1 monoclonal antibodies.
Expert profile
Wang Fenghua
Chief physician of the Department of Oncology, Sun Yat-sen University Cancer Center, attending professor, Ph.D.
Member of the Standing Committee and Secretary of the Gastric Cancer Professional Committee of the Chinese Clinical Oncology Association;
Member of the Pancreatic Cancer Professional Committee of the Chinese Clinical Oncology Association
Oncology of the Chinese Anti-Cancer Association Member of the Standing Committee of the Targeted Therapy Professional Committee and Chairman of the Youth Committee
Vice Chairman of the Cancer Support Professional Committee of the Chinese Anti-Cancer Association;
Member of the Professional Committee of Oncology Clinical Chemotherapy of the Chinese Anti-Cancer Association;
Member of the Internal Medicine Group of the Gastric Cancer Professional Committee of the Chinese Anti-Cancer Association;
Chairman-elect of the Guangdong Provincial Anti-Cancer Association’s Professional Committee on Targeted Tumor Therapy
Deputy Chairman of the Guangdong Provincial Anti-Cancer Association’s Professional Committee on Pancreatic Cancer
