Disease	Esophageal cancer
Stage of Disease/Treatment	Primary
Prior Therapy	None
Type of Study	Phase I/Ib
Primary Endpoints	Safety, toxicity
Secondary Endpoints	Efficacy, biomarker associations
Additional Details of Endpoints or Study Design
The main inclusion criteria were age ≥18 years; newly diagnosed, locally advanced ESCC (T3–4N0M0 or T1–4N+M0, stage II–IVa according to the 8th [2017] edition of the American Joint Committee on Cancer staging system); no prior antitumor treatment; ineligible for or declined concurrent chemoradiotherapy; Eastern Cooperative Oncology Group score 0 or 1; adequate liver function; and normal blood cell counts. The main exclusion criteria were diagnosis of immunodeficiency, ongoing systemic immunosuppressive therapy, active autoimmune disease, human immunodeficiency virus, and clinically significant concurrent cancer.
Cervical, thoracic, and above‐abdomen computed tomography scans and upper gastrointestinal radiography were obtained every 3 months after treatment until disease progression. All patients underwent endoscopic ultrasonography, the standard clinical practice for potential tumor biopsy, after receiving 40 Gy of radiation [20 ] (i.e., at the end of 4 weeks of RT) in order to confirm the pathological response rates and laboratory tests.
The primary endpoints were safety and feasibility. Treatment‐related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. We estimated that the risk of grade 5 adverse events would occur at a rate of about 5% according to the reported adverse events in concurrent chemoradiotherapy.
The secondary endpoints were radiologic and pathologic response, scored according to RECIST version 1.1 by individual clinicians. Outcome measures were objective response rate 4 weeks after the end of RT and PFS and OS. Locoregional recurrence–free survival (LRFS) and distant metastasis–free survival (DMFS) rates were also assessed in this study. We expected that median OS, being a benchmark, would exceed 14 months according to median OS of 12 months with RT alone.
The exploratory endpoints included biomarkers that associated with OS and PFS. Pairs of tumor tissue biopsy samples and EDTA‐anticoagulant–treated peripheral blood specimens were to be collected before treatment (i.e., baseline) and during treatment (after the delivery of 40 Gy RT). Immunohistochemistry and six‐color immunofluorescence were used to investigate PD‐L1 expression and identify tumor‐infiltrating lymphocytes in tumor tissues. Multiple‐color flow cytometry was applied to investigate markers in peripheral T‐cell populations.
Among enrolled and eligible patients, the truncated sequential probability test was used to evaluate objective response rate. Statistical tests included two‐sided Fisher's exact tests and two‐sided Mann‐Whitney U tests. The Kaplan‐Meier method was used to estimate PFS, OS, LRFS, and DMFS. The best cutoff of Kaplan‐Meier survival analysis was calculated by the Youden index of the receiver operating characteristic curve. Differences in survival and recurrence rates were compared with log‐rank tests for all markers. SPSS (version 21.0; STATA, College Station, TX) or R version 3.2.2 packages were used for all analyses. All reported p values were two‐sided, and the significance level was set at .05.
Investigator's Analysis	Drug tolerable, hints of efficacy