Prof. Feng Wang: ORIENT-15 is featured in BMJ Magazine!

Esophageal cancer is one of the common malignant tumors of upper gastrointestinal tract in China.
According to statistics, the incidence and fatality rate of esophageal cancer in China rank the sixth and fourth among all malignant tumors, which seriously endangers the health of the Chinese people
.

Especially in patients with advanced esophageal cancer, clinical treatment methods are limited
.

In recent years, the rapid development of immunotherapy has brought new treatment modes for advanced esophageal cancer
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In this regard, Yimaitong sincerely invites Professor Wang Feng from the Oncology Department of the First Affiliated Hospital of Zhengzhou University to conduct an exclusive interview to discuss the survival benefits of patients with advanced esophageal cancer and the future direction of immunotherapy around the ORIENT-15 study
.

Prof.
Wang Feng, Chief Physician, Professor, Doctoral Supervisor, Chief Physician, Professor and Doctoral Supervisor of the First Ward of Oncology Department of the First Affiliated Hospital of Zhengzhou University, Director of the Chinese Society of Clinical Oncology (CSCO), Director of the Chinese Branch of the International Society of Esophageal Diseases (CSDE), Chinese Society of Clinical Oncology (CSCO) for esophageal cancer, Member of Gastric Cancer Special Committee Member of Chinese Society of Clinical Oncology (CSCO) Liver Cancer and Pancreatic Cancer Special Committee Member of National Cancer Center Esophageal Cancer Quality Control Expert Committee Member of Chinese Anti-Cancer Association Esophageal Cancer, Sarcoma, International Medical Exchange Special Committee Member of Beijing Cancer Prevention Association Vice-chairman of the Special Committee on Esophageal Cancer and Gastric Cancer, Member of the Standing Committee of the Henan Provincial Medical Association Oncology Branch of the Esophageal Cancer Group, Member of the Standing Committee of the Oncology Branch, Director of the Henan Anti-Cancer Association, Chairman of the Sarcoma Specialized Committee, and Vice-chairman of the Pancreatic Cancer Specialized Committee Vice Chairman of Henan Anti-Cancer Association Tumor Drug Clinical Research Committee, Chairman of Youth Committee Vice Chairman of Henan Anti-Cancer Association Esophageal Cancer Committee, Chairman of Youth Committee Henan Provincial Health Science and Technology Leading Talent, Visiting Scholar of Georgetown University, USA 2020 Outstanding Contribution Award of "The People's Good Doctor Golden Camellia Project" (Esophageal Cancer Field) Distinguished Professor of Henan University of Science and Technology, Deputy Editor-in-Chief of "Esophageal Diseases", "Chinese Journal of Oncology", "Journal of Zhengzhou University" Reviewer Yimaitong: ORIENT-15 is the first international multi-center large-scale phase III study in the field of esophageal cancer initiated by domestic experts, and it has been selected into the ESMO 2021 list of 11 breakthrough innovations with significance for changing clinical practice worldwide
.

The full text of the study is published in the BMJ, one of the world's leading medical journals.
What does this mean for five first-line esophageal cancer immunotherapy studies with published data? At the 2021 ESMO conference, Professor Wang Feng presented the ORIENT-15 research in the form of an oral presentation, and was selected as 11 breakthrough innovation researches
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Eleven studies were selected by the ESMO Working Group of Practicing Oncologists from hundreds of research reports published at the 2021 ESMO Congress that have the potential to change future clinical practice, the ORIENT-15 study was the only selected study in esophageal cancer The importance of this research is self-evident, and it is also the only selected international multi-center research led by Chinese experts
.

Now the ORIENT-15 research results have been published in the world-renowned medical journal "British Medical Journal"¹ (2020 impact factor 39.
89), which means that the global research initiated by Chinese experts has reached the international first-class level, which is the result of the joint efforts of many Chinese experts It is also a major victory in the field of medical research in China, and will surely bring the gospel of life extension to the majority of patients with advanced esophageal cancer
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Yimaitong: As one of the PIs of the ORIENT-15 study, what are the main advantages of the ORIENT-15 study from a research perspective? Professor Wang Feng said that the ORIENT-15 study is impressive in terms of study design, efficacy and safety
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In terms of research design, ORIENT-15 is a randomized controlled, international multicenter study with a more comprehensive coverage of the subject population
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At the same time, researchers can choose TP (paclitaxel + cisplatin) or CF (cisplatin + 5-FU) as the basic chemotherapy regimen according to the clinical practice in different regions, which is close to the clinical practice and has more universality
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The results of this study successfully met the dual study endpoints, namely overall survival (OS) in the total population and the CPS ≥ 10 population
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Sintilimab combined with chemotherapy showed significant advantages in terms of OS, progression-free survival (PFS), objective response rate (ORR), and safety
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First, the ORIENT-15 study had the most obvious OS benefit
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ORIENT-15 showed an overall population OS improvement of 4.
2 months (16.
7 months vs 12.
5 months), the best result among all phase III studies with high data maturity
.

JUPITER-06 also released overall survival data not long ago, but JUPITER-06 overall survival data is not mature enough, the number of deaths is only 27.
2%², and longer-term follow-up may be required to determine the final survival benefit
.

Second, the ORIENT-15 study showed that the OS benefit was not affected by the expression level of PD-L1, and benefited both in the subgroups of patients with CPS ≥ 10 and CPS < 10
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Compared with the other four phase III studies, the benefit was not obvious in patients with low PD-L1 expression
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In terms of PFS, the 6-month PFS rate of sintilimab combined with chemotherapy compared with chemotherapy group was 63% vs 49%, and the 1-year PFS rate was 38% vs 15%, respectively
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That is to say, after 1 year of treatment, nearly 40% of patients are still in a disease-free state, which is almost double that of the chemotherapy group
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In the ORIENT-15 study, based on the TP/CF regimen, sintilimab increased the effective rate by more than 20%, reaching 66.
1%, indicating that the combination of immunotherapy and chemotherapy played a role of "1+1>2", and the ORR of The lift was also the highest of the five studies
.

In addition, in the ORIENT-15 study, the overall safety of sintilimab combined with chemotherapy group was controllable, and the incidence of treatment-related adverse events of grade 3 or above was similar between the two groups (60% vs 55%), and the incidence of adverse reactions of grade 3 or above Low, satisfactory, this program has brought us a great surprise, which is of great significance for guiding the first-line treatment of esophageal cancer mainly in squamous cell carcinoma in China
.

Figure 1: OS of sintilimab combined with chemotherapy (TP/CF) in ITT population and PD-L1 CPS ≥ 10 Figure 2: Sintilimab combined with chemotherapy (TP/CF) in ITT population and PD-L1 PFS Yimaitong for CPS≥10: You just mentioned that the ORIENT-15 study showed the benefit of the whole population, so do you think that all Chinese patients with esophageal cancer need to detect PD-L1 expression level? Professor Wang Feng said that regardless of the level of PD-L1 expression, sintilimab combined with chemotherapy benefited both the whole population (ITT population) and those with positive PD-L1 expression
.

This may be related to the selected population and chemotherapy regimens.
Most of the Chinese esophageal cancers in the study are squamous cell carcinomas, which are more likely to benefit from the combination of immunotherapy and chemotherapy.
Therefore, in the ORIENT-15 study, the combination of sintilimab combined with TP regimen chemotherapy is not effective.
Patients with negative PD-L1 expression are also effective, so PD-L1 testing can be considered as a non-essential item
.

Yimaitong: The 2022 CSCO guidelines recommend sintilimab combined with chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma (the current recommendation level is level II recommendation, class 1A evidence
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) Do you think sintilimab combined with chemotherapy can be selected , What is the significance for guiding the treatment of advanced esophageal cancer? Professor Wang Feng’s CSCO guidelines are guidelines with Chinese characteristics formulated with reference to international guidelines and fully considering Chinese patient data, treatment needs and drug availability.
It is also an authoritative guideline for Chinese clinical oncologists.
Its recommended model not only considers clinical research data The scientific reliability of the drug will also take into account the approval and inclusion of the drug in the National Medical Insurance Drug List
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The inclusion of sintilimab was also based on the release of the ORIENT-15 study
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It is an international multi-center, large-scale phase III RCT study with high-level evidence and scientifically reasonable research design.
It is globally recognized and ranks among the world's first-class research
.

The results of the study showed that the treatment regimen for first-line treatment of advanced esophageal cancer can bring a clear survival benefit, and it is safe and tolerated, so the CSCO esophageal cancer guidelines give a class II recommendation (category 1A evidence)
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Sintilimab has not been approved by the National Medical Products Administration (NMPA) and cannot be listed as a level I recommendation for the time being, but we believe that sintilimab will soon be approved for esophageal cancer indications and is expected to be listed as a level I recommendation next year
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As we all know, China is a big country with esophageal cancer in the world.
The number of new cases every year accounts for about half of the total number of patients in the world³, and a large part of esophageal cancer patients come from rural areas, and the economic burden of treating esophageal cancer is heavy
.

As one of the most cost-effective immune checkpoint inhibitors, sintilimab can be recommended by the CSCO guidelines.
In addition to providing new options for clinicians, it also greatly reduces the treatment burden of many esophageal cancer patients
.

It is believed that in the near future, with the approval of sintilimab for first-line treatment of esophageal cancer and inclusion in medical insurance, it will benefit more Chinese patients
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Yimaitong: Sintilimab combined with chemotherapy has achieved such a good therapeutic effect in the first-line treatment of advanced esophageal cancer.
Do you think that sintilimab has application prospects in the neoadjuvant treatment stage of esophageal cancer? Professor Wang Feng immunotherapy has become the main treatment method for advanced esophageal cancer, such as immune monotherapy as the second-line standard treatment, immune combination chemotherapy as the first-line standard treatment, and immunotherapy also plays a major role in the later line
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Given the high response rate of ORIENT-15 in advanced esophageal cancer, early application of immunotherapy in the neoadjuvant treatment stage may achieve better therapeutic effects, especially in patients with better performance status who have a better immune response basis
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Immune neoadjuvant therapy can improve the pathological response (pCR) rate and R0 resection rate of patients, which in turn translates into survival benefit
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At present, a number of studies on immune neoadjuvant therapy are being explored.
Sintilimab combined with chemotherapy has also been explored in small sample studies in the neoadjuvant therapy stage of esophageal squamous cell carcinoma
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The KEEP-G 03 study of sintilimab combined with liposomal paclitaxel + cisplatin + S-1 suggests that this regimen can achieve a pCR rate of 26.
7%, a major pathological response (MPR) rate of 53.
3%, and an R0 of 100%.
In terms of resection rate, the incidence of grade 3-4 TRAE was only 35.
3%
.

The preliminary results of the study show that sintilimab combined with neoadjuvant chemotherapy has a considerable pCR rate, a high R0 resection rate, no significant increase in adverse events and mortality, and no delay in surgery.
It is a direction worthy of continued exploration and has promising applications.
prospects
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Reference 1.
Lu Z, Wang J, Shu Y, Liu L, et al.
ORIENT-15 study group.
Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15) : multicentre, randomised, double blind, phase 3 trial.
BMJ.
2022 Apr 19;377:e068714.
2.
Yamamoto S, Kato K.
JUPITER-06 establishes immune checkpoint inhibitors as essential first-line drugs for the treatment of advanced esophageal squamous cell carcinoma.
Cancer Cell.
2022 Mar 14;40(3):238-240.
3.
He Jie, Kang Xiaozheng, Qin Jianjun, et al.
Chinese Expert Consensus on Perioperative Immunotherapy for Esophageal Cancer (2021)[J].
Zhonghua Chest Electronic Journal of Surgery, 2022, 9(1):11.
4.
Gu Y, Chen X, Wang D, et al.
A study of neoadjuvant sintilimab combined with triplet chemotherapy of lipo-paclitaxel, cisplatin, and S-1 for resectable esophageal squamous cell carcinoma(ESCC).
Annals of Oncology (2020) 31 (suppl_6): S1287-S1318.
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