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Abstract
Definitive chemoradiotherapy is the standard of care for inoperable locoregionally advanced esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have led to a paradigm shift in advanced, metastatic ESCC treatment; however, the effect of incorporating checkpoint inhibitors in the definitive management of ESCC is unclear. Tislelizumab is an anti-PD-1 antibody specifically engineered to minimize FcɣR binding on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The RATIONALE 311 study described here (BGB-A317-311; NCT03957590) is a registrational multicenter, double-blind, placebo-controlled, randomized, Phase III clinical trial designed to evaluate the efficacy and safety of tislelizumab combined with concurrent chemoradiotherapy in patients with inoperable localized ESCC.
Lay abstract
Esophageal cancer is a challenging disease that seriously threatens patients’ health and life. Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. Most patients who have inoperable stage II–IV ESCC are currently treated with a sequential combination of chemotherapy and radiation therapy, with the hopes of increasing the positive effects seen from either therapy alone. Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have shown encouraging results in patients with ESCC, but it is not known if combining checkpoint inhibitors with simultaneous chemotherapy and radiation therapy will provide additional benefits. The safety and efficacy of tislelizumab, an anti-PD-1 antibody specifically engineered to limit potential resistance to anti-PD-1 therapy, is being investigated in combination with simultaneous chemotherapy and radiation therapy in patients with inoperable stage II–IV ESCC in an actively enrolling clinical trial, RATIONALE 311 (NCT03957590). Our trial in progress article explains the reason RATIONALE 311 was started and provides important enrollment information for doctors.
Clinical trial registration: NCT03957590 (ClinicalTrials.gov)
Author contributions
All authors were involved in the design of this study. Additionally, all authors agreed to the submission of this manuscript and vouch for the completeness and accuracy of the information contained within. The corresponding author was responsible for the decision to submit the manuscript for publication.
Acknowledgments
The authors acknowledge the investigative center study staff, the study patients and their families.
Financial & competing interests disclosure
The study protocol was developed by BeiGene, Ltd. in collaboration with the study steering committee. BeiGene, Ltd. was also involved in data collection, analysis and interpretation of results. Statistical analyses were performed by statisticians at BeiGene, Ltd. Professional medical writers, funded by BeiGene, Ltd., assisted with the development and submission of this manuscript under the authors’ guidance. W Huang, L Li, W Yu, C Wei, Y Wang and W Shen are employees of Beigene. R Yu, W Wang, T Li, J Li, K Zhao, W Wang, L Liang, H Wu, D Ai and Z Xiao declare no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
BeiGene, Ltd. provided financial support for this manuscript, including writing and editorial assistance by S Lindsey and E Hermans, (Peloton Advantage, LLC, an OPEN Health company, NJ, USA).
Ethical conduct of research
The authors state that the study will be performed in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines and the principles of informed consent. Written informed consent will be obtained from each patient prior to screening. The protocol will be approved by regulatory authorities and independent ethics committees prior to initiation.
Data sharing statement
Upon request, and subject to certain criteria, conditions and exceptions, BeiGene will consider requests for the protocol, data dictionary and statistical analysis plan. Data requests may be submitted to [email protected].