Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial

Dashan Ai; Shengnan Hao; Wenbin Shen; Qibing Wu; Shengjian Zhang; Yun Chen; Qi Liu; Jiaying Deng; Hongcheng Zhu; Ke Chen; Miao Mo; Dayong Gu; Yatian Liu; Zhi Zhang; Guoren Zhou; Jingwen Hu; Zhen Zhang; Jinjun Ye; Kuaile Zhao

doi:10.1016/j.eclinm.2024.102471

Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial

EClinicalMedicine. 2024 Feb 6:69:102471. doi: 10.1016/j.eclinm.2024.102471. eCollection 2024 Mar.

Authors

Dashan Ai^{1

2

3}, Shengnan Hao^{1

2

3}, Wenbin Shen⁴, Qibing Wu⁵, Shengjian Zhang^{2

6}, Yun Chen^{1

2

3}, Qi Liu^{1

2

3}, Jiaying Deng^{1

2

3}, Hongcheng Zhu^{1

2

3}, Ke Chen^{2

7}, Miao Mo^{2

8}, Dayong Gu⁹, Yatian Liu⁹, Zhi Zhang¹⁰, Guoren Zhou¹¹, Jingwen Hu¹², Zhen Zhang^{1

2

3}, Jinjun Ye⁹, Kuaile Zhao^{1

2

3}

Affiliations

¹ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Shanghai Clinical Research Center for Radiation Oncology, Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
⁴ Department of Radiation Oncology, Hebei Medical University Fourth Hospital, Shijiazhuang, China.
⁵ Department of Radiation Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁶ Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁷ Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China.
⁸ Department of Cancer Prevention & Clinical Statistics Center, Fudan University Shanghai Cancer Center, Shanghai, China.
⁹ Department of Radiotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
¹⁰ Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
¹¹ Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
¹² Department of Endoscopy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.

Abstract

Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control.

Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046).

Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3-35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%-90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT.

Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment.

Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program.

Keywords: Chemoradiotherapy; Esophageal cancer; Immunotherapy; Radiosensitivity.

Associated data

ClinicalTrials.gov/NCT03985046