Professor Shen Lin: Xindilizumab successfully won the first-line indications for esophageal squamous cell carcinoma, and the high-quality ORIENT-15 highlighted the extraordinary "food" power

This article is from Tumor Information

On June 20, 2022, sindilizumab combined chemotherapy was officially approved by the State Drug Administration (NMPA) for the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma. This approval is based on the good results of the global multicenter, randomized, controlled, double-blind Phase III ORIENT-15 study[1]. ORIENT-15 is the first international multi-center clinical trial of first-line immunization for the treatment of esophageal squamous cell carcinoma led by Chinese experts and benefited the whole population, and the study was selected as the "2021 ESMO Breakthrough Study with the Potential to Change Clinical Practice", becoming the only selected study in China with outstanding performance. Professor Shen Lin of Peking University Cancer Hospital, a special guest of ORIENT-15 Research Leading PI, was invited to talk about the highlights and value of ORIENT-15 research and the new development trend of immunotherapy for esophageal cancer based on the treatment status of esophageal cancer in China.

Orient-15 research is based in China, looking at the world, the survival benefit of sindilizumab combined with chemotherapy has reached a record high

Professor Shen Lin: Esophageal cancer is a high-incidence tumor in the mainland, and the 2020 global cancer statistics report shows that the number of new and dead cases of esophageal cancer in China accounts for more than half of the world's [2]; This also means that if the problem of esophageal cancer in China can be solved, the problem of esophageal cancer in the world can be solved. ORIENT-15 is a multicenter Phase III clinical study with a global perspective on esophageal cancer in China.

At ESMO 2021, the ORIENT-15 study[1] presented its findings in the form of an oral presentation, and the clinical benefits of sindilizumab combined with chemotherapy first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma were significant. The chemotherapy regimen in this study is a chemotherapy compatibility regimen selected by the researchers themselves, including the cisplatin + paclitaxel regimen commonly used in Chinese clinical practice, and the cisplatin + 5-fluorouracil regimen commonly used abroad, that is, whether it is based on the basics of foreign clinical practice or the basics of clinical practice in China, both chemotherapy regimens have obtained very good efficacy. Compared with placebo combined chemotherapy, sindilizumab combined chemotherapy increased the absolute value of patient survival (OS) by more than 4 months (16.7 months vs 12.5 months, HR= 0.63) for the first time in the world, which is a record high in the current clinical study of PD-1 monoclonal antibody first-line treatment of advanced esophageal squamous cell carcinoma, and all patients have benefited significantly regardless of PD-L1 expression levels. This gives us full confidence in the use of sindilizumab plus chemotherapy regimens in the first-line treatment of esophageal squamous cell carcinoma.

As an international multicenter Phase III clinical study, the ORIENT-15 study will have a very important impact on both national and international clinical practices in the first-line treatment of esophageal cancer, and the results of the study were published in the British Medical Journal (BMJ) in April[3], indicating that the study and its good findings have been globally recognized; In addition, at the just-concluded Chinese Society of Clinical Oncology (CSCO) Guidelines Meeting in April, based on good data from the ORIENT-15 study, the Xindili monoclonal antibody combination chemotherapy regimen was successfully listed in the CSCO Esophageal Cancer Diagnosis and Treatment Guidelines (2022 Edition) with Class 1A evidence (Grade II recommendation) [4], becoming the standard first-line treatment for advanced esophageal cancer. In fact, more importantly, sindilizumab combined with chemotherapy has actually changed the prognosis of first-line treatment in patients with advanced esophageal squamous cell carcinoma.

Orient-15 studies four major characteristics, which effectively highlights the quality and level of China's leading international research

Professor Shen Lin: Although the mainland is a country with a high incidence of digestive system tumors, there are few international studies on digestive system tumors carried out by Chinese as leading PI. The ORIENT-15 study selected patients with esophageal squamous cell carcinoma as the study population because squamous cell carcinoma accounts for more than 95% of esophageal cancer cases in mainland China [2,5,6] and is also a high-incidence type worldwide, a design that has been recognized by international peers.

The ORIENT-15 study has the following characteristics: First, the selected population is the first international clinical study for patients with esophageal squamous cell carcinoma; Second, the research takes into account the standards and needs of domestic and international clinical practice and is in line with clinical practice; Third, after nearly two decades of development, the international multi-center clinical research carried out by the mainland can ensure that the conclusions obtained are reliable in the process of being supervised by the US Food and Drug Administration (FDA); Fourth, the analysis and summary of research data is equally important. None of the above four aspects are indispensable, and if any of them are ignored, it is impossible for us to present such a high-quality clinical study to the world.

Multi-factor combination of considerations to facilitate immunization in combination chemotherapy regimen decisions

Prof. Lin Shen: In clinical practice, when choosing sindilimab or other PD-1 monoclonal antibodies combined with chemotherapy, the factors to be considered include pathological type, stage, patient physical condition, and PD-L1 expression level. For patients with poor physical condition, the immunotherapy regimen needs to be adjusted, including dose adjustment, and whether to combine chemotherapy. PD-L1 expression levels are very important biomarkers, and in clinical treatment practice it can also be found that PD-L1 high expression is closely related to the efficacy of immunotherapy combined with chemotherapy. In addition, there are special cases, such as our finding in translational studies that immunotherapy is not effective in patients with esophageal cancer with multiple gene amplifications, especially those with high amplification copies. For such patients, consideration needs to be given to whether they can benefit from immunotherapy; If the assessment does not benefit, we will choose an individualized treatment regimen such as chemoradiotherapy and chemotherapy that is more suitable for the patient.

Challenges and opportunities coexist, and the prospect of immunotherapy for esophageal cancer entering the perioperative period is promising

Prof. Lin Shen: Although immunotherapy has achieved significant efficacy in the treatment of advanced esophageal cancer, not all patients can benefit from immunotherapy. Therefore, the first challenge facing the field of immunotherapy for esophageal cancer is to select sensitive populations and screen patients by biomarkers such as PD-L1 expression and gene copy number load, such as high gene copy number load can be used as an exclusion criterion for immunotherapy.

The second is to explore the second-line and post-line treatment options after PD-1 monoclonal antibody resistance, which is currently in full swing, including targeted therapy for EGFR amplification, as well as cell cycle regulation, epimodulation and anti-angiogenesis therapy, etc. Whether these treatment strategies can benefit patients after PD-1 monoclonal antibody therapy failure needs to be further explored.

Third, although some early and medium-term patients can be cured by radiation therapy or surgical treatment, and immunotherapy can further prolong the survival of patients with advanced esophageal cancer, the overall cure rate of esophageal cancer is still very low. The "Healthy China 2030" program proposes a goal of increasing the 5-year survival rate of cancer patients by 15%. To achieve this goal, a combination of treatments should be used for patients with early, mid-, and locally advanced stages, and perioperative immunotherapy may significantly improve the 5-year survival and cure rates of these patients. I believe that immunotherapy will bring opportunities for the cure of esophageal cancer, and I also hope that more perioperative immunotherapy research on esophageal cancer can be carried out at home and abroad in the future, including the combination of immunity and radiotherapy, etc. At present, some phase II studies show that immunotherapy has great potential in this regard, and I am full of expectations.

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[1] Lin Shen, Zhihao Lu, Junye Wang, et al. Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First Results of the Phase 3 ORIENT-15 study. 2021 ESMO, LBA 52.

[2] 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[J]. CA Cancer J Clin, 2021;71(3):209-249.

[3] Zhihao Lu, Junye Wang, Yongqian Shu, et al. 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;377:e068714.

Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Esophageal Cancer (2022 Edition).

[5] Arnold M, Ferlav J, van Berae Henegouwen MI, et al. Global burden of oesophageal anogastric cancer by histology and subsite in 2018. Gut, 2020;69: 1564-71.

[6] Mao Yousheng, Gao Shugeng, Wang Qun, et al. Big data analysis of clinical epidemiological characteristics and surgical treatment profile of esophageal cancer in China[J].Chinese Journal of Oncology,2020, 42(3):228-233.