Professor Huang Jing: O+ chemotherapy and O+Y each show "food" power, CheckMate-648 sets two new standards for the first-line esophageal squamous cell carcinoma

*For medical professionals' reference only, regardless of the level of PD-L1 expression, nivolumab combined with chemotherapy or ipilimumab can bring significant OS benefits
.

China is a country with a high incidence of esophageal cancer.
In 2020, there will be about 320,000 new cases of esophageal cancer in China, and about 300,000 people will die of esophageal cancer [1]
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2021 is a "harvest year" for esophageal cancer immunotherapy; among them, the iconic CheckMate-648[2] study not only achieved a significant benefit in the overall survival (OS) of the first-line esophageal squamous cell carcinoma, but also achieved significant benefits.
The "de-chemotherapy" program of wulimumab combined with ipilimumab (O+Y) is the first success in this field, and it is expected to contribute two new standards of "O+ chemotherapy" and "O+Y" to this field at one time
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Coinciding with the CSCO conference in 2021, the Medical Oncology Channel had the honor to invite Professor Huang Jing from the Cancer Hospital of the Chinese Academy of Medical Sciences to give an in-depth interpretation of the progress and clinical application of advanced esophageal cancer immunotherapy
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Professor Huang Jing Deputy Director of Internal Medicine, Cancer Hospital of Chinese Academy of Medical Sciences, Director of Internal Medicine, Cancer Hospital of Chinese Academy of Medical Sciences, Shenzhen Hospital, Doctor of Medicine, Professor, Doctoral Supervisor, Deputy Chairman and Secretary-General of CSCO Esophageal Cancer Expert Committee, Director, Chinese Association of Clinical Oncology (CSCO) Vice-Chairman of the Cancer Rehabilitation Branch of the Society of Geriatrics and GeriatricsDeputy Chairman of the Colorectal Tumor Professional Committee of the Beijing Medical Doctor Association Deputy Chairman of the Committee, Vice Chairman of the Gastric Cancer Group of the Cancer Prevention and Treatment Expert Committee of the Cross-Strait Medical and Health Exchange Association, Director of the Beijing Xisike Clinical Oncology Research Foundation, Member of the Beijing Chaoyang District Youth Federation, Member of the Editorial Board of the Chinese Electronic Journal of Colorectal Diseases, Professor Huang Jing, member of the editorial board of the Journal of Cancer Progress and deputy editor-in-chief of the Chinese Journal of Biochemical Pharmaceutics, pointed out that esophageal cancer is a tumor that is relatively sensitive to immunotherapy, which may be related to its pathological and genetic characteristics
.

In the literature published in Nature in the early years, the frequency of somatic mutations in different cancers was tested, and it was found that the incidence of somatic mutations in esophageal cancer was higher
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In recent years, breakthroughs have been made in immunotherapy for esophageal cancer, and 2021 will be even more advanced.
The Phase III study represented by CheckMate-648 has lightened the hope of first-line immunotherapy for esophageal cancer
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Among the many studies, when it comes to the reasons why the CheckMate-648 study is particularly concerned, Professor Huang Jing believes that there are three main factors: first, CheckMate-648 is the largest global study in the field of esophageal squamous cell carcinoma; secondly, the CheckMate-648 study A total of 3 cohorts are included.
In addition to the conventional chemotherapy control group and immune combination chemotherapy, it also includes the double-immune "de-chemotherapy" cohort.
Finally, the two immunotherapy groups in the CheckMate-648 study both achieved the results regardless of the PD-L1 expression level.
OS positive result
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CheckMate -648 study: The sample size is the largest so far, and for the first time to evaluate the efficacy of "de-chemotherapy" in the first-line treatment of esophageal squamous cell carcinoma.
The efficacy and safety of nivolumab combined with chemotherapy (O+ chemotherapy group) or nivolumab combined with ipilimumab (O+Y group) in patients with advanced unresectable or metastatic esophageal squamous cell carcinoma
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Professor Huang Jing pointed out that in the first-line treatment of advanced esophageal squamous cell carcinoma based on immune checkpoint inhibitors, CheckMate-648 is by far the largest randomized, global phase III study, including China and other countries from all over the world.
970 patients in many countries and regions
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Not only that, it is currently the only phase III clinical study evaluating the dual-immunity (PD-1 inhibitor + CTLA-4 inhibitor) "de-chemotherapy" regimen for the first-line treatment of advanced esophageal squamous cell carcinoma, which has attracted widespread attention
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The CheckMate -648 study was designed to benefit the entire population of OS.
The two major immunotherapeutic schemes demonstrate the "food" power of the CheckMate -648 study.
The results of the CheckMate -648 study showed that among all randomized populations, the median OS of the O+ chemotherapy group compared with the chemotherapy alone group (13.
2 Month vs.
10.
7 months, HR 0.
74, p=0.
0021) was significantly prolonged, and the objective response rate (47% vs 27%) was higher, suggesting that O+ chemotherapy can bring benefits to the entire population regardless of PD-L1 expression
.

O+ chemotherapy group and chemotherapy alone group OS/ORR/DoR results of the whole population The O+Y group also observed significant benefits compared with chemotherapy alone group, and it is also not limited by PD-L1 level
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In all randomized populations, the median OS of the O+Y group was 12.
8 months, which was significantly better than the 10.
7 months of the chemotherapy alone group (HR 0.
78, p=0.
0110); the ORR was 28%, compared with the chemotherapy alone group (27% ) Is equivalent; the median duration of response (DoR) is 11.
1 months, which is more than 1.
5 times that of the chemotherapy alone group (7.
1 months)
.

The OS/ORR/DoR results of the whole population in the O+Y group and the chemotherapy alone group "There is no doubt about the OS/ORR/DoR results of immune combined chemotherapy compared with chemotherapy alone
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But what is even more commendable is that in the CheckMate-648 study, regardless of PD- Regardless of the expression level of L1, the O+Y group has a significant OS benefit compared with the chemotherapy alone group; and the median DoR of the O+Y group is longer, reaching 11.
1 months in all populations.
It is the chemotherapy alone group (7.
1 It is 1.
5 times higher than that of the tumor PD-L1 expression level of 1% or more (11.
8 months vs 5.
7 months) in the patient population with tumor PD-L1 expression level ≥ 1%
.

"Professor Huang Jing pointed out that dual immunotherapy not only achieved significant gains in OS It is beneficial, and can bring long-term relief, and the effective rate is equivalent to chemotherapy
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The above results suggest that some patients with advanced esophageal squamous cell carcinoma can get rid of chemotherapy in the first-line treatment stage.
In the future, the advantages of this program may be further explored to benefit the population, so that more patients can avoid chemotherapy
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It is well tolerated, and the "de-chemotherapy" program guarantees the quality of life of patients.
In the CheckMate-648 study, the overall tolerance of immune combination chemotherapy and dual immunotherapy was good, and no unexpected adverse events were found
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Surprisingly, the O+Y group had a lower incidence of grade 3-4 adverse events than the chemotherapy alone group (32% vs 36%)
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In this regard, Professor Huang Jing said that the overall adverse events of pure immunotherapy are less than that of chemotherapy, and the toxicity spectrum of the two is different
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Toxic reactions in the dual immunotherapy group were more reflected in immune-related adverse events, while adverse events in chemotherapy were mainly bone marrow suppression and gastrointestinal reactions
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Overall, dual immunotherapy is better tolerated than chemotherapy-containing regimens
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Since the adverse reactions of chemotherapy often have a greater impact on the quality of life of patients, the future "de-chemotherapy" program has a broad application prospect
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Immunotherapy is blooming at multiple points.
The first-line esophageal squamous cell carcinoma/adenocarcinoma and postoperative auxiliary "full coverage" are also in the field of advanced esophageal cancer.
Professor Huang Jing said that based on the results of the previous CheckMate-649 study, nivolumab is combined Chemotherapy has been approved domestically for the first-line treatment of gastric cancer, esophageal adenocarcinoma, and gastroesophageal junction cancer; coupled with the positive results of the CheckMate-648 study, the benefiting population of nivolumab has covered all pathological types of upper gastrointestinal tract , The first-line treatment of cancer at the diseased site has brought new options for more patients
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In addition, Professor Huang Jing mentioned that CheckMate-577 is also a landmark study in the field of esophageal cancer.
Patients with esophageal cancer who have undergone simultaneous radiotherapy and chemotherapy and sequential surgical resection, but still have pathological residues, should be treated with nivolumab as adjuvant therapy.
Comparing placebo to disease-free survival (DFS) doubles
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This result suggests that even for patients with esophageal cancer who have received thorough local treatment, improving their immune status is still of great value
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CheckMate -577 not only lays a theoretical basis for the follow-up exploration in this field, but also provides a new clinical treatment model
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In the era of esophageal cancer immunity, clinical application requires comprehensive consideration of multiple factors.
As immunotherapy continues to "conquer the city" in the field of esophageal cancer, for the future clinical application of immunotherapy, Professor Huang Jing pointed out that the following aspects should also be paid attention to: ● First, PD-L1 does not completely predict the efficacy
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In the CheckMate -648 study, PD-L1 positive patients benefited more, but all randomized patients who received immunotherapy regardless of PD-L1 expression achieved significant benefits in OS
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In the future, more exploration is needed for predicting the efficacy of immunotherapy
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● Second, factors such as the choice of combined chemotherapy and the duration of treatment still need to be considered
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The CheckMate-648 study used a weaker four-week FP regimen, but it achieved a "miraculous effect" after combining with nivolumab.
The ORR was greatly improved compared with chemotherapy alone, which increased by 33% (53% vs.
20%), an increase of 20% (47% vs 27%) in the entire population, which is greater than similar studies, suggesting that when performing immunotherapy, it is necessary to pay attention to factors such as the intensity and frequency of the chemotherapy regimen to achieve 1+1≥2 The effect
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● Third, further pursue individualized treatment
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"When choosing a treatment mode, we should choose the right medicine and the right combination according to the specific situation of the patient
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" In addition, the occurrence of adverse reactions of the patient should also be paid attention to in the treatment, so as to adjust in time
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Because patients with esophageal squamous cell carcinoma have the habit of smoking and drinking, there is a difference in tolerance to treatment compared with other cancer patients, so special attention is needed
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Reference: [1]WHO, Globocan 2020 China.
Available from http://gco.
iarc.
fr/today/data/factsheets/populations/160-china-fact-sheets.
pdf.
[2]Chau I, Doki Y , Ajani JA, et al.
Nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: First results of the CheckMate 648 study.
2021 ASCO Annual Meeting.
Abstract 4001.
*This article is for use only Providing scientific information to medical professionals does not represent the views of this platform