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▎The editor of WuXi AppTec's content team.
Gastric cancer is the fifth most common cancer in the world, and China has one of the highest incidences of gastric cancer in the world.
The population of China accounts for 20% of the world’s population, but the incidence and deaths of gastric cancer account for 44% of the world’s total.
And 50%, 80% of Chinese gastric cancer patients are already at an advanced stage when they are diagnosed.
A week ago, Liao Qizhi, known as the golden supporting role of the Hong Kong movie, died of gastric cancer, which once again reminded people of the challenges in treating advanced gastric cancer.
So, what kind of strategy should we adopt to treat advanced gastric cancer? A review published in Nature Reviews Clinical Oncology a few days ago pointed out that according to the molecular biological characteristics of different gastric cancer patients, they are divided into different subtypes, and then for the different subtypes of patients, develop or use Targeted targeted therapy is becoming a new model of gastric cancer treatment.
This review provides evidence to support the optimization of the treatment of patients with gastric cancer based on biomarkers, and outlines a blueprint for the precise treatment of patients with advanced gastric cancer in the future.
Biomarkers that have been approved to predict the efficacy of targeted therapy for gastric cancer.
For patients with unresectable or metastatic gastric cancer and gastroesophageal junction (GEJ) cancer, chemotherapy is still the standard treatment option for most patients.
However, the analysis of the molecular characteristics of gastric cancer has produced three biomarkers that can predict the efficacy of targeted therapy.
They are HER2 expression level, high microsatellite instability (MSI-H) or high tumor mutational burden (TMB).
And the expression level of PD-L1.
HER2 is overexpressed in 15%-25% of gastric/GEJ cancer patients.
This biomarker has been used to screen for the first-line combination of trastuzumab, a monoclonal antibody targeting HER2, and chemotherapy.
Treated patients.It has also been used to screen patients with gastric cancer treated with the antibody-conjugated drug Enhertu jointly developed by AstraZeneca and Daiichi Sankyo.
MSI-H and high TMB have been approved by the FDA for screening patients who are suitable for second-line treatment with the PD-1 inhibitor Keytruda.
PD-L1 expression has also become the standard for receiving Keytruda's third-line treatment.
Image source: 123RF is a biomarker for targeted therapy under development.
In addition to the above-mentioned biomarkers that have been approved by the FDA for screening gastric cancer patients, there are also many other biomarkers that have become targets for targeted therapy.
Used in clinical trials to screen patients with gastric cancer.
Some of these targeted therapies have obtained positive results in clinical trials and are expected to further improve the pattern of precision treatment for patients with gastric cancer.
Fibroblast growth factor receptor 2 (FGFR2) FGFR2 gene amplification occurs in approximately 5% of gastric cancer/GEJ cancer patients and may be associated with a poor prognosis.
The monoclonal antibody therapy for FGFR2, bemarituzumab, has obtained positive results in phase 2 clinical trials.
When combined with chemotherapy, the first-line treatment of FGFR2b-positive and HER2-negative patients can improve the overall survival, progression-free survival and objective remission rate of patients.
Amgen recently acquired Five Prime, which developed this therapy, for nearly US$2 billion.
In China, Zai Lab has its development rights in Greater China.
▲The mechanism of action of Bemarituzumab (picture source: Five Prime company official website) In addition to Bemarituzumab, futibatinib, a highly selective irreversible FGFR1-4 inhibitor, is also currently used in phase 2 clinical trials to treat patients with solid tumors carrying FGFR gene mutations.
This includes patients with gastric cancer carrying FGFR2 amplification. Claudin 18.
2 Claudin 18.
2 (CLDN 18.
2) is a component of the tight junctions between cells.
In healthy tissues, it is only expressed on the gastric mucosa, but it is widely expressed in a variety of cancers, including gastric cancer/GEJ cancer.
CLDN18-ARHGAP26/6 gene fusion is found in 15% of gastric cancer/GEJ cancer patients.
They are usually associated with poor prognosis and resistance to chemotherapy.
There are currently a variety of targeted therapies targeting Claudin 18.
2 in clinical development.
Among them, the antibody therapy zolbetuximab combined with first-line chemotherapy in phase 2 clinical trials can improve progression-free survival and overall survival (OS) in Claudin 18.
2 positive patients.
And the analysis of patient subgroups showed that more than 70% of patients with Claudin 18.
2 expressed in tumors had higher OS benefits.
Currently, this investigational therapy is being tested in two phase 3 clinical trials, combined with chemotherapy in the first-line treatment of patients with Claudin 18.
2 high expression.
These patients account for 30% of all gastric cancer/GEJ cancer patients.
Image source: 123RF vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) preclinical gastric cancer models show that these tumors can secrete cytokines that promote angiogenesis, so anti-angiogenesis therapy has also become a research direction in the treatment of gastric cancer.
In this regard, Eli Lilly’s anti-VEGFR2 antibody ramucirumab combined with paclitaxel, compared with paclitaxel alone, significantly improved the patient’s OS.
As a second-line monotherapy, it also showed better efficacy than placebo.
In addition, the specific VEGFR2 inhibitor apatinib improved the OS of patients compared with placebo in a phase 3 clinical trial in the treatment of gastric cancer/GEJ cancer patients who had received at least two chemotherapies.
In addition to these targets, currently targeted therapies targeting EGFR, MET and PARP are also being used in clinical trials to treat patients with gastric cancer.
The success of using biomarkers to segment patients in clinical trials With the development of high-throughput sequencing technology and the development of multiple targeted therapies, clinical trials can now perform sequencing-based molecular biology on patient-carried tumors Analyze, determine the existence of multiple biomarkers at one time, and subdivide patients based on this information, and match specific patients with the most suitable targeted therapy.
Image source: In the umbrella trial called VIKTORY conducted by 123RF in South Korea, patients with metastatic gastric cancer were based on 8 different biomarkers (including RAS mutations, TP53 mutations, PIK3CA mutations or amplifications, and MET expansions).
The analysis can be assigned to 10 phase 2 clinical trials testing different targeted therapies.
The test results show that compared with patients receiving traditional second-line therapy, patients receiving targeted therapy based on biomarker selection have prolonged PFS and OS, demonstrating the feasibility and effectiveness of this biomarker-guided treatment strategy .
In Japan, researchers have also carried out screening of cancer patients based on large-scale gene sequencing, so as to match patients with rare gene mutations with corresponding targeted therapies.
The study found that the use of circulating tumor DNA sequencing to subdivide patients and guide clinical trial enrollment shortened patient screening time, but did not reduce the quality of patient segmentation and the effectiveness of targeted therapies.
These results all show that incorporating the sequencing of tumor tissue or circulating tumor DNA into routine patient treatment procedures can help discover gene variants that can be targeted, so that precise drugs can be selected for treatment.
The author of the review of the future of precision treatment of gastric cancer pointed out that the success of clinical research to segment patients through molecular biological characteristics means that the era of routine comprehensive molecular biological characterization of gastric cancer/GEJ cancer patients is coming.
▲ Schematic diagram of subdividing patients based on molecular biomarkers and selecting the corresponding precision therapy (picture source: reference [1]) Before the first-line therapy, specific molecular tests should be carried out (for example, HER2 and PD-L1 expression) Level of immunohistochemical testing and PCR testing of MSI status) to determine whether the patient can benefit from HER2 targeted therapy or immune checkpoint inhibitor therapy.
In addition, sequencing-based analysis of tumor tissues will be more conducive to recruiting and registering patients to participate in clinical trials of precision therapy.
Sequencing methods based on circulating tumor DNA may not only take a shorter time, and are more conducive to early detection of targets that guide the selection of first-line treatment, but also can be used to monitor the evolution of tumors and the emergence of drug resistance.
Although only three biomarkers are routinely used to screen gastric cancer patients for specific targeted therapies, a deeper understanding of gastric cancer tumor biology has provided information on the relationship between biomarkers and targeted therapy efficacy and drug resistance.
More insights.
This knowledge will further promote the use of precision therapy in patients with gastric cancer in the near future.
Reference materials: [1] Nakamura et al.
, (2021).
Biomarker- targeted therapies for advanced- stage gastric and gastro- oesophageal junction cancers: an emerging paradigm.
Nature Reviews Clinical Oncology, https://doi.
org/10.
1038/ s41571-021-00492-2 Note: This article aims to introduce the progress of medical and health research, and is not a treatment plan recommendation.
If you need guidance on treatment plans, please go to a regular hospital for treatment.
Gastric cancer is the fifth most common cancer in the world, and China has one of the highest incidences of gastric cancer in the world.
The population of China accounts for 20% of the world’s population, but the incidence and deaths of gastric cancer account for 44% of the world’s total.
And 50%, 80% of Chinese gastric cancer patients are already at an advanced stage when they are diagnosed.
A week ago, Liao Qizhi, known as the golden supporting role of the Hong Kong movie, died of gastric cancer, which once again reminded people of the challenges in treating advanced gastric cancer.
So, what kind of strategy should we adopt to treat advanced gastric cancer? A review published in Nature Reviews Clinical Oncology a few days ago pointed out that according to the molecular biological characteristics of different gastric cancer patients, they are divided into different subtypes, and then for the different subtypes of patients, develop or use Targeted targeted therapy is becoming a new model of gastric cancer treatment.
This review provides evidence to support the optimization of the treatment of patients with gastric cancer based on biomarkers, and outlines a blueprint for the precise treatment of patients with advanced gastric cancer in the future.
Biomarkers that have been approved to predict the efficacy of targeted therapy for gastric cancer.
For patients with unresectable or metastatic gastric cancer and gastroesophageal junction (GEJ) cancer, chemotherapy is still the standard treatment option for most patients.
However, the analysis of the molecular characteristics of gastric cancer has produced three biomarkers that can predict the efficacy of targeted therapy.
They are HER2 expression level, high microsatellite instability (MSI-H) or high tumor mutational burden (TMB).
And the expression level of PD-L1.
HER2 is overexpressed in 15%-25% of gastric/GEJ cancer patients.
This biomarker has been used to screen for the first-line combination of trastuzumab, a monoclonal antibody targeting HER2, and chemotherapy.
Treated patients.It has also been used to screen patients with gastric cancer treated with the antibody-conjugated drug Enhertu jointly developed by AstraZeneca and Daiichi Sankyo.
MSI-H and high TMB have been approved by the FDA for screening patients who are suitable for second-line treatment with the PD-1 inhibitor Keytruda.
PD-L1 expression has also become the standard for receiving Keytruda's third-line treatment.
Image source: 123RF is a biomarker for targeted therapy under development.
In addition to the above-mentioned biomarkers that have been approved by the FDA for screening gastric cancer patients, there are also many other biomarkers that have become targets for targeted therapy.
Used in clinical trials to screen patients with gastric cancer.
Some of these targeted therapies have obtained positive results in clinical trials and are expected to further improve the pattern of precision treatment for patients with gastric cancer.
Fibroblast growth factor receptor 2 (FGFR2) FGFR2 gene amplification occurs in approximately 5% of gastric cancer/GEJ cancer patients and may be associated with a poor prognosis.
The monoclonal antibody therapy for FGFR2, bemarituzumab, has obtained positive results in phase 2 clinical trials.
When combined with chemotherapy, the first-line treatment of FGFR2b-positive and HER2-negative patients can improve the overall survival, progression-free survival and objective remission rate of patients.
Amgen recently acquired Five Prime, which developed this therapy, for nearly US$2 billion.
In China, Zai Lab has its development rights in Greater China.
▲The mechanism of action of Bemarituzumab (picture source: Five Prime company official website) In addition to Bemarituzumab, futibatinib, a highly selective irreversible FGFR1-4 inhibitor, is also currently used in phase 2 clinical trials to treat patients with solid tumors carrying FGFR gene mutations.
This includes patients with gastric cancer carrying FGFR2 amplification. Claudin 18.
2 Claudin 18.
2 (CLDN 18.
2) is a component of the tight junctions between cells.
In healthy tissues, it is only expressed on the gastric mucosa, but it is widely expressed in a variety of cancers, including gastric cancer/GEJ cancer.
CLDN18-ARHGAP26/6 gene fusion is found in 15% of gastric cancer/GEJ cancer patients.
They are usually associated with poor prognosis and resistance to chemotherapy.
There are currently a variety of targeted therapies targeting Claudin 18.
2 in clinical development.
Among them, the antibody therapy zolbetuximab combined with first-line chemotherapy in phase 2 clinical trials can improve progression-free survival and overall survival (OS) in Claudin 18.
2 positive patients.
And the analysis of patient subgroups showed that more than 70% of patients with Claudin 18.
2 expressed in tumors had higher OS benefits.
Currently, this investigational therapy is being tested in two phase 3 clinical trials, combined with chemotherapy in the first-line treatment of patients with Claudin 18.
2 high expression.
These patients account for 30% of all gastric cancer/GEJ cancer patients.
Image source: 123RF vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) preclinical gastric cancer models show that these tumors can secrete cytokines that promote angiogenesis, so anti-angiogenesis therapy has also become a research direction in the treatment of gastric cancer.
In this regard, Eli Lilly’s anti-VEGFR2 antibody ramucirumab combined with paclitaxel, compared with paclitaxel alone, significantly improved the patient’s OS.
As a second-line monotherapy, it also showed better efficacy than placebo.
In addition, the specific VEGFR2 inhibitor apatinib improved the OS of patients compared with placebo in a phase 3 clinical trial in the treatment of gastric cancer/GEJ cancer patients who had received at least two chemotherapies.
In addition to these targets, currently targeted therapies targeting EGFR, MET and PARP are also being used in clinical trials to treat patients with gastric cancer.
The success of using biomarkers to segment patients in clinical trials With the development of high-throughput sequencing technology and the development of multiple targeted therapies, clinical trials can now perform sequencing-based molecular biology on patient-carried tumors Analyze, determine the existence of multiple biomarkers at one time, and subdivide patients based on this information, and match specific patients with the most suitable targeted therapy.
Image source: In the umbrella trial called VIKTORY conducted by 123RF in South Korea, patients with metastatic gastric cancer were based on 8 different biomarkers (including RAS mutations, TP53 mutations, PIK3CA mutations or amplifications, and MET expansions).
The analysis can be assigned to 10 phase 2 clinical trials testing different targeted therapies.
The test results show that compared with patients receiving traditional second-line therapy, patients receiving targeted therapy based on biomarker selection have prolonged PFS and OS, demonstrating the feasibility and effectiveness of this biomarker-guided treatment strategy .
In Japan, researchers have also carried out screening of cancer patients based on large-scale gene sequencing, so as to match patients with rare gene mutations with corresponding targeted therapies.
The study found that the use of circulating tumor DNA sequencing to subdivide patients and guide clinical trial enrollment shortened patient screening time, but did not reduce the quality of patient segmentation and the effectiveness of targeted therapies.
These results all show that incorporating the sequencing of tumor tissue or circulating tumor DNA into routine patient treatment procedures can help discover gene variants that can be targeted, so that precise drugs can be selected for treatment.
The author of the review of the future of precision treatment of gastric cancer pointed out that the success of clinical research to segment patients through molecular biological characteristics means that the era of routine comprehensive molecular biological characterization of gastric cancer/GEJ cancer patients is coming.
▲ Schematic diagram of subdividing patients based on molecular biomarkers and selecting the corresponding precision therapy (picture source: reference [1]) Before the first-line therapy, specific molecular tests should be carried out (for example, HER2 and PD-L1 expression) Level of immunohistochemical testing and PCR testing of MSI status) to determine whether the patient can benefit from HER2 targeted therapy or immune checkpoint inhibitor therapy.
In addition, sequencing-based analysis of tumor tissues will be more conducive to recruiting and registering patients to participate in clinical trials of precision therapy.
Sequencing methods based on circulating tumor DNA may not only take a shorter time, and are more conducive to early detection of targets that guide the selection of first-line treatment, but also can be used to monitor the evolution of tumors and the emergence of drug resistance.
Although only three biomarkers are routinely used to screen gastric cancer patients for specific targeted therapies, a deeper understanding of gastric cancer tumor biology has provided information on the relationship between biomarkers and targeted therapy efficacy and drug resistance.
More insights.
This knowledge will further promote the use of precision therapy in patients with gastric cancer in the near future.
Reference materials: [1] Nakamura et al.
, (2021).
Biomarker- targeted therapies for advanced- stage gastric and gastro- oesophageal junction cancers: an emerging paradigm.
Nature Reviews Clinical Oncology, https://doi.
org/10.
1038/ s41571-021-00492-2 Note: This article aims to introduce the progress of medical and health research, and is not a treatment plan recommendation.
If you need guidance on treatment plans, please go to a regular hospital for treatment.
