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*For medical professionals to read and refer to Prof.
Xu Jianming's detailed explanation of the CheckMate-648 study
.
China is a country with a high incidence of esophageal cancer.
According to the 2020 edition of the Global Cancer Statistical Report (GLOBOCAN 2020), there will be about 320,000 new cases of esophageal cancer in China in 2020, and about 300,000 people will die of esophageal cancer, of which more than 90% of the patients are Esophageal squamous cell carcinoma
.
For most esophageal cancer patients, radical resection cannot be performed at the time of diagnosis, few treatment options and poor prognosis are the biggest clinical features
.
The CheckMate 648 study[1] is a phase III, randomized, global clinical study evaluating the efficacy of nivolumab combined with chemotherapy or ipilimumab versus chemotherapy alone in the first-line treatment of advanced or metastatic esophageal squamous cell carcinoma
.
Recently, the latest data analysis of the study was published in the internationally renowned medical journal "New England Journal of Medicine"
.
The Medical Oncology Channel specially invited Professor Xu Jianming, the PI of the CheckMate-648 study in China and the director of the Division of Digestive Oncology at the Fifth Medical Center of the PLA General Hospital, to interpret and analyze the latest research data released by the CheckMate 648 study
.
Study Abstract▌ BackgroundThe first-line chemotherapy in patients with advanced esophageal squamous cell carcinoma was not effective in the past, and nivolumab showed better overall survival than chemotherapy in previously treated patients with advanced esophageal squamous cell carcinoma ( OS) benefit
.
▌ Research Methods The researchers randomly assigned 1:1:1 patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma to receive nivolumab combined with chemotherapy, nivolumab The primary endpoints of the study were OS and progression-free survival (PFS) as assessed by a blinded independent central review committee (BICR)
.
The study first stratified analysis in patients with PD-L1 expression ≥1%, and then in the overall patient population
.
▌ Research results A total of 970 patients were randomized.
After a minimum of 13 months of follow-up, in patients with PD-L1 expression ≥1% (15.
4 months vs 9.
1 months; HR=0.
54; P<0.
001 ) and all patients (13.
2 months vs 10.
7 months; HR = 0.
74; P = 0.
002), patients who received nivolumab plus chemotherapy had longer OS than those who received chemotherapy alone
.
In patients with PD-L1 expression ≥1% (13.
7 months vs 9.
1 months; HR=0.
64; P=0.
001) and in the overall population (12.
7 months vs 10.
7 months; HR=0.
78; P=0.
01) , patients receiving nivolumab combined with ipilimumab also had significantly better OS than chemotherapy alone
.
In patients with PD-L1 expression ≥1%, nivolumab plus chemotherapy improved PFS compared with chemotherapy alone (HR=0.
65; 98.
5% CI, 0.
46-0.
92; P=0.
002), while nivolumab There was no significant improvement in PFS in patients in the utimab combined with ipilimumab group
.
The incidence of grade 3 and 4 treatment-related adverse events was 47%, 32%, and 36% in the nivolumab plus chemotherapy group, the nivolumab plus ipilimumab group, and the chemotherapy alone group, respectively
.
▌ Conclusion Compared with chemotherapy alone, nivolumab combined with chemotherapy or ipilimumab in the first-line treatment of patients with advanced esophageal squamous cell carcinoma significantly prolongs the OS, and no new safety signal was found
.
What was the purpose of the trial design of the CheckMate 648 study? In the past decades, the first-line treatment of metastatic esophageal cancer has been mainly chemotherapy, and the prognosis of patients is usually poor, and the OS is generally less than 12 months
.
With the advent of the immune era, the treatment of esophageal cancer has gradually shifted from chemotherapy alone to immunotherapy combined with chemotherapy or double immune combined therapy
.
The "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Gastric Cancer 2021"[2] has even listed nivolumab combined with chemotherapy as the first-line treatment for patients with advanced metastatic gastric cancer
.
In the CheckMate-648 study, researchers randomly assigned patients with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma in a 1:1:1 ratio to receive nivolumab Primary endpoints of the study included OS and progression-free survival (PFS), as determined by a blinded independent central review, in combination with chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone
.
The researchers analyzed the PFS and OS of patients with PD-L1 expression ≥1% and all patients by stratified detection of patients
.
In this regard, Professor Xu Jianming said: "The CheckMate-648 study was designed for the following two reasons
.
First, at the beginning of the study design, researchers could not predict the efficacy of immunotherapy for patients with esophageal squamous cell carcinoma.
Research data show that patients with positive PD-L1 expression are more likely to benefit, so the patient's PD-L1 expression level is used as a stratification factor to analyze the efficacy data of patients
.
"Secondly, chemotherapy was the first-line standard treatment for such patients before immunotherapy, and according to previous clinical research data and practical experience, patients with esophageal squamous cell carcinoma usually have better survival after receiving immunotherapy.
To explore whether immunotherapy combined with chemotherapy can improve the survival benefit of such patients, and whether the double-immunity combined treatment plan can achieve the purpose of clinical 'de-chemotherapy', three groups of patients were given nivolumab combined with chemotherapy, nivolumab combined with chemotherapy, and nivolumab.
Antibiotic combined with ipilimumab and chemotherapy alone
.
"Can immunotherapy combined with chemotherapy really benefit all patients? According to the research data reported in this report, compared with the chemotherapy group alone, the treatment regimen of nivolumab combined with chemotherapy can improve the PFS and OS of patients.
Significant benefit, while the combination of nivolumab and ipilimumab can benefit OS in all patients, but only benefit PFS in patients with PD-L1 expression ≥1%
.
Figure 1 CheckMate Regarding the PFS and OS data of patients in the -648 study, Professor Xu Jianming said: "In clinical practice, the applicable population of immunotherapy combined with chemotherapy is relatively wider, and the 'de-chemotherapy' regimen of double immunity combined needs to be considered for the applicable population.
filter
.
The main reason for the difference in the efficacy of the two treatment regimens in different populations may be due to the differences in the tumor immune microenvironment in the final analysis
.
"Although the CheckMate-648 study showed that the combination of nivolumab with chemotherapy or ipilimumab resulted in an OS benefit in all patients
.
However, the researchers pointed out that compared with patients with PD-L1 expression ≥1% In comparison, patients with PD-L1 expression <1% had a relatively lower overall survival benefit
.
In the chemotherapy alone group, patients with PD-L1 expression <1% also had a longer median OS than those with PD-L1 expression ≥1%
.
Although observed in patients with PD-L1 expression <1%, the proportion of patients with duration of response (DoR) greater than one year was higher in patients treated with the nivolumab combination regimen than in the chemotherapy alone group However, whether it can ultimately be transformed into patients with PFS and OS benefits still needs further follow-up observation
.
Professor Xu Jianming pointed out: "In patients with PD-L1 expression <1%, the survival benefit of nivolumab combination therapy for patients is minimal, considering that patients with PD-L1 expression <1% are in the study of the overall patient population.
The proportion of nivolumab combined with chemotherapy is relatively small.
Whether the treatment regimen of nivolumab combined with chemotherapy can 'really' benefit PFS and OS in all patients remains to be further verified.
Be cautious
.
" At the same time, Professor Xu Jianming also gave his views on the future exploration of clinical predictors of patient prognosis
.
He said: "In recent years, clinicians have paid more attention to the exploration of tumor biomarkers, but there is a lack of research on the clinical influencing factors of non-biomarkers
.
According to previous clinical practice experience, in tumor Among patients with metastases, those with liver metastases may have a relatively small survival benefit from immunotherapy alone compared with those with metastases from other sites
.
" "In addition, the neutrophil-to-lymphocyte ratio (NLR) ) may also become an important predictor of patient prognosis
.
It
is well known that neutrophils and lymphocytes are human immune cells, so NLR is also very likely to affect the efficacy of immunotherapy on patients
.
"There is a related Meta-analysis [ 3] showed that NLR was associated with the prognosis of non-small cell lung cancer (NSCLC) receiving systemic therapy, and higher NLR before treatment was associated with worse PFS and OS after systemic therapy (including chemotherapy, immunotherapy, and targeted therapy) in patients related
.
Similar results were also observed in the ORIENT-2 study [4], which showed that patients with NLR <3 had significantly longer OS and PFS than patients with NLR ≥ 3 before and 6 weeks after treatment
.
At the same time, this study pointed out that NLR can reflect the differences in immune status during the occurrence and development of cancer, and can be used as a biomarker to predict the prognosis of patients with esophageal cancer receiving immune checkpoint inhibitor (ICI) combined with chemoradiotherapy
.
Figure 2 OS and PFS data of patients with NLR<3 and NLR≥3 before treatment and 6 weeks after treatment Compared with "no chemotherapy", "individualized" treatment may be the direction that should be paid more attention in clinical practice! In the CheckMate-648 study, the double-immunity combination therapy of nivolumab combined with ipilimumab not only sparked discussions among relevant researchers on patient screening, but also sparked concerns about the "de-chemotherapy" treatment for esophageal squamous cell carcinoma discussion
.
Professor Xu Jianming also explained his views on this: "For the treatment of esophageal cancer and gastric cancer, it is difficult to achieve 'de-chemotherapy', and there is still a long way to go in the future
.
Judging from the CheckMate-648 study alone The status of chemotherapy is still unshakable
.
" "With the continuous development of immunotherapy, new immune pathway therapeutic drugs are constantly being developed
.
In the
future, new immunotherapy drugs will be licensed to develop, which are compatible with existing immune checkpoint inhibitors (ICIs).
) drugs in combination may enable patients to obtain good survival benefits without chemotherapy
.
” But Professor Xu Jianming also emphasized, “Although there are currently a lot of related studies on immunotherapy drugs, there are also many The research is exploring the efficacy of different 'chemoimmune combined' regimens for the treatment of esophageal cancer, but more attention should be paid to the discussion of 'individualized' treatment for patients in the future
.
Since each patient's tumor microenvironment is different, the same treatment regimen has different therapeutic benefits for different patients.
It is only the exploration of 'individualized' treatment for different patients, and it is difficult to organize relevant clinical research at present
.
"Expert Profile Professor Xu Jianming Director, Professor, Doctoral Supervisor, Department of Digestive Oncology, Fifth Medical Center, PLA General Hospital, Vice Chairman of the Big Data and Real World Professional Committee of China Anti-Cancer Association, Vice Chairman of the Professional Committee of Oncology of China Research Hospitals, China Clinical Oncology References: 1.
Doki Y, Ajani JA, Xu J, et al.
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
N Engl J Med.
2022 Feb 3;386 (5): 449-462.
doi: 10.
1056/NEJMoa2111380.
PMID: 35108470.
https:// Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Gastric Cancer 20213.
Wang Z , Zhan P, Lv Y, et al.
Prognostic role of pretreatment neutrophil-to-lymphocyte ratio in non-small cell lung cancer patients treated with systemic therapy: a meta-analysis.
Transl Lung Cancer Res.
2019 Jun; 8(3) : 214-226.
doi: 10.
21037/tlcr.
2019.
06.
10.
PMID: 31367535; PMCID: PMC6626865.
https://tlcr.
amegroups.
com/article/view/29661/215514.
Xu J, Li Y, Fan Q, et al.
Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2).
Nat Commun.
2022 Feb 14;13(1):857 .
doi: 10.
1038/s41467-022-28408-3.
PMID: 35165274.
https://
Xu Jianming's detailed explanation of the CheckMate-648 study
.
China is a country with a high incidence of esophageal cancer.
According to the 2020 edition of the Global Cancer Statistical Report (GLOBOCAN 2020), there will be about 320,000 new cases of esophageal cancer in China in 2020, and about 300,000 people will die of esophageal cancer, of which more than 90% of the patients are Esophageal squamous cell carcinoma
.
For most esophageal cancer patients, radical resection cannot be performed at the time of diagnosis, few treatment options and poor prognosis are the biggest clinical features
.
The CheckMate 648 study[1] is a phase III, randomized, global clinical study evaluating the efficacy of nivolumab combined with chemotherapy or ipilimumab versus chemotherapy alone in the first-line treatment of advanced or metastatic esophageal squamous cell carcinoma
.
Recently, the latest data analysis of the study was published in the internationally renowned medical journal "New England Journal of Medicine"
.
The Medical Oncology Channel specially invited Professor Xu Jianming, the PI of the CheckMate-648 study in China and the director of the Division of Digestive Oncology at the Fifth Medical Center of the PLA General Hospital, to interpret and analyze the latest research data released by the CheckMate 648 study
.
Study Abstract▌ BackgroundThe first-line chemotherapy in patients with advanced esophageal squamous cell carcinoma was not effective in the past, and nivolumab showed better overall survival than chemotherapy in previously treated patients with advanced esophageal squamous cell carcinoma ( OS) benefit
.
▌ Research Methods The researchers randomly assigned 1:1:1 patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma to receive nivolumab combined with chemotherapy, nivolumab The primary endpoints of the study were OS and progression-free survival (PFS) as assessed by a blinded independent central review committee (BICR)
.
The study first stratified analysis in patients with PD-L1 expression ≥1%, and then in the overall patient population
.
▌ Research results A total of 970 patients were randomized.
After a minimum of 13 months of follow-up, in patients with PD-L1 expression ≥1% (15.
4 months vs 9.
1 months; HR=0.
54; P<0.
001 ) and all patients (13.
2 months vs 10.
7 months; HR = 0.
74; P = 0.
002), patients who received nivolumab plus chemotherapy had longer OS than those who received chemotherapy alone
.
In patients with PD-L1 expression ≥1% (13.
7 months vs 9.
1 months; HR=0.
64; P=0.
001) and in the overall population (12.
7 months vs 10.
7 months; HR=0.
78; P=0.
01) , patients receiving nivolumab combined with ipilimumab also had significantly better OS than chemotherapy alone
.
In patients with PD-L1 expression ≥1%, nivolumab plus chemotherapy improved PFS compared with chemotherapy alone (HR=0.
65; 98.
5% CI, 0.
46-0.
92; P=0.
002), while nivolumab There was no significant improvement in PFS in patients in the utimab combined with ipilimumab group
.
The incidence of grade 3 and 4 treatment-related adverse events was 47%, 32%, and 36% in the nivolumab plus chemotherapy group, the nivolumab plus ipilimumab group, and the chemotherapy alone group, respectively
.
▌ Conclusion Compared with chemotherapy alone, nivolumab combined with chemotherapy or ipilimumab in the first-line treatment of patients with advanced esophageal squamous cell carcinoma significantly prolongs the OS, and no new safety signal was found
.
What was the purpose of the trial design of the CheckMate 648 study? In the past decades, the first-line treatment of metastatic esophageal cancer has been mainly chemotherapy, and the prognosis of patients is usually poor, and the OS is generally less than 12 months
.
With the advent of the immune era, the treatment of esophageal cancer has gradually shifted from chemotherapy alone to immunotherapy combined with chemotherapy or double immune combined therapy
.
The "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Gastric Cancer 2021"[2] has even listed nivolumab combined with chemotherapy as the first-line treatment for patients with advanced metastatic gastric cancer
.
In the CheckMate-648 study, researchers randomly assigned patients with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma in a 1:1:1 ratio to receive nivolumab Primary endpoints of the study included OS and progression-free survival (PFS), as determined by a blinded independent central review, in combination with chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone
.
The researchers analyzed the PFS and OS of patients with PD-L1 expression ≥1% and all patients by stratified detection of patients
.
In this regard, Professor Xu Jianming said: "The CheckMate-648 study was designed for the following two reasons
.
First, at the beginning of the study design, researchers could not predict the efficacy of immunotherapy for patients with esophageal squamous cell carcinoma.
Research data show that patients with positive PD-L1 expression are more likely to benefit, so the patient's PD-L1 expression level is used as a stratification factor to analyze the efficacy data of patients
.
"Secondly, chemotherapy was the first-line standard treatment for such patients before immunotherapy, and according to previous clinical research data and practical experience, patients with esophageal squamous cell carcinoma usually have better survival after receiving immunotherapy.
To explore whether immunotherapy combined with chemotherapy can improve the survival benefit of such patients, and whether the double-immunity combined treatment plan can achieve the purpose of clinical 'de-chemotherapy', three groups of patients were given nivolumab combined with chemotherapy, nivolumab combined with chemotherapy, and nivolumab.
Antibiotic combined with ipilimumab and chemotherapy alone
.
"Can immunotherapy combined with chemotherapy really benefit all patients? According to the research data reported in this report, compared with the chemotherapy group alone, the treatment regimen of nivolumab combined with chemotherapy can improve the PFS and OS of patients.
Significant benefit, while the combination of nivolumab and ipilimumab can benefit OS in all patients, but only benefit PFS in patients with PD-L1 expression ≥1%
.
Figure 1 CheckMate Regarding the PFS and OS data of patients in the -648 study, Professor Xu Jianming said: "In clinical practice, the applicable population of immunotherapy combined with chemotherapy is relatively wider, and the 'de-chemotherapy' regimen of double immunity combined needs to be considered for the applicable population.
filter
.
The main reason for the difference in the efficacy of the two treatment regimens in different populations may be due to the differences in the tumor immune microenvironment in the final analysis
.
"Although the CheckMate-648 study showed that the combination of nivolumab with chemotherapy or ipilimumab resulted in an OS benefit in all patients
.
However, the researchers pointed out that compared with patients with PD-L1 expression ≥1% In comparison, patients with PD-L1 expression <1% had a relatively lower overall survival benefit
.
In the chemotherapy alone group, patients with PD-L1 expression <1% also had a longer median OS than those with PD-L1 expression ≥1%
.
Although observed in patients with PD-L1 expression <1%, the proportion of patients with duration of response (DoR) greater than one year was higher in patients treated with the nivolumab combination regimen than in the chemotherapy alone group However, whether it can ultimately be transformed into patients with PFS and OS benefits still needs further follow-up observation
.
Professor Xu Jianming pointed out: "In patients with PD-L1 expression <1%, the survival benefit of nivolumab combination therapy for patients is minimal, considering that patients with PD-L1 expression <1% are in the study of the overall patient population.
The proportion of nivolumab combined with chemotherapy is relatively small.
Whether the treatment regimen of nivolumab combined with chemotherapy can 'really' benefit PFS and OS in all patients remains to be further verified.
Be cautious
.
" At the same time, Professor Xu Jianming also gave his views on the future exploration of clinical predictors of patient prognosis
.
He said: "In recent years, clinicians have paid more attention to the exploration of tumor biomarkers, but there is a lack of research on the clinical influencing factors of non-biomarkers
.
According to previous clinical practice experience, in tumor Among patients with metastases, those with liver metastases may have a relatively small survival benefit from immunotherapy alone compared with those with metastases from other sites
.
" "In addition, the neutrophil-to-lymphocyte ratio (NLR) ) may also become an important predictor of patient prognosis
.
It
is well known that neutrophils and lymphocytes are human immune cells, so NLR is also very likely to affect the efficacy of immunotherapy on patients
.
"There is a related Meta-analysis [ 3] showed that NLR was associated with the prognosis of non-small cell lung cancer (NSCLC) receiving systemic therapy, and higher NLR before treatment was associated with worse PFS and OS after systemic therapy (including chemotherapy, immunotherapy, and targeted therapy) in patients related
.
Similar results were also observed in the ORIENT-2 study [4], which showed that patients with NLR <3 had significantly longer OS and PFS than patients with NLR ≥ 3 before and 6 weeks after treatment
.
At the same time, this study pointed out that NLR can reflect the differences in immune status during the occurrence and development of cancer, and can be used as a biomarker to predict the prognosis of patients with esophageal cancer receiving immune checkpoint inhibitor (ICI) combined with chemoradiotherapy
.
Figure 2 OS and PFS data of patients with NLR<3 and NLR≥3 before treatment and 6 weeks after treatment Compared with "no chemotherapy", "individualized" treatment may be the direction that should be paid more attention in clinical practice! In the CheckMate-648 study, the double-immunity combination therapy of nivolumab combined with ipilimumab not only sparked discussions among relevant researchers on patient screening, but also sparked concerns about the "de-chemotherapy" treatment for esophageal squamous cell carcinoma discussion
.
Professor Xu Jianming also explained his views on this: "For the treatment of esophageal cancer and gastric cancer, it is difficult to achieve 'de-chemotherapy', and there is still a long way to go in the future
.
Judging from the CheckMate-648 study alone The status of chemotherapy is still unshakable
.
" "With the continuous development of immunotherapy, new immune pathway therapeutic drugs are constantly being developed
.
In the
future, new immunotherapy drugs will be licensed to develop, which are compatible with existing immune checkpoint inhibitors (ICIs).
) drugs in combination may enable patients to obtain good survival benefits without chemotherapy
.
” But Professor Xu Jianming also emphasized, “Although there are currently a lot of related studies on immunotherapy drugs, there are also many The research is exploring the efficacy of different 'chemoimmune combined' regimens for the treatment of esophageal cancer, but more attention should be paid to the discussion of 'individualized' treatment for patients in the future
.
Since each patient's tumor microenvironment is different, the same treatment regimen has different therapeutic benefits for different patients.
It is only the exploration of 'individualized' treatment for different patients, and it is difficult to organize relevant clinical research at present
.
"Expert Profile Professor Xu Jianming Director, Professor, Doctoral Supervisor, Department of Digestive Oncology, Fifth Medical Center, PLA General Hospital, Vice Chairman of the Big Data and Real World Professional Committee of China Anti-Cancer Association, Vice Chairman of the Professional Committee of Oncology of China Research Hospitals, China Clinical Oncology References: 1.
Doki Y, Ajani JA, Xu J, et al.
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
N Engl J Med.
2022 Feb 3;386 (5): 449-462.
doi: 10.
1056/NEJMoa2111380.
PMID: 35108470.
https:// Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Gastric Cancer 20213.
Wang Z , Zhan P, Lv Y, et al.
Prognostic role of pretreatment neutrophil-to-lymphocyte ratio in non-small cell lung cancer patients treated with systemic therapy: a meta-analysis.
Transl Lung Cancer Res.
2019 Jun; 8(3) : 214-226.
doi: 10.
21037/tlcr.
2019.
06.
10.
PMID: 31367535; PMCID: PMC6626865.
https://tlcr.
amegroups.
com/article/view/29661/215514.
Xu J, Li Y, Fan Q, et al.
Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2).
Nat Commun.
2022 Feb 14;13(1):857 .
doi: 10.
1038/s41467-022-28408-3.
PMID: 35165274.
https://
