TGF-β and PD-L1 inhibition combined with definitive chemoradiotherapy in esophageal squamous cell carcinoma: A phase II clinical trial (NCT04595149).

Abstract

TPS4154 Background: Esophageal cancer is the 6th leading cause of mortality worldwide, with an overall 5-year survival rate of 10%. This is in part due to more than 50% of patients presenting with irresectable or metastatic disease. With the introduction of definitive chemoradiation, 3-year survival rates of patients with irresectable tumors have risen to up to 40% (Hulshof et\xa0al., ASCO GI Oral Presentation, 2020). However, treatment still fails in the majority of patients due to locoregional recurrences or development of metastatic disease. Recently, it has been shown that addition of TGF-β inhibition to chemoradiation may improve treatment efficacy (Steins et\xa0al., Int J Cancer, 2019). Additionally, PD-L1 inhibition has emerged as a relevant therapeutic strategy in specific patient subgroups, such as squamous cell carcinoma (Kato et\xa0al., The Lancet Oncology, 2019). In this phase II study, we will investigate the feasibility of addition of bintrafusp alfa, a bifunctional fusion protein blocking TGF-β and PD-L1, to definitive chemoradiation in patients with esophageal squamous cell carcinoma. Methods: To assess feasibility, 52 patients will receive definitive chemoradiation combined with three doses of bintrafusp alfa at week 1, 4 and 7 (Table). Feasibility is defined as ≥80% of patients completing 2 cycles of bintrafusp alfa and will be tested with a one-sample test for a binomial proportion, comparing the observed percentage to the fixed reference value of unfeasibility (62%). Secondary endpoints are toxicity, progression-free survival, overall survival and quality of life. Additionally, exploratory endpoints include development of biomarkers to predict treatment response. Eligible for inclusion are patients with surgically irresectable (T1-4a N+ M0) squamous cell carcinoma of the esophagus or gastro-esophageal junction, or patients with resectable tumors refraining from radical surgery. Patients with M1 disease solely on the basis of supraclavicular metastasis are eligible. Patients with locoregional recurrences are eligible, provided that full dose of radiation can be safely delivered. Currently, 2 of planned 52 patients have been enrolled. Clinical trial information: NCT04595149. [Table: see text]