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▎WuXi AppTec Content Team Editor According to data from the International Agency for Research on Cancer (IARC), gastric cancer is the fifth most common cancer and the fourth leading cause of cancer death in the world.
In 2020, 769,000 people died of gastric cancer
.
Among the global gastric cancer cases, nearly 75% are in Asia, and nearly 50% are in China
.
Incidence rates in East Asian populations, including China, are significantly higher than those in other regions of the world
.
For HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer, the standard of care for first-line treatment over the past 10 years has been limited to doublet chemotherapy
.
In the past year, the first-line treatment of gastric cancer has finally entered the era of immunotherapy
.
With the success of the CheckMate-649 trial, the blockbuster PD-1 inhibitor nivolumab (Odivo, O drug) has been approved for the first-line treatment of gastric cancer in the United States and China
.
A few days ago, another important study, ATTRACTION-4, has made positive progress in the phase 3 trial of first-line immunotherapy for advanced gastric cancer in Asian patients.
The results were recently published in The Lancet Oncology, a top academic journal in the field of cancer Oncology)
.
Screenshot source: The Lancet Oncology ATTRACTION-4 study shows that nivolumab plus chemotherapy significantly and durable prolongs progression-free survival in Asian patients with untreated, unresectable advanced or recurrent gastric or gastroesophageal junction cancer It may be a new first-line treatment option to improve the remission rate and remission duration, regardless of the level of PD-L1 expression in patients
.
ATTRACTION-4 Trial Main Results ATTRACTION-4 is a randomized, multicenter, double-blind, placebo-controlled Phase 2-3 trial
.
The phase 3 trial was conducted at 130 centers in Japan, South Korea, and Taiwan, and between March 23, 2017, and May 10, 2018, a total of 724 patients were randomized 1:1 to receive nivolumab plus chemotherapy (362 people) or placebo in combination with chemotherapy (362 people)
.
The chemotherapy regimen was oxaliplatin combined with S-1 (SOX regimen) or oxaliplatin combined with capecitabine (CAPOX)
.
Previous studies have suggested that oxaliplatin can induce immunogenic cell death, so immune checkpoint inhibitors combined with oxaliplatin-based chemotherapy may have a synergistic antitumor effect
.
Patient inclusion criteria: age ≥20 years, previously untreated (except neoadjuvant or adjuvant chemotherapy completed ≥180 days prior to recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer (regardless of PD) -L1 expression level), at least one measurable lesion according to the Solid Tumor Guidelines (version 1.
1) Response Evaluation Criteria, and a baseline ECOG performance status of 0 or 1
.
Progression-free survival analysis data as of October 31, 2018, with a median follow-up time of 11.
6 months, nivolumab combined with chemotherapy significantly prolonged progression-free survival (10.
45 months vs 8.
34 months), disease progression or a significantly lower risk of death by 32% (HR 0.
68; 98.
51% CI 0.
51-0.
90; p=0.
0007)
.
A consistent trend of benefit was observed in the vast majority of subgroup analyses
.
Overall survival analysis data was as of January 31, 2020, with a median follow-up of 26.
6 months
.
There was no statistically significant difference in overall survival between the nivolumab plus chemotherapy group (17.
45 months) and the placebo plus chemotherapy group (17.
15 months) (HR 0.
90; 95% CI 0.
75-1.
08; p=0.
26)
.
Subgroup analyses showed that an overall survival benefit was observed in patients with no more than one organ metastases (40% lower risk of death) and no peritoneal metastases (31% lower risk of death)
.
However, at this time (as of January 31, 2020), among all randomized patients, there was still a significant advantage in progression-free survival in the nivolumab plus chemotherapy arm (10.
94 months vs 8.
41 months, a risk reduction of 30%).
%)
.
Importantly, the addition of nivolumab to chemotherapy resulted in a durable benefit in terms of continued separation of survival curves, the paper noted
.
▲The progression-free survival (A) and overall survival (B) curves of the two groups of patients (Image source: Reference [1]) More patients in the nivolumab combined chemotherapy group achieved objective responses (57% vs 48%) ) and longer duration of remission (median 12.
91 months vs 8.
67 months)
.
Disease control rates and median time to onset of response were similar between the two groups
.
The trial assessed safety in all patients who received at least one dose of the indicated treatment
.
The results suggest that nivolumab in combination with chemotherapy was well tolerated and consistent with the known safety profile of nivolumab and each chemotherapy, with no new safety signals observed
.
The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (20% in the nivolumab plus chemotherapy group vs 16% in the placebo plus chemotherapy group) and platelet count (9% vs 9%)
.
Treatment-related serious adverse events of any grade were observed in 25% and 14% of patients in the two groups, respectively, the most common being decreased appetite (5% vs 3%)
.
A total of 6 treatment-related deaths occurred: 3 in the nivolumab-chemotherapy group (1 each for febrile neutropenia, liver failure, and sudden death) and 3 in the placebo-chemotherapy group (sepsis, hemolysis 1 case each of anemia and interstitial lung disease)
.
Comparing similar studies, the inspiration for the selection of treatment options is based on these data, and the paper also discusses the results of other first-line immunotherapy trials for gastric cancer: (1) The use of nivolumab for first-line treatment of gastric cancer is supported by the consistent results of multiple efficacy endpoints
.
In the CheckMate-649 trial, nivolumab in combination with chemotherapy also showed longer progression-free survival and higher response rates, with longer duration of response, compared to chemotherapy alone
.
Consistent results for these efficacy endpoints demonstrate the clinical relevance of nivolumab in combination with chemotherapy as first-line treatment for patients with HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer
.
(2) Subsequent treatment may dilute the overall survival benefit gap of first-line treatment
.
In the CheckMate-649 trial, the combination of nivolumab and chemotherapy significantly improved overall survival, whereas the improvement in this outcome measure in the ATTRACTION-4 trial was not significant
.
The CheckMate-649 subgroup results did not show ethnic differences in the efficacy of immune checkpoint inhibitors combined with chemotherapy
.
The difference in overall survival benefit between the two trials may be due to the fact that more patients in the ATTRACTION-4 trial received subsequent anticancer therapy (66% vs 39%)
.
This difference may reflect different patterns of clinical practice in different regions, and it is known that Asian patients (especially Japanese patients) generally receive more subsequent anticancer drug treatment and have relatively better survival outcomes compared with European and American patients
.
In the ATTRACTION-4 trial, patients in the nivolumab-plus-chemotherapy arm or placebo-plus-chemotherapy arm had the longest median overall survival of such a phase 3 trial
.
(3) The choice of combination chemotherapy regimen may also affect the benefit
.
In contrast, in the KEYNOTE-062 study, pembrolizumab (Kreuximab) was administered to patients with advanced or recurrent gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS ≥1 and PD-L1 CPS ≥10.
DA, K drug) combined with chemotherapy did not significantly improve overall survival compared with chemotherapy alone
.
The choice of combination chemotherapy regimen may be a potential reason for the difference
.
Both ATTRACTION-4 and CheckMate-649 use oxaliplatin-based chemotherapy, while KEYNOTE-062 uses cisplatin-based chemotherapy
.
Considering that in cancers other than gastric cancer, several trials have shown positive results with the combination of immune checkpoint inhibitors with cisplatin-based chemotherapy, further research is needed to investigate whether immune checkpoint inhibitors combined with different chemotherapy affects the results
.
Summary: Potential new options for first-line treatment of gastric cancer The paper concluded that the ATTRACTION-4 trial found that the addition of nivolumab to chemotherapy significantly improved progression-free survival, increased objective response rates, and more durable responses.
Controllable security
.
Results from CheckMate-649 also support the benefit of nivolumab in combination with oxaliplatin-based chemotherapy
.
Therefore, nivolumab combined with SOX or CAPOX chemotherapy may become a new first-line treatment option for Asian patients with HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer
.
In 2020, 769,000 people died of gastric cancer
.
Among the global gastric cancer cases, nearly 75% are in Asia, and nearly 50% are in China
.
Incidence rates in East Asian populations, including China, are significantly higher than those in other regions of the world
.
For HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer, the standard of care for first-line treatment over the past 10 years has been limited to doublet chemotherapy
.
In the past year, the first-line treatment of gastric cancer has finally entered the era of immunotherapy
.
With the success of the CheckMate-649 trial, the blockbuster PD-1 inhibitor nivolumab (Odivo, O drug) has been approved for the first-line treatment of gastric cancer in the United States and China
.
A few days ago, another important study, ATTRACTION-4, has made positive progress in the phase 3 trial of first-line immunotherapy for advanced gastric cancer in Asian patients.
The results were recently published in The Lancet Oncology, a top academic journal in the field of cancer Oncology)
.
Screenshot source: The Lancet Oncology ATTRACTION-4 study shows that nivolumab plus chemotherapy significantly and durable prolongs progression-free survival in Asian patients with untreated, unresectable advanced or recurrent gastric or gastroesophageal junction cancer It may be a new first-line treatment option to improve the remission rate and remission duration, regardless of the level of PD-L1 expression in patients
.
ATTRACTION-4 Trial Main Results ATTRACTION-4 is a randomized, multicenter, double-blind, placebo-controlled Phase 2-3 trial
.
The phase 3 trial was conducted at 130 centers in Japan, South Korea, and Taiwan, and between March 23, 2017, and May 10, 2018, a total of 724 patients were randomized 1:1 to receive nivolumab plus chemotherapy (362 people) or placebo in combination with chemotherapy (362 people)
.
The chemotherapy regimen was oxaliplatin combined with S-1 (SOX regimen) or oxaliplatin combined with capecitabine (CAPOX)
.
Previous studies have suggested that oxaliplatin can induce immunogenic cell death, so immune checkpoint inhibitors combined with oxaliplatin-based chemotherapy may have a synergistic antitumor effect
.
Patient inclusion criteria: age ≥20 years, previously untreated (except neoadjuvant or adjuvant chemotherapy completed ≥180 days prior to recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer (regardless of PD) -L1 expression level), at least one measurable lesion according to the Solid Tumor Guidelines (version 1.
1) Response Evaluation Criteria, and a baseline ECOG performance status of 0 or 1
.
Progression-free survival analysis data as of October 31, 2018, with a median follow-up time of 11.
6 months, nivolumab combined with chemotherapy significantly prolonged progression-free survival (10.
45 months vs 8.
34 months), disease progression or a significantly lower risk of death by 32% (HR 0.
68; 98.
51% CI 0.
51-0.
90; p=0.
0007)
.
A consistent trend of benefit was observed in the vast majority of subgroup analyses
.
Overall survival analysis data was as of January 31, 2020, with a median follow-up of 26.
6 months
.
There was no statistically significant difference in overall survival between the nivolumab plus chemotherapy group (17.
45 months) and the placebo plus chemotherapy group (17.
15 months) (HR 0.
90; 95% CI 0.
75-1.
08; p=0.
26)
.
Subgroup analyses showed that an overall survival benefit was observed in patients with no more than one organ metastases (40% lower risk of death) and no peritoneal metastases (31% lower risk of death)
.
However, at this time (as of January 31, 2020), among all randomized patients, there was still a significant advantage in progression-free survival in the nivolumab plus chemotherapy arm (10.
94 months vs 8.
41 months, a risk reduction of 30%).
%)
.
Importantly, the addition of nivolumab to chemotherapy resulted in a durable benefit in terms of continued separation of survival curves, the paper noted
.
▲The progression-free survival (A) and overall survival (B) curves of the two groups of patients (Image source: Reference [1]) More patients in the nivolumab combined chemotherapy group achieved objective responses (57% vs 48%) ) and longer duration of remission (median 12.
91 months vs 8.
67 months)
.
Disease control rates and median time to onset of response were similar between the two groups
.
The trial assessed safety in all patients who received at least one dose of the indicated treatment
.
The results suggest that nivolumab in combination with chemotherapy was well tolerated and consistent with the known safety profile of nivolumab and each chemotherapy, with no new safety signals observed
.
The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (20% in the nivolumab plus chemotherapy group vs 16% in the placebo plus chemotherapy group) and platelet count (9% vs 9%)
.
Treatment-related serious adverse events of any grade were observed in 25% and 14% of patients in the two groups, respectively, the most common being decreased appetite (5% vs 3%)
.
A total of 6 treatment-related deaths occurred: 3 in the nivolumab-chemotherapy group (1 each for febrile neutropenia, liver failure, and sudden death) and 3 in the placebo-chemotherapy group (sepsis, hemolysis 1 case each of anemia and interstitial lung disease)
.
Comparing similar studies, the inspiration for the selection of treatment options is based on these data, and the paper also discusses the results of other first-line immunotherapy trials for gastric cancer: (1) The use of nivolumab for first-line treatment of gastric cancer is supported by the consistent results of multiple efficacy endpoints
.
In the CheckMate-649 trial, nivolumab in combination with chemotherapy also showed longer progression-free survival and higher response rates, with longer duration of response, compared to chemotherapy alone
.
Consistent results for these efficacy endpoints demonstrate the clinical relevance of nivolumab in combination with chemotherapy as first-line treatment for patients with HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer
.
(2) Subsequent treatment may dilute the overall survival benefit gap of first-line treatment
.
In the CheckMate-649 trial, the combination of nivolumab and chemotherapy significantly improved overall survival, whereas the improvement in this outcome measure in the ATTRACTION-4 trial was not significant
.
The CheckMate-649 subgroup results did not show ethnic differences in the efficacy of immune checkpoint inhibitors combined with chemotherapy
.
The difference in overall survival benefit between the two trials may be due to the fact that more patients in the ATTRACTION-4 trial received subsequent anticancer therapy (66% vs 39%)
.
This difference may reflect different patterns of clinical practice in different regions, and it is known that Asian patients (especially Japanese patients) generally receive more subsequent anticancer drug treatment and have relatively better survival outcomes compared with European and American patients
.
In the ATTRACTION-4 trial, patients in the nivolumab-plus-chemotherapy arm or placebo-plus-chemotherapy arm had the longest median overall survival of such a phase 3 trial
.
(3) The choice of combination chemotherapy regimen may also affect the benefit
.
In contrast, in the KEYNOTE-062 study, pembrolizumab (Kreuximab) was administered to patients with advanced or recurrent gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS ≥1 and PD-L1 CPS ≥10.
DA, K drug) combined with chemotherapy did not significantly improve overall survival compared with chemotherapy alone
.
The choice of combination chemotherapy regimen may be a potential reason for the difference
.
Both ATTRACTION-4 and CheckMate-649 use oxaliplatin-based chemotherapy, while KEYNOTE-062 uses cisplatin-based chemotherapy
.
Considering that in cancers other than gastric cancer, several trials have shown positive results with the combination of immune checkpoint inhibitors with cisplatin-based chemotherapy, further research is needed to investigate whether immune checkpoint inhibitors combined with different chemotherapy affects the results
.
Summary: Potential new options for first-line treatment of gastric cancer The paper concluded that the ATTRACTION-4 trial found that the addition of nivolumab to chemotherapy significantly improved progression-free survival, increased objective response rates, and more durable responses.
Controllable security
.
Results from CheckMate-649 also support the benefit of nivolumab in combination with oxaliplatin-based chemotherapy
.
Therefore, nivolumab combined with SOX or CAPOX chemotherapy may become a new first-line treatment option for Asian patients with HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer
.
