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 al., 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 al., 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 al., 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]

Treatment patterns and survival in advanced unresectable esophageal squamous cell cancer: A population‐based study

“…24 Currently, clinical trials are underway to explore the addition of PD-1 inhibitors and/or TGFβ to definitive chemoradiotherapy and will hopefully improve outcomes for patients with ESCC who are eligible for definitive chemoradiotherapy. 25,26 The phase III CheckMate 648 trial reported a survival time of 10.7 months for patients receiving chemotherapy alone, and an increased survival of 12.8 and 13.2 months for patients receiving nivolumab plus chemotherapy and nivolumab plus ipilimumab, respectively. 7…”

“…As the phase III ARTDECO study showed that dose escalation up to 61.6 Gy did not improve outcomes in patients with esophageal cancer, including patients with ESCC 24 . Currently, clinical trials are underway to explore the addition of PD‐1 inhibitors and/or TGF‐β to definitive chemoradiotherapy and will hopefully improve outcomes for patients with ESCC who are eligible for definitive chemoradiotherapy 25,26 …”

The role of miR-145-5p in esophageal squamous cell carcinoma tumor-associated macrophages and selection of immunochemotherapy

“…ESCC is one of the leading causes of cancer-related deaths in Asia, especially in southern and central Asia. Despite recent advances in therapeutics against ESCC, the 5-year survival rate still ranges from 9% to 27.1% ( 1 , 2 ). Among the many different therapeutic approaches, the focus has now shifted to immunotherapy.…”