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Gastric cancer is still one of the most important causes of cancer deaths in the world.
The biological differences between Eastern and Western countries have increased the complexity of choosing standard treatments based on international clinical trials.
Systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy are among the most common in gastric adenocarcinoma.
All have a certain effect, and multidisciplinary treatment has a vital role in the treatment of gastric cancer.
Recently, the journal CA Cancer J Clin published a review summarizing the current status of gastric cancer treatment, immune and targeted therapy related content and the latest progress.
This article summarizes the current status and latest developments in the treatment of metastatic or unresectable gastric cancer.
Treatment status 01 First-line treatment Several cytotoxic drugs are effective in advanced gastric cancer, including fluorouracil, platinum, taxanes and irinotecan.
The choice of treatment plan depends on the patient's physical status, complications and drug toxicity.
Compared with a single drug, the combined treatment program has a higher effective rate and can improve patient survival.
Although there is no first-line standard treatment plan, fluorouracil and platinum-based dual drugs are generally the basic treatment plan for most patients.
Oxaliplatin is considered as effective as cisplatin and is currently the first choice for most basic treatment options.
In order to obtain a higher effective and longer PFS, a three-drug combination of fluorouracil + oxaliplatin + docetaxel can be considered for patients with better physical conditions and able to withstand higher toxicity.
For patients who are not suitable for intensive chemotherapy, fluorouracil, irinotecan, or taxanes can be considered.
For patients with HER2 overexpression or amplification, trastuzumab should be added to the first-line treatment.
For patients with PD-L1 CPS≥5, nivolumab can be considered as the first-line treatment.
02 Second-line and third-line treatment For the second-line treatment of patients with metastatic gastric cancer, cytotoxic chemotherapy may consider treatment options that have not been used in the first-line treatment.
A few years ago, studies showed that the addition of ramucirumab can enhance the anti-tumor activity of chemotherapy.
The phase III REGARD study showed that compared with placebo, ramucirumab can prolong the overall survival (OS) of patients with advanced gastric adenocarcinoma by 1.
4 months.
The phase III AINBOW study showed that the median OS of second-line paclitaxel + ramucirumab and paclitaxel + placebo were 9.
6 months and 7.
4 months, respectively.
In patients with advanced gastric cancer in good physical condition, after first-line fluorouracil + platinum therapy progresses, the preferred second-line treatment is paclitaxel + ramucirumab; in addition, chemotherapy alone or ramucirumab alone can also be considered.
Phase III studies have confirmed that tipiracil (5.
7 months) compared with placebo (3.
6 months) can significantly prolong the OS of patients with refractory gastric cancer.
It has been approved by the FDA for the third-line treatment of advanced gastric cancer.
Immunotherapy In the past 10 years, immune checkpoint inhibitors have become a new type of treatment for multiple tumor types, including PD-1 monoclonal antibodies, PD-L1 monoclonal antibodies, and CTLA-4 inhibitors.
01 MSI-H/dMMR tumors and research progress In a study, the Cancer Genome Atlas (TCGA) project divided gastric cancer into 4 subtypes: highly microsatellite instability (MSI-H) tumors, EBV-positive tumors, and chromosomal unstable tumors And genomic stable tumors.
Studies have shown that among newly treated patients, MSI-H patients account for 22%.
A recent study showed that the incidence of MSI-H in stage IV patients is only 3%.
Among all tumor types, dMMR patients are more effective against PD-1 inhibitors.
The KEYNOTE-158 study showed that 11 patients with gastric cancer (24 cases in total) achieved remission, of which 4 cases had a complete remission, with a median progression-free stage (PFS) reaching 11 months.
Based on this, pembrolizumab was approved by the FDA for the treatment of unresectable or metastatic MSI-H or mismatch repair defect (dMMR) solid tumors that have progressed in previous treatments.
02 Other research progress Phase II KEYNOTE-059 study included patients with advanced gastric cancer after at least second-line treatment failure.
The objective response rate (ORR) of the total population was 11.
6%, and the median duration of response (DOR) was 8.
4 months.
The ORR of patients with PD-L1 CPS≥1 was 15.
5%, and the median DOR was 16.
3 months.
Based on this, pembrolizumab was approved by the FDA for the third-line treatment of patients with PD-L1 CPS≥1 gastric adenocarcinoma.
The KEYNOTE-062 study explored the efficacy and safety of pembrolizumab±chemotherapy versus chemotherapy for the first-line treatment of adenocarcinoma at the gastric or gastroesophageal junction with PD-L1 CPS≥1.
The results showed that pembrolizumab compared with chemotherapy can prolong the OS of patients, but there is no significant difference.
Pembrolizumab + chemotherapy also did not improve OS and PFS in patients with CPS ≥ 1 or 10.
The phase III ATTRACTION-2 study aims to evaluate the efficacy and safety of nivolumab versus placebo in the third and later lines of advanced gastric adenocarcinoma.
The results showed that the median OS of the nivolumab group and the placebo group were 5.
3 months and 4.
1 months, respectively.
This study was conducted in Asian populations and did not screen PD-L1 expressing populations.
Nivolumab has been approved in Japan for the treatment of chemotherapy-resistant gastric cancer.
The Phase III CheckMate649 study evaluated the efficacy and safety of nivolumumab + chemotherapy or nivolumumab + ipilimumab versus chemotherapy for the first-line treatment of metastatic HER2-gastric cancer.
Preliminary analysis showed that compared with chemotherapy (11.
1 months), nivolumab + chemotherapy (14.
4 months) can significantly improve the median OS of patients with PD-L1 CPS≥5.
The final analysis showed that nivolumab + chemotherapy (14.
4 months) can significantly improve the median OS of patients with PD-L1 CPS≥5.
The median PFS of the anti+chemotherapy group and the chemotherapy group were 7.
7 months and 6.
1 months, respectively.
Similarly, OS benefit was also observed in all randomized populations.
This is a clinical study with significance to change clinical practice, establishing a new first-line treatment standard for patients with PD-L1 CPS ≥ 5 HER2- gastric cancer.
03 Related exploration of immunotherapy biomarkers Tumor mutational burden (TMB) gastric cancer is a group of heterogeneous diseases that have different responses to immunotherapy.
Researchers are constantly exploring whether multiple biomarkers can predict the response or efficacy of immunotherapy.
Another biomarker being explored is TMB.
TMB quantifies the number of somatic mutations in the coding region of each genome.
Researchers speculate that a large number of mutated tumors can generate a large number of neoantigens, leading to T cell infiltration, which may potentially increase the response to immunotherapy.
Based on a retrospective analysis, in June 2020, the FDA approved pembrolizumab for the treatment of unresectable or metastatic TMB-H (≥10Mut/Megabase) solid tumors after initial treatment has progressed.
This study analyzed the TMB-H patients in the KEYNOTE-158 study.
Among 790 evaluable patients, the ORR of TMB-H (13%) patients reached 29%, and the median DOR was not reached.
In the exploratory analysis of the KEYNOTE-061 study, TMB was positively correlated with the clinical outcome of pembrolizumab in the treatment of gastric cancer.
Studies have shown that compared with paclitaxel, pembrolizumab can bring OS benefits to patients with TMB≥10, even if patients with MSI-H are excluded, there are still OS benefits.
EBVEBV is a human herpes virus, which may be related to a variety of malignant tumors including gastric adenocarcinoma.
EBV-positive gastric cancer is a gastric cancer subtype identified by TCGA, which is related to CD8+ T cell infiltration, PD-L1, PD-L2 expression.
Therefore, this subtype may be more sensitive to PD-1 inhibitors.
Studies have shown that EBV-positive tumors have a strong response to immune checkpoint inhibitors, but further prospective studies are still needed.
HER2+ gastric cancer treatment progress.
HER2 overexpression or amplification is seen in about 15%-20% of patients with advanced gastric/gastroesophageal junction adenocarcinoma.
Compared with diffuse or mixed gastric cancer, HER2+ is more common in intestinal gastric cancer.
Trastuzumab is a humanized monoclonal antibody targeting the HER2 receptor, which can inhibit downstream signal activation and ultimately induce antibody-dependent cytotoxicity.
The Phase III ToGA study established the first-line treatment standard for chemotherapy and trastuzumab for patients with HER2+ advanced gastric adenocarcinoma.
Compared with chemotherapy, trastuzumab + chemotherapy can improve the median OS of HER2+ patients.
In particular, it should be pointed out that in the post-mortem analysis, compared with chemotherapy, trastuzumab + chemotherapy can prolong the median OS of patients with HER2+ immunohistochemistry score of 3+ or 2+ by more than 4 months.
The bit OS was 16 months and 11.
8 months, respectively.
Subsequently, multiple clinical studies of multiple HER2 inhibitors for gastric cancer ended in failure.
New HER2 inhibitors bring new hope for HER2+ gastric cancer.
Studies have shown that ZW25 shows good anti-tumor activity and good tolerability in HER2+ tumors that have progressed in multi-line therapy.
Margetuximab also shows good anti-tumor activity in HER2+ tumors.
At present, the most potential is the antibody drug conjugate trastuzumab deruxtecan.
Phase II DESTINY-Gastric01 study showed that compared with chemotherapy, trastuzumab deruxtecan can improve the OS and remission rate of patients with HER2+ gastric/gastroesophageal junction adenocarcinoma.
The median OS of trastuzumab deruxtecan and chemotherapy were 12.
5 months and 8.
4 months, respectively , The remission rates of the two groups were 51% and 14%, respectively.
Immunotherapy has also successfully added anti-HER2 targeted therapy.
A phase II study showed that pembrolizumab+trastuzumab is safe in HER2+ metastatic gastric adenocarcinoma.
It is worth noting that the remission rate of the combined program reached 91%, and the median OS reached 27.
3 months.
The results suggest that immunotherapy combined with trastuzumab may have a synergistic anti-tumor effect.
The phase III KEYNOTE-811 study is currently underway To further verify its efficacy.
Progress in anti-angiogenic drug therapy ramucirumab is a monoclonal antibody that targets VEGFR-2.
Studies have confirmed that single agent or combined with paclitaxel can bring OS benefits in the second-line treatment of gastric cancer.
Both lenvatinib and regorafenib are multikinase inhibitors.
Studies have shown that the remission rate of lenvatinib + pembrolizumab in the first-line and second-line treatment of advanced gastric cancer is 69%.
Phase I studies have shown that regorafenib + nivolumab is safe in patients with gastric cancer and has good anti-tumor activity.
References: Joshi SS, Badgwell BD.
Current treatment and recent progress in gastric cancer.
CA Cancer J Clin.
2021 Feb 16.
doi: 10.
3322/caac.
21657.
Epub ahead of print.
PMID: 33592120.
The biological differences between Eastern and Western countries have increased the complexity of choosing standard treatments based on international clinical trials.
Systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy are among the most common in gastric adenocarcinoma.
All have a certain effect, and multidisciplinary treatment has a vital role in the treatment of gastric cancer.
Recently, the journal CA Cancer J Clin published a review summarizing the current status of gastric cancer treatment, immune and targeted therapy related content and the latest progress.
This article summarizes the current status and latest developments in the treatment of metastatic or unresectable gastric cancer.
Treatment status 01 First-line treatment Several cytotoxic drugs are effective in advanced gastric cancer, including fluorouracil, platinum, taxanes and irinotecan.
The choice of treatment plan depends on the patient's physical status, complications and drug toxicity.
Compared with a single drug, the combined treatment program has a higher effective rate and can improve patient survival.
Although there is no first-line standard treatment plan, fluorouracil and platinum-based dual drugs are generally the basic treatment plan for most patients.
Oxaliplatin is considered as effective as cisplatin and is currently the first choice for most basic treatment options.
In order to obtain a higher effective and longer PFS, a three-drug combination of fluorouracil + oxaliplatin + docetaxel can be considered for patients with better physical conditions and able to withstand higher toxicity.
For patients who are not suitable for intensive chemotherapy, fluorouracil, irinotecan, or taxanes can be considered.
For patients with HER2 overexpression or amplification, trastuzumab should be added to the first-line treatment.
For patients with PD-L1 CPS≥5, nivolumab can be considered as the first-line treatment.
02 Second-line and third-line treatment For the second-line treatment of patients with metastatic gastric cancer, cytotoxic chemotherapy may consider treatment options that have not been used in the first-line treatment.
A few years ago, studies showed that the addition of ramucirumab can enhance the anti-tumor activity of chemotherapy.
The phase III REGARD study showed that compared with placebo, ramucirumab can prolong the overall survival (OS) of patients with advanced gastric adenocarcinoma by 1.
4 months.
The phase III AINBOW study showed that the median OS of second-line paclitaxel + ramucirumab and paclitaxel + placebo were 9.
6 months and 7.
4 months, respectively.
In patients with advanced gastric cancer in good physical condition, after first-line fluorouracil + platinum therapy progresses, the preferred second-line treatment is paclitaxel + ramucirumab; in addition, chemotherapy alone or ramucirumab alone can also be considered.
Phase III studies have confirmed that tipiracil (5.
7 months) compared with placebo (3.
6 months) can significantly prolong the OS of patients with refractory gastric cancer.
It has been approved by the FDA for the third-line treatment of advanced gastric cancer.
Immunotherapy In the past 10 years, immune checkpoint inhibitors have become a new type of treatment for multiple tumor types, including PD-1 monoclonal antibodies, PD-L1 monoclonal antibodies, and CTLA-4 inhibitors.
01 MSI-H/dMMR tumors and research progress In a study, the Cancer Genome Atlas (TCGA) project divided gastric cancer into 4 subtypes: highly microsatellite instability (MSI-H) tumors, EBV-positive tumors, and chromosomal unstable tumors And genomic stable tumors.
Studies have shown that among newly treated patients, MSI-H patients account for 22%.
A recent study showed that the incidence of MSI-H in stage IV patients is only 3%.
Among all tumor types, dMMR patients are more effective against PD-1 inhibitors.
The KEYNOTE-158 study showed that 11 patients with gastric cancer (24 cases in total) achieved remission, of which 4 cases had a complete remission, with a median progression-free stage (PFS) reaching 11 months.
Based on this, pembrolizumab was approved by the FDA for the treatment of unresectable or metastatic MSI-H or mismatch repair defect (dMMR) solid tumors that have progressed in previous treatments.
02 Other research progress Phase II KEYNOTE-059 study included patients with advanced gastric cancer after at least second-line treatment failure.
The objective response rate (ORR) of the total population was 11.
6%, and the median duration of response (DOR) was 8.
4 months.
The ORR of patients with PD-L1 CPS≥1 was 15.
5%, and the median DOR was 16.
3 months.
Based on this, pembrolizumab was approved by the FDA for the third-line treatment of patients with PD-L1 CPS≥1 gastric adenocarcinoma.
The KEYNOTE-062 study explored the efficacy and safety of pembrolizumab±chemotherapy versus chemotherapy for the first-line treatment of adenocarcinoma at the gastric or gastroesophageal junction with PD-L1 CPS≥1.
The results showed that pembrolizumab compared with chemotherapy can prolong the OS of patients, but there is no significant difference.
Pembrolizumab + chemotherapy also did not improve OS and PFS in patients with CPS ≥ 1 or 10.
The phase III ATTRACTION-2 study aims to evaluate the efficacy and safety of nivolumab versus placebo in the third and later lines of advanced gastric adenocarcinoma.
The results showed that the median OS of the nivolumab group and the placebo group were 5.
3 months and 4.
1 months, respectively.
This study was conducted in Asian populations and did not screen PD-L1 expressing populations.
Nivolumab has been approved in Japan for the treatment of chemotherapy-resistant gastric cancer.
The Phase III CheckMate649 study evaluated the efficacy and safety of nivolumumab + chemotherapy or nivolumumab + ipilimumab versus chemotherapy for the first-line treatment of metastatic HER2-gastric cancer.
Preliminary analysis showed that compared with chemotherapy (11.
1 months), nivolumab + chemotherapy (14.
4 months) can significantly improve the median OS of patients with PD-L1 CPS≥5.
The final analysis showed that nivolumab + chemotherapy (14.
4 months) can significantly improve the median OS of patients with PD-L1 CPS≥5.
The median PFS of the anti+chemotherapy group and the chemotherapy group were 7.
7 months and 6.
1 months, respectively.
Similarly, OS benefit was also observed in all randomized populations.
This is a clinical study with significance to change clinical practice, establishing a new first-line treatment standard for patients with PD-L1 CPS ≥ 5 HER2- gastric cancer.
03 Related exploration of immunotherapy biomarkers Tumor mutational burden (TMB) gastric cancer is a group of heterogeneous diseases that have different responses to immunotherapy.
Researchers are constantly exploring whether multiple biomarkers can predict the response or efficacy of immunotherapy.
Another biomarker being explored is TMB.
TMB quantifies the number of somatic mutations in the coding region of each genome.
Researchers speculate that a large number of mutated tumors can generate a large number of neoantigens, leading to T cell infiltration, which may potentially increase the response to immunotherapy.
Based on a retrospective analysis, in June 2020, the FDA approved pembrolizumab for the treatment of unresectable or metastatic TMB-H (≥10Mut/Megabase) solid tumors after initial treatment has progressed.
This study analyzed the TMB-H patients in the KEYNOTE-158 study.
Among 790 evaluable patients, the ORR of TMB-H (13%) patients reached 29%, and the median DOR was not reached.
In the exploratory analysis of the KEYNOTE-061 study, TMB was positively correlated with the clinical outcome of pembrolizumab in the treatment of gastric cancer.
Studies have shown that compared with paclitaxel, pembrolizumab can bring OS benefits to patients with TMB≥10, even if patients with MSI-H are excluded, there are still OS benefits.
EBVEBV is a human herpes virus, which may be related to a variety of malignant tumors including gastric adenocarcinoma.
EBV-positive gastric cancer is a gastric cancer subtype identified by TCGA, which is related to CD8+ T cell infiltration, PD-L1, PD-L2 expression.
Therefore, this subtype may be more sensitive to PD-1 inhibitors.
Studies have shown that EBV-positive tumors have a strong response to immune checkpoint inhibitors, but further prospective studies are still needed.
HER2+ gastric cancer treatment progress.
HER2 overexpression or amplification is seen in about 15%-20% of patients with advanced gastric/gastroesophageal junction adenocarcinoma.
Compared with diffuse or mixed gastric cancer, HER2+ is more common in intestinal gastric cancer.
Trastuzumab is a humanized monoclonal antibody targeting the HER2 receptor, which can inhibit downstream signal activation and ultimately induce antibody-dependent cytotoxicity.
The Phase III ToGA study established the first-line treatment standard for chemotherapy and trastuzumab for patients with HER2+ advanced gastric adenocarcinoma.
Compared with chemotherapy, trastuzumab + chemotherapy can improve the median OS of HER2+ patients.
In particular, it should be pointed out that in the post-mortem analysis, compared with chemotherapy, trastuzumab + chemotherapy can prolong the median OS of patients with HER2+ immunohistochemistry score of 3+ or 2+ by more than 4 months.
The bit OS was 16 months and 11.
8 months, respectively.
Subsequently, multiple clinical studies of multiple HER2 inhibitors for gastric cancer ended in failure.
New HER2 inhibitors bring new hope for HER2+ gastric cancer.
Studies have shown that ZW25 shows good anti-tumor activity and good tolerability in HER2+ tumors that have progressed in multi-line therapy.
Margetuximab also shows good anti-tumor activity in HER2+ tumors.
At present, the most potential is the antibody drug conjugate trastuzumab deruxtecan.
Phase II DESTINY-Gastric01 study showed that compared with chemotherapy, trastuzumab deruxtecan can improve the OS and remission rate of patients with HER2+ gastric/gastroesophageal junction adenocarcinoma.
The median OS of trastuzumab deruxtecan and chemotherapy were 12.
5 months and 8.
4 months, respectively , The remission rates of the two groups were 51% and 14%, respectively.
Immunotherapy has also successfully added anti-HER2 targeted therapy.
A phase II study showed that pembrolizumab+trastuzumab is safe in HER2+ metastatic gastric adenocarcinoma.
It is worth noting that the remission rate of the combined program reached 91%, and the median OS reached 27.
3 months.
The results suggest that immunotherapy combined with trastuzumab may have a synergistic anti-tumor effect.
The phase III KEYNOTE-811 study is currently underway To further verify its efficacy.
Progress in anti-angiogenic drug therapy ramucirumab is a monoclonal antibody that targets VEGFR-2.
Studies have confirmed that single agent or combined with paclitaxel can bring OS benefits in the second-line treatment of gastric cancer.
Both lenvatinib and regorafenib are multikinase inhibitors.
Studies have shown that the remission rate of lenvatinib + pembrolizumab in the first-line and second-line treatment of advanced gastric cancer is 69%.
Phase I studies have shown that regorafenib + nivolumab is safe in patients with gastric cancer and has good anti-tumor activity.
References: Joshi SS, Badgwell BD.
Current treatment and recent progress in gastric cancer.
CA Cancer J Clin.
2021 Feb 16.
doi: 10.
3322/caac.
21657.
Epub ahead of print.
PMID: 33592120.
