Editor's note: [Expert Group Draft] With ingenuity, respect the original intention. Professor Li Gaofeng of Yunnan Provincial Cancer Hospital is the executive editor-in-chief of this issue, and experts in the field of gastrointestinal/thoracic tumors are invited to share academic views, a total of 5 issues for exchange.
Phase 1
Title: Research Progress on Immunity and Targeted Therapy for Esophageal Cancer
Authors: Li Gaofeng, Zhao Wentao, Yunnan Provincial Cancer Hospital
Expert Profile
Prof. Li Gaofeng
Vice President of Yunnan Hospital, Peking University Cancer Hospital (Yunnan Provincial Cancer Hospital, Third Affiliated Hospital of Kunming Medical University).
Doctoral supervisor, postdoctoral cooperative supervisor, second-level professor, chief physician
Yunnan Health Guard, Provincial Association for Science and Technology Outstanding Society Worker
President of Yunnan Translational Medicine Society
Vice Chairman of Yunnan Anti-Cancer Association
Chairman of the Thoracic and Cardiovascular Surgery Branch of Yunnan Medical Association
Chairman of the Minimally Invasive Treatment Committee of Thoracic Tumors of Yunnan Anti-Cancer Association
Executive Director of Yunnan Preventive Medicine Association and Chairman of Lung Cancer Professional Committee
Member of the International Association for the Study of Lung Cancer
He is a member of the Standing Committee of the Mediastinal Tumor Professional Committee of the Chinese Anti-Cancer Association
Member of the Thoracoscopic Surgery Group of the Thoracic and Cardiovascular Surgery Branch of the Chinese Medical Association
Member of the Working Committee of the Medical Consortium of the Chinese Hospital Association
Member of the National Lung Cancer MDT Expert Committee
National outstanding scientific and technological worker, expert enjoying special allowance of the State Council
Winner of the National May Day Labor Medal, Yunnan Provincial Medical Leading Talent, Yunling Famous Doctor
Yunnan Province has outstanding professional and technical personnel with outstanding contributions and experts contacted by the provincial party committee
Zhao Wentao
Deputy Chief Physician of the Department of Digestive Oncology, Yunnan Hospital, Peking University Cancer Hospital (Yunnan Provincial Cancer Hospital, Third Affiliated Hospital of Kunming Medical University).
Doctoral supervisor, postdoctoral fellow, master's supervisor
Yunnan Province "Xingdian Talent Support Program" young talents
Youth Committee Member of Southern Oncology Clinical Research Association
Member of Yunnan Translational Medicine Branch of China Translational Medicine Alliance
Member of the Pain Physician Branch of Yunnan Medical Doctor Association
He is a member of the Pancreatic Cancer Prevention and Treatment Professional Committee of Yunnan Preventive Medicine Association
The number of new cases of esophageal cancer in mainland China accounts for about half of the total number of patients in the world every year, which seriously endangers national health. The 3-year and 5-year overall survival rates of the more mature esophageal cancer surgery centers in mainland China have increased to 61.6% and 52.9% respectively. Despite this, after a median follow-up of 52 months, the recurrence rate of locally advanced esophageal cancer is still as high as 33.7%, and the 5-year survival rate is only 15%-34%. This article briefly reviews the progress of clinical application of immunotherapy and targeted therapy drugs in esophageal cancer.
1
Use of immunotherapy in preoperative neoadjuvant therapy
A small number of phase I and II small clinical studies have explored the efficacy of neoadjuvant concurrent chemoradiotherapy combined with immunotherapy for esophageal cancer, and the results suggest that after surgery after neoadjuvant concurrent chemoradiotherapy combined with immunotherapy, the overall pathologic complete response (pCR) rate after surgery has achieved good data, and the overall pCR rate fluctuates around 50% (see Table 1).
Although neoadjuvant concurrent chemoradiotherapy is the standard treatment for locally advanced esophageal cancer, according to the big data analysis of the clinical prevalence characteristics of esophageal cancer in mainland China, the implementation rate of neoadjuvant chemoradiotherapy in the real world in mainland China is not high, and most patients in the real world receive neoadjuvant chemotherapy.
A retrospective study suggested that there was no difference in 5-year survival between neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy (77.3%: 61.3%; HR=1.57; 95%CI: 0.86~2.87; P=0.141). The results of a number of phase I and II small clinical studies suggest that the safety of neoadjuvant immunotherapy combined with chemotherapy is mostly controllable, but the pCR rate varies greatly between studies (Table 1).
The results of neoadjuvant immunotherapy for esophageal cancer have been preliminarily demonstrated in the perioperative period of neoadjuvant immunotherapy for esophageal cancer, and the pCR data of some studies are close to the results of classical CROSS studies, but the long-term survival results after surgery still need to be continuously verified and verified.
In these clinical studies reported so far, it can be found that the survival time of TP regimen combined with immunotherapy is longer than that of CF regimen (fluorouracil + cisplatin), therefore, most of the recently reported studies use immunotherapy plus TP regimen, and the pCR rate is higher than that of previous chemotherapy with non-TP regimen. In the NICE study, the chemotherapy dose was larger, and albumin-paclitaxel was selected, albumin-paclitaxel has the effect of selective local enrichment of tumors, its concentration in tumor tissues is higher, and the damage to the body's immune system is reduced to a certain extent, and more importantly, the use of albumin-paclitaxel also avoids the negative immune regulatory effect caused by hormone shock, but when combined with immunotherapy, whether albumin-paclitaxel is better than paclitaxel still needs to be confirmed by head-to-head clinical studies.
Regarding the sequence of chemotherapy combined with immunotherapy, the American Society of Clinical Oncology (ASCO) 4051 study reported that sequential immunotherapy with chemotherapy can achieve a higher pCR rate, and the possible mechanism is that chemotherapy drugs can be metabolized out of the body before PD-1 inhibitor use, thereby reducing the killing effect of chemotherapy drugs on T cells and retaining their function of killing tumor cells. However, the sequence of combination therapy still needs to be confirmed by randomized controlled studies.
2
Use of immunotherapy in postoperative adjuvant therapy
For patients with esophageal cancer who have not received neoadjuvant therapy and R0 resection before surgery, the current major guidelines do not recommend the use of immunotherapy drugs in postoperative adjuvant therapy. For patients with locally advanced esophageal cancer who have the possibility of surgery after conversion therapy, preoperative neoadjuvant concurrent chemoradiotherapy and sequential radical resection is the standard treatment mode for locally advanced esophageal cancer widely recommended by various clinical guidelines. Postoperative adjuvant immunotherapy is recommended for patients who have not obtained pCR after preoperative neoadjuvant concurrent chemoradiotherapy sequential radical resection with pathological evaluation. This is based on the results of a global multicenter, double-blind, randomized controlled phase III clinical study, CheckMate-577, presented as evidence-based evidence. The results of this study showed that nivolumab reduced distant metastasis (29 versus 39 percent) and local metastasis (12 versus 17 percent) and significantly prolonged distant metastasis-free survival (28.3 versus 17.6 months; HR=0.74; 95% CI: 0.60-0.92) in patients with esophageal cancer and gastroesophageal junction cancer who did not achieve pCR after preoperative neoadjuvant therapy. Based on the results of this study, both the U.S. Food and Drug Administration and the Chinese Society of Clinical Oncology guidelines for esophageal cancer recommend nivolumab for the treatment of patients with esophageal cancer who have received neoadjuvant concurrent chemoradiotherapy and still have residual pathological tumors after surgical R0 resection.
3
Use of immunotherapy in the treatment of unresectable locally advanced or metastatic esophageal cancer
First-line chemotherapy combined with immunotherapy has become the standard of care for unresectable locally advanced or metastatic esophageal cancer. The KEYNOTE 590 study made its debut at the European Society for Medical Oncology Congress in 2020, and six more studies emerged from 2021 to 2023 to support the first-line treatment of unresectable locally advanced or metastatic esophageal cancer with chemotherapy in combination with PD-1 inhibitors, which established the role and status of immunotherapy combined with chemotherapy in the first-line treatment of advanced esophageal cancer (Table 3).
4
4. Study of CAR-T therapy in esophageal cancer
The structures of targeted CARs associated with esophageal cancer mainly include intracellular, transmembrane, and extracellular domains. The extracellular domain consists of a single-chain variable fragment and a hinge region of a monoclonal antibody that recognizes and specifically binds to antigens, and the intracellular domain consists of a costimulatory domain and a signaling domain. The outstanding advantage of CAR-T therapy is that its structure can be modified and optimized to enhance anti-tumor activity. Since the advent of the first generation of CAR, CAR-T therapy has developed rapidly, and has now developed to the fifth generation, and has achieved good clinical results in some hematological tumors. At present, CAR-T for solid tumors is still in the exploratory stage, but some progress has been made in CAR-T research for the treatment of ESCC.
At present, the most studied CAR-T antigen targets are: CD276 (B7-H3), erythropoietin hepatocyte receptor A2, HER-2, mesothelin (MSLN), and mucin-1 (MUC1). At present, there are also some clinical studies for other antigenic targets, such as NY-ESO-1, CEA, EpCAM, and MUC1, which can provide new ideas and insights for the treatment of esophageal squamous cell carcinoma in the future.
5
The use of targeted therapy in the treatment of esophageal cancer
Targeted therapies associated with esophageal cancer mainly include the following categories: anti-epidermal growth factor receptor (EGFR) pathway, anti-vascular endothelial growth factor (VEGF), and anti-human epidermal growth factor-2 (human epidermal growth factor). receptor-2, HER-2). Among them, trastuzumab, an anti-HER-2 monoclonal antibody, is currently the targeted drug for the treatment of advanced esophageal cancer with the highest level of recommendation in the 2022 CSCO guidelines. In the first-line treatment of HER-2-positive advanced esophageal adenocarcinoma, trastuzumab combined with cisplatin + fluorouracil regimen has been recommended by level I experts and supported by class 1A evidence, trastuzumab combined with pembrolizumab + cisplatin or oxaliplatin + fluorouracil has been recommended by level II experts and supported by class 1A evidence, and trastuzumab combined with other first-line chemotherapy regimens has been recommended by level III experts and supported by class 2B evidence. Bang et al. conducted a phase III open-label randomized controlled trial of trastuzumab plus chemotherapy versus chemotherapy alone in HER-2-positive advanced gastric cancer or gastroesophageal junction cancer, which included a total of 594 patients, with a median overall survival of 13.8 months for patients receiving trastuzumab plus chemotherapy (n=298) and 11.1 months for patients receiving chemotherapy alone (n=296). This laid the foundation for trastuzumab in combination with chemotherapy as a treatment option for patients with HER-2-positive advanced gastric cancer or gastroesophageal junction cancer.
In the 2022 and 2023 CSCO guidelines for the first-line treatment of advanced esophageal squamous cell carcinoma, apatinib combined with camrelizumab + TP has also been recommended by level III experts and supported by 3 types of evidence, and anlotinib combined with TP has also been recommended by level III experts and supported by 3 types of evidence. Trastuzumab plus paclitaxel is recommended for patients with HER-2-positive esophageal adenocarcinoma who have failed platinum-based therapy and have not received prior trastuzumab therapy in the recommendation for the second-line or above treatment of advanced esophageal cancer (level I expert recommendation, supported by category 2A evidence). Among the recommendations for the second-line and above treatment of advanced esophageal cancer, anlotinib is recommended as the treatment of patients with esophageal squamous cell carcinoma (recommended by level II experts, supported by category 2A evidence), apatinib is recommended as the third-line and above treatment of esophageal adenocarcinoma (recommended by level II experts, supported by category 1A evidence), apatinib is also recommended by level II experts and supported by category 3 evidence as the treatment of patients with esophageal squamous cell carcinoma; vedicitumab is recommended as the third-line and above treatment of patients with HER-2-positive esophageal adenocarcinoma (recommended by level II experts, Apatinib plus camrelizumab is also recommended as a treatment for patients with esophageal squamous cell carcinoma (recommended by level III experts, supported by category 3 evidence).
Other targeted therapies include anti-EGFR therapies: cetuximab, nimotuzumab, panitumab, erlotinib, and anti-VEGF therapies: bevacizumab, sorafenib, and recombinant human endostatin injector. At present, there are some small sample of phase II clinical studies that show that these targeted drugs have certain efficacy, but there is a lack of evidence from phase III randomized controlled clinical studies, and major guidelines have not yet given clear recommendations for the above drugs. In summary, targeted therapy for esophageal cancer is a long way to go and is still being explored.
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