Immunotherapy + Neoadjuvant Chemoradiation may Improve Outcomes in Esophageal Cancer

Esophageal cancer* is a common malignant tumor that occurs in the mucosal epithelium of the esophagus and is a gastrointestinal malignant tumor.** Globally, it is the sixth most common cause of cancer-related deaths. Available treatment strategies for esophageal cancer include surgery, chemotherapy, radiation therapy, molecular targeted therapy, or combinations of these treatment modalities. However, the disease remains challenging because it is often diagnosed in advanced stages, resulting in an overall poor prognosis. [1][2]

Definitive concurrent chemoradiotherapy (dCCRT) has been the standard treatment modality for unresectable locally advanced esophageal squamous cell cancer (ESCC). However, this treatment approach has several known disadvantages, including a high local failure rate (observed to be up to ~50% within 3 years) and a median overall survival (OS) time of 16.9 months. Furthermore, the 5‑year overall survival rate at ~21% for patients with ESCC with TNM stage T1‑3N0‑1M0, is considered relatively low. [3]

A novel approach
A new approach shows that in patients diagnosed with unresectable, locally advanced esophageal cancer, the triple combination of radiation, chemotherapy, and immunotherapy made tumors more amenable to surgery, which was associated with significantly improved outcomes, including a better survival rate rather compared to non-surgical treatment alone.

This is the conclusion of a study supported by Beijing Xisike Clinical Oncology Research Foundation and Special Program for Basic Resource Survey of the Chinese Ministry of Science and Technology. The results were published in the November 15, 2024, issue of Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).[4]

“Curative resection unequivocally serves as the cornerstone for treating resectable esophageal squamous cell carcinoma (ESCC); however, because of lack of symptoms and early detection, fewer than half of patients have resectable disease at the time of diagnosis,” explained Yin Li, MD, senior author of the study and director of section of esophageal and mediastinal oncology at the Chinese Academy of Medical Sciences and Peking Union Medical College.

Given the unfavorable long-term prognosis of patients who receive chemoradiation alone—only about 36% survive at least five years, according to Li—there is a desperate need for improved strategies.

Immune checkpoint inhibitors, both alone and in combination with chemotherapy, are standard –of care for those with advanced, recurrent, and metastatic ESCC. They’re also approved for adjuvant therapy after complete resection following neoadjuvant chemoradiation. But Li and his team wanted to investigate whether adding immune checkpoint inhibitors to chemoradiation can help downstage tumors and improve resectability.

Study design
To address this possibility, in a phase 2 clinical trial, patients between the ages of 18-75 were enrolled at their institution to receive three steps of treatment: radiation in conjunction with nab-paclitaxel (Abraxane®; Abraxis BioScience, a wholly owned subsidiary of Bristol-Myers Squibb) and cisplatin chemotherapy (Platinol®; Bristol-Myers Squibb) in step 1, the immune checkpoint inhibitor tislelizumab (Tevimbra®; BeiGene)*** plus chemotherapy in step 2, and, if possible, surgery in step 3.

Study outcomes
Of the 30 patients enrolled, five discontinued treatment during chemoradiotherapy and one patient received surgery ahead of schedule without subsequent immunotherapy. Of the 24 patients who also received subsequent chemoimmunotherapy, four discontinued the treatment, and 19 received surgery.

Overall, 20 patients underwent surgery and had complete resections.

Of these 20 patients, 19 had experienced major pathologic responses at the time of surgery, with 13 having complete pathologic responses. Most importantly, compared to the 10 patients who did not undergo surgery, the 20 who had surgery had significantly longer survival, both overall and without disease progression, with 82% and 72% reductions in risk of death and progression, respectively, at one year follow-up. More than half of those who underwent surgery were still free of disease at two years.

Effectiveness of combination
“The neoadjuvant treatment approach we tested has the potential to make initially unresectable tumors resectable, giving patients the opportunity to have a durable cancer-free state,” Yin Li said.

“Our trial clearly demonstrated the effectiveness of combining chemoradiotherapy, chemoimmunotherapy, and surgery compared to nonsurgical management alone,” according to Li. “We were confident in potential benefits of adding immunotherapy to chemoradiotherapy, but the remarkable pathologic complete response and the strong survival outcomes far exceeded our expectations.”

The clinical study also utilized circulating tumor DNA (ctDNA)-based liquid biopsies throughout the course of care, including monitoring for relapse, according to, Li. “allowed us to gain valuable insights into the molecular landscape and minimal residual disease trajectory of these patients.”

Study limitation
Limitations of the study include its small sample size, due in part to treatment discontinuations, and thus point to the need for phase 3 trials to validate these findings as well as explore the optimal sequencing of therapies.

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Note: * Esophageal cancer includes two histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs more often on Western countries. The median age of diagnosis for esophageal cancer is 68 years. The risk of developing the disease increases with age. Fewer than 15% of people diagnosed with esophageal cancer are under 55 years old.
** in Traditional Chinese medicine (TCM) esophageal cancer is categorized as dysphagia.  in ancient Chinese medicine books Siwu-Yin or SWY, a traditional Chinese medicinal formula, is listed as a treatment for esophageal dysphagia, which has similar symptoms and prognosis esophageal cancer. The effect of this treatment has, however, not been established in vivo, bu a recent study by a team of researchers from the Department of Traditional Chinese Medicine, The Fourth Hospital of Hebei Medical University, Hebei Cancer Hospital, Shijiazhuang, China in collaboration with the Institute for Biotechnology, St. John’s University, Queens, NY, United States, confirmed that SWY could inhibit the occurrence of esophageal precancerous lesions. [5]

Highlights of prescribing information
Nab-paclitaxel (Abraxane®; Bristol-Myers Squibb) [Prescribing Information]
Cisplatin (Platinol®; Bristol-Myers Squibb) [Perscription Information]
Tislelizumab (Tevimbra®; BeiGene) [Prescription Information]

Reference
[1] He S, Xu J, Liu X, Zhen Y. Advances and challenges in the treatment of esophageal cancer. Acta Pharm Sin B. 2021 Nov;11(11):3379-3392. doi: 10.1016/j.apsb.2021.03.008. Epub 2021 Mar 9. PMID: 34900524; PMCID: PMC8642427.
[2] Eisner DC. Esophageal cancer: Treatment advances and need for screening. JAAPA. 2024 Apr 1;37(4):19-24. doi: 10.1097/01.JAA.0001007328.84376.da. Epub 2024 Mar 26. PMID: 38484297.
[3] Wang X, Bai H, Li R, Wang L, Zhang W, Liang J, Yuan Z. High versus standard radiation dose of definitive concurrent chemoradiotherapy for esophageal cancer: A systematic review and meta-analysis of randomized clinical trials. Radiother Oncol. 2023 Mar;180:109463. doi: 10.1016/j.radonc.2023.109463. Epub 2023 Jan 13. PMID: 36642387.
[4] Wang X, Kang X, Zhang R, Xue L, Xu J, Zhao X, Ou Q, Yu N, Feng G, Li J, Zheng Z, Chen X, Wang Z, Zheng Q, Li Y, Qin J, Bi N, Li Y. Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial. Clin Cancer Res. 2024 Nov 15;30(22):5061-5072. doi: 10.1158/1078-0432.CCR-24-1236. PMID: 39544026.
[5] Shi HJ, Chen XY, Chen XR, Wu ZB, Li JY, Sun YQ, Shi DX, Li J. Chinese Medicine Formula Siwu-Yin Inhibits Esophageal Precancerous Lesions by Improving Intestinal Flora and Macrophage Polarization. Front Pharmacol. 2022 Mar 3;13:812386. doi: 10.3389/fphar.2022.812386. PMID: 35308250; PMCID: PMC8927885.

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DOI: 10.14229/onco.2024.11.15.001