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▎The editor of WuXi AppTec's content team.
Gastric cancer is the fourth leading cause of cancer-related deaths in the world and the third leading cause of cancer deaths in China
.
However, for the vast majority of HER2-negative (about 85%) patients with gastric cancer, there has been little progress in the first-line treatment of advanced disease in the past 10 years.
After standard first-line treatment (platinum and fluoropyrimidine combined chemotherapy), the median total patient The survival period is only about 11 months
.
Until April this year, the treatment of advanced gastric cancer finally ushered in the first first-line immunotherapy
.
The US FDA approved Opdivo (nivolumab), a blockbuster PD-1 inhibitor, in combination with chemotherapy for the first-line treatment of advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer and esophageal adenocarcinoma
.
Adenocarcinoma is the most common (>90%) histological type of gastric cancer and gastroesophageal junction cancer.
Esophageal adenocarcinoma accounts for 15% of global esophageal cancers
.
This approval is mainly based on evidence from the large randomized phase 3 clinical trial CheckMate-649
.
Recently, the results of this phase 3 trial were published in full in the main journal of the top medical journal "The Lancet"! Peer-reviewed detailed data once again show that the addition of immunotherapy on the basis of chemotherapy has refreshed the survival period of these patients
.
The "Lancet" concurrent review article also pointed out that CheckMate-649 is an important milestone in the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma
.
Screenshot source: The paper published by The Lancet reports the results of Opdivo combined chemotherapy and chemotherapy alone in the CheckMate-649 study
.
This phase 3 trial recruited previously untreated, unresectable, non-HER2-positive adult patients (≥18 years of age) with gastric, gastroesophageal junction, or esophageal adenocarcinoma in 29 countries around the world
.
A total of 1581 patients were randomized 1:1 to receive Opdivo combined chemotherapy (789 cases) or chemotherapy alone (792 cases)
.
The chemotherapy regimen used is the existing standard treatment, capecitabine + oxaliplatin, a cycle every 3 weeks; or leucovorin, 5 FU + oxaliplatin, a cycle every 2 weeks
.
The trial reached the primary endpoints of overall survival (OS) and progression-free survival (PFS) at the same time, and the data for different population segments are encouraging
.
Patients with high PD-L1 expression levels in tumor samples (comprehensive positive score [CPS] ≥ 5) benefit the most
.
Among these patients, the Opdivo combined chemotherapy group had a significant reduction in the risk of death by 29%, a median OS extension of 3.
3 months (14.
4 months vs 11.
1 months); a significant reduction in the risk of disease progression or death by 32% (median PFS 7.
7 months vs.
6.
0 months)
.
The 1-year overall survival rate (57% vs 46%) and 1-year progression-free survival rate (36% vs 22%) of the Opdivo combined chemotherapy group were higher than those of the chemotherapy alone group
.
Positive PD-L1 expression and CPS≥1 are also beneficial
.
In this part of patients, the Opdivo combined chemotherapy group had a significant reduction in the risk of death by 23% (median OS 14.
0 months vs 11.
3 months); a significant reduction in the risk of disease progression or death by 26% (median PFS 7.
5 months vs 6.
9 months)
.
The 1-year overall survival rate (56% vs 47%) and 1-year progression-free survival rate (34% vs 22%) of the Opdivo combined chemotherapy group were also higher
.
Even without considering the expression of PD-L1, in all enrolled patients, the advantages brought by Opdivo combined with chemotherapy can still be seen! The Opdivo combined chemotherapy group significantly reduced the risk of death by 20% (median OS 13.
8 months vs 11.
6 months); the risk of disease progression or death was significantly reduced by 23% (median PFS 7.
7 months vs 6.
9 months)
.
The 1-year overall survival rate (55% vs 48%) and 1-year progression-free survival rate (33% vs 23%) of the Opdivo combined chemotherapy group were higher
.
▲In CPS ≥ 5 (A), CPS ≥ 1 (B) and all patients, Opdivo combined with chemotherapy prolonged the overall survival (picture source: reference [1]) further analysis showed that regardless of the microsatellite instability state In any case, Opdivo combined with chemotherapy has survival benefits; most demographic characteristics or disease characteristics do not affect the survival benefits of Opdivo combined with chemotherapy
.
Regardless of the expression level of PD-L1, Opdivo combined with chemotherapy also brought a higher remission rate
.
▲ Among patients with different PD-L1 expression levels, Opdivo combined with chemotherapy has a higher remission rate (data source: reference [1]; tabulation: new medical perspectives).
No new safety signals have been observed in the study
.
Among all patients receiving treatment, 59% of patients in the Opdivo combined chemotherapy group and 44% of patients in the chemotherapy alone group experienced grade 3-4 treatment-related adverse events
.
The most common (≥25%) treatment-related adverse events of any grade in the two groups were nausea, diarrhea, and peripheral neuropathy
.
Moreover, the health-related quality of life of the two groups of patients in the overall population was not affected
.
The paper pointed out that in the previously untreated patients with advanced gastric, gastroesophageal junction or esophageal adenocarcinoma, compared to chemotherapy alone, Opdivo is the first to show superior OS, PFS benefits and acceptable safety in combination with chemotherapy PD-1 inhibitor
.
Opdivo combined with chemotherapy represents the new standard first-line treatment for these patients
.
It is worth noting that the main results of the CheckMate-649 Chinese subgroup have also been announced before, and Chinese patients have also benefited! The results of this treatment plan in Chinese patients are consistent with the results of the global population in the CheckMate-649 study
.
The "2021 CSCO Guidelines for Gastric Cancer Diagnosis and Treatment" has also included this program as a recommendation.
It is recommended that patients with HER2-negative gastric cancer with PD-L1 CPS ≥ 5 use chemotherapy combined with Opdivo (Class 1A evidence, Class I recommendation)
.
Image source: The 123RF research team also discussed the results of other immunotherapy trials for gastric cancer
.
In the KEYNOTE-062 study, for patients with advanced or recurrent gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS≥1 and PD-L1 CPS≥10, Keytruda (Pembrolizumab) combined chemotherapy was not compared with chemotherapy alone Significantly improved OS; in the ATTRACTION-4 study for Asian patients, the first-line treatment of advanced gastric cancer and gastroesophageal junction cancer, Opdivo combined with chemotherapy significantly improved PFS but did not improve OS
.
The research team stated that the difference in efficacy observed between CheckMate-649 and these two studies may be due to differences in study design (such as statistical considerations, biomarker selection, patient population, geography, and treatment options) and follow-up therapies
.
The same review article mentioned that more and more evidence supports the role of checkpoint inhibitors in the treatment of upper gastrointestinal cancer
.
In esophageal cancer, Keytruda has been approved by the U.
S.
FDA for second-line treatment of squamous cell carcinoma with CPS ≥ 10.
It has been proven in trials that combined with first-line chemotherapy can increase the survival rate of adenocarcinoma and squamous cell carcinoma.
Opdivo has also been approved by the FDA As a second-line treatment for squamous cell carcinoma, regardless of PD-L1 expression
.
Among early curable cancers, Opdivo's neoadjuvant treatment of esophagus and gastroesophageal junction cancer patients also doubled disease-free survival
.
With the publication of positive data from the CheckMate-649 trial, the status of the first-line application of immunotherapy in the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma will be further supported
.
It is expected that with the continuous advancement of targeted therapy and immunotherapy, patients with gastric cancer and related upper gastrointestinal cancers will be able to obtain more and better treatment options and prolong their lives
.
Related reading What are the new targets and new therapies for precise treatment of advanced gastric cancer? The "Nature" sub-published the blueprint "The Lancet-Oncology": A new choice for the first-line treatment of advanced gastric cancer in Asians? TAS-118 combined with oxaliplatin is superior to the standard program JAMA Sub-Journal: Chinese team clinical trials prove that laparoscopic total gastrectomy is safe and feasible for early gastric cancer.
Reference materials [1] Yelena Y Janjigian, et al.
, (2021) .
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.
The Lancet, DOI: https://doi.
org /10.
1016/S0140-6736(21)00797-2 Note: This article aims to introduce the progress of medical and health research, not a treatment plan recommendation
.
If you need guidance on the treatment plan, please go to a regular hospital for treatment
.
Gastric cancer is the fourth leading cause of cancer-related deaths in the world and the third leading cause of cancer deaths in China
.
However, for the vast majority of HER2-negative (about 85%) patients with gastric cancer, there has been little progress in the first-line treatment of advanced disease in the past 10 years.
After standard first-line treatment (platinum and fluoropyrimidine combined chemotherapy), the median total patient The survival period is only about 11 months
.
Until April this year, the treatment of advanced gastric cancer finally ushered in the first first-line immunotherapy
.
The US FDA approved Opdivo (nivolumab), a blockbuster PD-1 inhibitor, in combination with chemotherapy for the first-line treatment of advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer and esophageal adenocarcinoma
.
Adenocarcinoma is the most common (>90%) histological type of gastric cancer and gastroesophageal junction cancer.
Esophageal adenocarcinoma accounts for 15% of global esophageal cancers
.
This approval is mainly based on evidence from the large randomized phase 3 clinical trial CheckMate-649
.
Recently, the results of this phase 3 trial were published in full in the main journal of the top medical journal "The Lancet"! Peer-reviewed detailed data once again show that the addition of immunotherapy on the basis of chemotherapy has refreshed the survival period of these patients
.
The "Lancet" concurrent review article also pointed out that CheckMate-649 is an important milestone in the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma
.
Screenshot source: The paper published by The Lancet reports the results of Opdivo combined chemotherapy and chemotherapy alone in the CheckMate-649 study
.
This phase 3 trial recruited previously untreated, unresectable, non-HER2-positive adult patients (≥18 years of age) with gastric, gastroesophageal junction, or esophageal adenocarcinoma in 29 countries around the world
.
A total of 1581 patients were randomized 1:1 to receive Opdivo combined chemotherapy (789 cases) or chemotherapy alone (792 cases)
.
The chemotherapy regimen used is the existing standard treatment, capecitabine + oxaliplatin, a cycle every 3 weeks; or leucovorin, 5 FU + oxaliplatin, a cycle every 2 weeks
.
The trial reached the primary endpoints of overall survival (OS) and progression-free survival (PFS) at the same time, and the data for different population segments are encouraging
.
Patients with high PD-L1 expression levels in tumor samples (comprehensive positive score [CPS] ≥ 5) benefit the most
.
Among these patients, the Opdivo combined chemotherapy group had a significant reduction in the risk of death by 29%, a median OS extension of 3.
3 months (14.
4 months vs 11.
1 months); a significant reduction in the risk of disease progression or death by 32% (median PFS 7.
7 months vs.
6.
0 months)
.
The 1-year overall survival rate (57% vs 46%) and 1-year progression-free survival rate (36% vs 22%) of the Opdivo combined chemotherapy group were higher than those of the chemotherapy alone group
.
Positive PD-L1 expression and CPS≥1 are also beneficial
.
In this part of patients, the Opdivo combined chemotherapy group had a significant reduction in the risk of death by 23% (median OS 14.
0 months vs 11.
3 months); a significant reduction in the risk of disease progression or death by 26% (median PFS 7.
5 months vs 6.
9 months)
.
The 1-year overall survival rate (56% vs 47%) and 1-year progression-free survival rate (34% vs 22%) of the Opdivo combined chemotherapy group were also higher
.
Even without considering the expression of PD-L1, in all enrolled patients, the advantages brought by Opdivo combined with chemotherapy can still be seen! The Opdivo combined chemotherapy group significantly reduced the risk of death by 20% (median OS 13.
8 months vs 11.
6 months); the risk of disease progression or death was significantly reduced by 23% (median PFS 7.
7 months vs 6.
9 months)
.
The 1-year overall survival rate (55% vs 48%) and 1-year progression-free survival rate (33% vs 23%) of the Opdivo combined chemotherapy group were higher
.
▲In CPS ≥ 5 (A), CPS ≥ 1 (B) and all patients, Opdivo combined with chemotherapy prolonged the overall survival (picture source: reference [1]) further analysis showed that regardless of the microsatellite instability state In any case, Opdivo combined with chemotherapy has survival benefits; most demographic characteristics or disease characteristics do not affect the survival benefits of Opdivo combined with chemotherapy
.
Regardless of the expression level of PD-L1, Opdivo combined with chemotherapy also brought a higher remission rate
.
▲ Among patients with different PD-L1 expression levels, Opdivo combined with chemotherapy has a higher remission rate (data source: reference [1]; tabulation: new medical perspectives).
No new safety signals have been observed in the study
.
Among all patients receiving treatment, 59% of patients in the Opdivo combined chemotherapy group and 44% of patients in the chemotherapy alone group experienced grade 3-4 treatment-related adverse events
.
The most common (≥25%) treatment-related adverse events of any grade in the two groups were nausea, diarrhea, and peripheral neuropathy
.
Moreover, the health-related quality of life of the two groups of patients in the overall population was not affected
.
The paper pointed out that in the previously untreated patients with advanced gastric, gastroesophageal junction or esophageal adenocarcinoma, compared to chemotherapy alone, Opdivo is the first to show superior OS, PFS benefits and acceptable safety in combination with chemotherapy PD-1 inhibitor
.
Opdivo combined with chemotherapy represents the new standard first-line treatment for these patients
.
It is worth noting that the main results of the CheckMate-649 Chinese subgroup have also been announced before, and Chinese patients have also benefited! The results of this treatment plan in Chinese patients are consistent with the results of the global population in the CheckMate-649 study
.
The "2021 CSCO Guidelines for Gastric Cancer Diagnosis and Treatment" has also included this program as a recommendation.
It is recommended that patients with HER2-negative gastric cancer with PD-L1 CPS ≥ 5 use chemotherapy combined with Opdivo (Class 1A evidence, Class I recommendation)
.
Image source: The 123RF research team also discussed the results of other immunotherapy trials for gastric cancer
.
In the KEYNOTE-062 study, for patients with advanced or recurrent gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS≥1 and PD-L1 CPS≥10, Keytruda (Pembrolizumab) combined chemotherapy was not compared with chemotherapy alone Significantly improved OS; in the ATTRACTION-4 study for Asian patients, the first-line treatment of advanced gastric cancer and gastroesophageal junction cancer, Opdivo combined with chemotherapy significantly improved PFS but did not improve OS
.
The research team stated that the difference in efficacy observed between CheckMate-649 and these two studies may be due to differences in study design (such as statistical considerations, biomarker selection, patient population, geography, and treatment options) and follow-up therapies
.
The same review article mentioned that more and more evidence supports the role of checkpoint inhibitors in the treatment of upper gastrointestinal cancer
.
In esophageal cancer, Keytruda has been approved by the U.
S.
FDA for second-line treatment of squamous cell carcinoma with CPS ≥ 10.
It has been proven in trials that combined with first-line chemotherapy can increase the survival rate of adenocarcinoma and squamous cell carcinoma.
Opdivo has also been approved by the FDA As a second-line treatment for squamous cell carcinoma, regardless of PD-L1 expression
.
Among early curable cancers, Opdivo's neoadjuvant treatment of esophagus and gastroesophageal junction cancer patients also doubled disease-free survival
.
With the publication of positive data from the CheckMate-649 trial, the status of the first-line application of immunotherapy in the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma will be further supported
.
It is expected that with the continuous advancement of targeted therapy and immunotherapy, patients with gastric cancer and related upper gastrointestinal cancers will be able to obtain more and better treatment options and prolong their lives
.
Related reading What are the new targets and new therapies for precise treatment of advanced gastric cancer? The "Nature" sub-published the blueprint "The Lancet-Oncology": A new choice for the first-line treatment of advanced gastric cancer in Asians? TAS-118 combined with oxaliplatin is superior to the standard program JAMA Sub-Journal: Chinese team clinical trials prove that laparoscopic total gastrectomy is safe and feasible for early gastric cancer.
Reference materials [1] Yelena Y Janjigian, et al.
, (2021) .
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.
The Lancet, DOI: https://doi.
org /10.
1016/S0140-6736(21)00797-2 Note: This article aims to introduce the progress of medical and health research, not a treatment plan recommendation
.
If you need guidance on the treatment plan, please go to a regular hospital for treatment
.
