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Stomach cancer, a disease that sounds familiar and scary to us
.
We are familiar with it because it has a high incidence in our country, and the reason for fear is that it ranks the fourth cause of cancer death in the world [1]
.
What is the most effective treatment plan for such diseases? Not long ago, Professor Kohei Shitara from the East Hospital of the National Cancer Research Center of Japan led multiple research teams around the world to announce the results of a Phase III clinical study called CheckMate 649 in the journal The Lancet [2], which will help patients with advanced gastric cancer Immunotherapy finally sees light! The results of the study showed that: compared with chemotherapy alone, the PD-1 inhibitor nivolumab combined with chemotherapy extended the median overall survival time of patients by 3.
3 months
.
In other words, the combination of nivolumab and chemotherapy reduced the patient's risk of death by 29%
.
Screenshot of the paper's homepage.
At this stage, for HER2-negative advanced/metastatic gastric cancer (GC)/gastroesophageal junction cancer (GEJC)/esophageal adenocarcinoma (EAC) patients, first-line chemotherapy based on the combined use of fluorouracil and platinum, the treatment effect Still not ideal, the median overall survival (OS) is less than one year [3]
.
Although there are some other targeted drugs that are constantly being introduced, they still cannot significantly prolong the survival period of patients [4]
.
What makes people’s eyes brighter is that in the Phase III ATTRACTION-2 study, the PD-1 inhibitor Nivolumab (Nivolumab, NIVO) is more effective than the placebo group for GCs who have previously received two or more chemotherapy regimens.
/GEJC patients, bring significant survival benefits [5]
.
Therefore, researchers have launched a large number of clinical trials on GC/GEJC disease models based on immune checkpoint therapy, such as ATTRACTION-4 (first-line treatment), KEYNOTE-062 (first-line treatment), KEYNOTE-590 (first-line treatment), JAVELIN Gastric 100 ( Second-line treatment after chemotherapy induction) and so on
.
In summary, it is found that the first-line chemotherapy combined with immunotherapy for advanced gastric cancer, which is expected to be highly anticipated, only KEYNOTE-590 can improve PFS/OS in a sublayer analysis based on a specific disease model [2]
.
So can chemotherapy combined with immunotherapy really benefit untreated patients with advanced gastric cancer? To further confirm the effectiveness of nivolumab in the first-line treatment of GC/GEJC patients, the investigators conducted a phase III clinical trial called CheckMate 649 to evaluate the effectiveness of nivolumab compared with chemotherapy alone.
(NIVO) Combination chemotherapy for the treatment effect of advanced untreated GC/GEJC/EAC patients
.
CheckMate 649 is a global, randomized, multi-center, open-label clinical study conducted in an orderly manner in 175 hospitals and cancer centers in 29 countries
.
The entry criteria and specific test plan are shown in the figure below: Research design of CheckMate 649 Next, let's take a look at the main results of this research together
.
First, based on the analysis of the primary endpoint, for patients with PD-L1 CPS ≥ 5, the median overall survival (OS) is 11.
1 months in the chemotherapy alone group, 14.
4 months in the NIVO combined chemotherapy group, and 14.
4 months in the combined treatment group.
The median overall survival time was extended by 3.
3 months
.
In other words, NIVO combined with chemotherapy reduced the patient's risk of death by 29% (HR 0.
71, P<0.
0001)
.
From the perspective of median progression-free survival (PFS), the chemotherapy alone group was 6.
0 months, and the NIVO combined chemotherapy group was 7.
7 months.
The combined treatment reduced the patient’s risk of disease progression by 32% (HR 0.
68, P<0.
0001)
.
After the overall survival curve of patients with PD-L1 CPS ≥ 5, based on the analysis of secondary endpoints, for patients with PD-L1 CPS ≥ 1, from the perspective of median overall survival (OS), the chemotherapy alone group was 11.
3 months, NIVO The combined chemotherapy group was 14.
0 months.
NIVO combined with chemotherapy reduced the patient’s risk of death by 23% (HR 0.
77, P＜0.
0001); from the perspective of the median progression-free survival (PFS), the chemotherapy group alone was 6.
9 months.
The NIVO combined chemotherapy group is 7.
5 months
.
The overall survival curve of patients with PD-L1 CPS ≥ 1 For all patients, the median overall survival time (OS) is 11.
6 months in the chemotherapy group alone, 13.
8 months in the NIVO combined chemotherapy group, and NIVO combined chemotherapy The risk of death was reduced by 20% (HR 0.
80, P=0.
0002)
.
From the perspective of median progression-free survival (PFS), the chemotherapy alone group was 6.
9 months, and the NIVO combined chemotherapy group was 7.
7 months, indicating that all patients have PFS benefit
.
Overall survival curve of all randomized patients As for the safety of NIVO combined with chemotherapy, the most common adverse reactions in combination therapy and single therapy are nausea, diarrhea and peripheral neuropathy
.
For grade 3-4 treatment-related adverse reactions, the NIVO combined chemotherapy group had 462 patients (59%) out of 782 patients, and the chemotherapy alone group had 341 patients (44%) out of 767 patients
.
Although the number of adverse reactions in the NIVO combined chemotherapy group was relatively large, the number of adverse reactions related to immunity was less than 5%, and no new adverse reaction signals were observed
.
Therefore, overall the safety of the combination therapy is acceptable and within a controllable range
.
Based on the results of this large-scale clinical study of CheckMate 649, the FDA has approved nivolumab combined with fluorouracil and platinum drugs for the treatment of patients with advanced or metastatic GC/GEJC/EAC
.
The success of this research may come from many factors
.
First, for gastric cancer, existing studies have proved the effectiveness of nivolumab in GC/GEJC/EAC treatment; secondly, the effective combination of chemotherapy and immunotherapy.
Chemotherapy drugs can not only play a killing effect, but also can pass immunogenicity.
The death effect enhances the immune response [6]; the more important point is that two chemotherapy dosing regimens are set, and the tolerability of the combination therapy, as well as the differences and compliance of different patients, can be better Personalized treatment
.
This clinical trial result not only dispels clinical controversy and hesitation on immunotherapy for gastric cancer, but also allows more advanced gastric cancer patients to benefit from it and obtain long-term high-quality survival.
It is expected to change the pattern of first-line treatment for gastric cancer; at the same time, it is immunotherapy.
The scientific research of combined chemotherapy can inject a dose of invigorating acupuncture, which can encourage more researchers to explore new ideas for combined immunotherapy in the future
.
References: [1] Sung H, Ferlay J, Siegel RL, et al.
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
CA Cancer J Clin.
2021;71(3):209 -249.
doi:10.
3322/caac.
21660[2] Janjigian YY, Shitara K, Moehler M, et al.
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 [published online ahead of print, 2021 Jun 4].
Lancet.
2021;S0140-6736(21)00797-2.
doi:10.
1016/S0140-6736(21)00797-2 [3] National Comprehensive Cancer Network.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).
Gastric cancer.
Version 2.
2021.
https:// pdf/gastric.
pdf (accessed March 17 , 2021).
[4] Shah MA, Bang YJ, Lordick F,et al.
Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
JAMA Oncol.
2017;3(5):620-627.
doi:10.
1001/ jamaoncol.
2016.
5580[5] Kang YK, Boku N, Satoh T, et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet.
2017;390(10111):2461-2471.
doi:10.
1016/S0140-6736(17)31827-5[6] Park SJ, Ye W, Xiao R, et al.
Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
Oral Oncol.
2019;95:127-135.
doi:10.
1016/j.
oraloncology.
2019.
06.
016 EditBioTalkerEffect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
JAMA Oncol.
2017;3(5):620-627.
doi:10.
1001/jamaoncol.
2016.
5580 [5] Kang YK, Boku N, Satoh T, et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2 ): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet.
2017;390(10111):2461-2471.
doi:10.
1016/S0140-6736(17)31827-5[6] Park SJ, Ye W, Xiao R, et al.
Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
Oral Oncol.
2019;95:127-135.
doi:10.
1016/j.
oraloncology.
2019.
06.
016 Chief EditorBioTalkerEffect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
JAMA Oncol.
2017;3(5):620-627.
doi:10.
1001/jamaoncol.
2016.
5580 [5] Kang YK, Boku N, Satoh T, et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2 ): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet.
2017;390(10111):2461-2471.
doi:10.
1016/S0140-6736(17)31827-5[6] Park SJ, Ye W, Xiao R, et al.
Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
Oral Oncol.
2019;95:127-135.
doi:10.
1016/j.
oraloncology.
2019.
06.
016 Chief EditorBioTalker016 Chief EditorBioTalker
.
We are familiar with it because it has a high incidence in our country, and the reason for fear is that it ranks the fourth cause of cancer death in the world [1]
.
What is the most effective treatment plan for such diseases? Not long ago, Professor Kohei Shitara from the East Hospital of the National Cancer Research Center of Japan led multiple research teams around the world to announce the results of a Phase III clinical study called CheckMate 649 in the journal The Lancet [2], which will help patients with advanced gastric cancer Immunotherapy finally sees light! The results of the study showed that: compared with chemotherapy alone, the PD-1 inhibitor nivolumab combined with chemotherapy extended the median overall survival time of patients by 3.
3 months
.
In other words, the combination of nivolumab and chemotherapy reduced the patient's risk of death by 29%
.
Screenshot of the paper's homepage.
At this stage, for HER2-negative advanced/metastatic gastric cancer (GC)/gastroesophageal junction cancer (GEJC)/esophageal adenocarcinoma (EAC) patients, first-line chemotherapy based on the combined use of fluorouracil and platinum, the treatment effect Still not ideal, the median overall survival (OS) is less than one year [3]
.
Although there are some other targeted drugs that are constantly being introduced, they still cannot significantly prolong the survival period of patients [4]
.
What makes people’s eyes brighter is that in the Phase III ATTRACTION-2 study, the PD-1 inhibitor Nivolumab (Nivolumab, NIVO) is more effective than the placebo group for GCs who have previously received two or more chemotherapy regimens.
/GEJC patients, bring significant survival benefits [5]
.
Therefore, researchers have launched a large number of clinical trials on GC/GEJC disease models based on immune checkpoint therapy, such as ATTRACTION-4 (first-line treatment), KEYNOTE-062 (first-line treatment), KEYNOTE-590 (first-line treatment), JAVELIN Gastric 100 ( Second-line treatment after chemotherapy induction) and so on
.
In summary, it is found that the first-line chemotherapy combined with immunotherapy for advanced gastric cancer, which is expected to be highly anticipated, only KEYNOTE-590 can improve PFS/OS in a sublayer analysis based on a specific disease model [2]
.
So can chemotherapy combined with immunotherapy really benefit untreated patients with advanced gastric cancer? To further confirm the effectiveness of nivolumab in the first-line treatment of GC/GEJC patients, the investigators conducted a phase III clinical trial called CheckMate 649 to evaluate the effectiveness of nivolumab compared with chemotherapy alone.
(NIVO) Combination chemotherapy for the treatment effect of advanced untreated GC/GEJC/EAC patients
.
CheckMate 649 is a global, randomized, multi-center, open-label clinical study conducted in an orderly manner in 175 hospitals and cancer centers in 29 countries
.
The entry criteria and specific test plan are shown in the figure below: Research design of CheckMate 649 Next, let's take a look at the main results of this research together
.
First, based on the analysis of the primary endpoint, for patients with PD-L1 CPS ≥ 5, the median overall survival (OS) is 11.
1 months in the chemotherapy alone group, 14.
4 months in the NIVO combined chemotherapy group, and 14.
4 months in the combined treatment group.
The median overall survival time was extended by 3.
3 months
.
In other words, NIVO combined with chemotherapy reduced the patient's risk of death by 29% (HR 0.
71, P<0.
0001)
.
From the perspective of median progression-free survival (PFS), the chemotherapy alone group was 6.
0 months, and the NIVO combined chemotherapy group was 7.
7 months.
The combined treatment reduced the patient’s risk of disease progression by 32% (HR 0.
68, P<0.
0001)
.
After the overall survival curve of patients with PD-L1 CPS ≥ 5, based on the analysis of secondary endpoints, for patients with PD-L1 CPS ≥ 1, from the perspective of median overall survival (OS), the chemotherapy alone group was 11.
3 months, NIVO The combined chemotherapy group was 14.
0 months.
NIVO combined with chemotherapy reduced the patient’s risk of death by 23% (HR 0.
77, P＜0.
0001); from the perspective of the median progression-free survival (PFS), the chemotherapy group alone was 6.
9 months.
The NIVO combined chemotherapy group is 7.
5 months
.
The overall survival curve of patients with PD-L1 CPS ≥ 1 For all patients, the median overall survival time (OS) is 11.
6 months in the chemotherapy group alone, 13.
8 months in the NIVO combined chemotherapy group, and NIVO combined chemotherapy The risk of death was reduced by 20% (HR 0.
80, P=0.
0002)
.
From the perspective of median progression-free survival (PFS), the chemotherapy alone group was 6.
9 months, and the NIVO combined chemotherapy group was 7.
7 months, indicating that all patients have PFS benefit
.
Overall survival curve of all randomized patients As for the safety of NIVO combined with chemotherapy, the most common adverse reactions in combination therapy and single therapy are nausea, diarrhea and peripheral neuropathy
.
For grade 3-4 treatment-related adverse reactions, the NIVO combined chemotherapy group had 462 patients (59%) out of 782 patients, and the chemotherapy alone group had 341 patients (44%) out of 767 patients
.
Although the number of adverse reactions in the NIVO combined chemotherapy group was relatively large, the number of adverse reactions related to immunity was less than 5%, and no new adverse reaction signals were observed
.
Therefore, overall the safety of the combination therapy is acceptable and within a controllable range
.
Based on the results of this large-scale clinical study of CheckMate 649, the FDA has approved nivolumab combined with fluorouracil and platinum drugs for the treatment of patients with advanced or metastatic GC/GEJC/EAC
.
The success of this research may come from many factors
.
First, for gastric cancer, existing studies have proved the effectiveness of nivolumab in GC/GEJC/EAC treatment; secondly, the effective combination of chemotherapy and immunotherapy.
Chemotherapy drugs can not only play a killing effect, but also can pass immunogenicity.
The death effect enhances the immune response [6]; the more important point is that two chemotherapy dosing regimens are set, and the tolerability of the combination therapy, as well as the differences and compliance of different patients, can be better Personalized treatment
.
This clinical trial result not only dispels clinical controversy and hesitation on immunotherapy for gastric cancer, but also allows more advanced gastric cancer patients to benefit from it and obtain long-term high-quality survival.
It is expected to change the pattern of first-line treatment for gastric cancer; at the same time, it is immunotherapy.
The scientific research of combined chemotherapy can inject a dose of invigorating acupuncture, which can encourage more researchers to explore new ideas for combined immunotherapy in the future
.
References: [1] Sung H, Ferlay J, Siegel RL, et al.
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
CA Cancer J Clin.
2021;71(3):209 -249.
doi:10.
3322/caac.
21660[2] Janjigian YY, Shitara K, Moehler M, et al.
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 [published online ahead of print, 2021 Jun 4].
Lancet.
2021;S0140-6736(21)00797-2.
doi:10.
1016/S0140-6736(21)00797-2 [3] National Comprehensive Cancer Network.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).
Gastric cancer.
Version 2.
2021.
https:// pdf/gastric.
pdf (accessed March 17 , 2021).
[4] Shah MA, Bang YJ, Lordick F,et al.
Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
JAMA Oncol.
2017;3(5):620-627.
doi:10.
1001/ jamaoncol.
2016.
5580[5] Kang YK, Boku N, Satoh T, et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet.
2017;390(10111):2461-2471.
doi:10.
1016/S0140-6736(17)31827-5[6] Park SJ, Ye W, Xiao R, et al.
Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
Oral Oncol.
2019;95:127-135.
doi:10.
1016/j.
oraloncology.
2019.
06.
016 EditBioTalkerEffect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
JAMA Oncol.
2017;3(5):620-627.
doi:10.
1001/jamaoncol.
2016.
5580 [5] Kang YK, Boku N, Satoh T, et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2 ): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet.
2017;390(10111):2461-2471.
doi:10.
1016/S0140-6736(17)31827-5[6] Park SJ, Ye W, Xiao R, et al.
Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
Oral Oncol.
2019;95:127-135.
doi:10.
1016/j.
oraloncology.
2019.
06.
016 Chief EditorBioTalkerEffect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
JAMA Oncol.
2017;3(5):620-627.
doi:10.
1001/jamaoncol.
2016.
5580 [5] Kang YK, Boku N, Satoh T, et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2 ): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet.
2017;390(10111):2461-2471.
doi:10.
1016/S0140-6736(17)31827-5[6] Park SJ, Ye W, Xiao R, et al.
Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
Oral Oncol.
2019;95:127-135.
doi:10.
1016/j.
oraloncology.
2019.
06.
016 Chief EditorBioTalker016 Chief EditorBioTalker
