PURPOSE: Neoadjuvant chemoradiation (NCRT) followed by surgical resection represents a standard approach for patients with locally advanced esophageal/gastroesophageal junction (GEJ) cancers. Sotigalimab is a high-affinity CD40 agonist antibody capable of inducing and expanding antitumor immune responses by activating dendritic cells, T and B lymphocytes, NK cells, and M1 macrophages. This study examined the safety and efficacy of combining sotigalimab with NCRT in patients with esophageal or GEJ cancers. PATIENTS AND METHODS: Patients with resectable (T1-3 Nx) adenocarcinoma or squamous cell carcinoma of the esophagus or GEJ were eligible. T1N0 and cervical tumors were excluded. Study treatment: weekly carboplatin/paclitaxel with concurrent radiation 5,040 cGy plus 3 to 4 doses of sotigalimab prior to Ivor Lewis esophagectomy. Primary efficacy endpoint was the pathologic complete response (path CR) rate. RESULTS: Thirty-three patients were enrolled (adenocarcinoma 76%, squamous cell carcinoma 24%
and clinical stage III 67%). Ninety percent of patients received all planned doses of sotigalimab. The most common adverse events attributed to sotigalimab were nausea, fever/chills, fatigue, and cytokine release syndrome
most of these were grade 1 to 2. Grade ≥3 cytokine release syndrome was observed in 3 patients (9%). Twenty-five of the 29 efficacy-evaluable patients underwent an R0 resection (87.9%), with an overall path CR rate of 37.9% (11/29). Post-tumor samples demonstrated increased infiltration and activation of dendritic cells, monocytes, and cytotoxic T cells compared with baseline. CONCLUSIONS: Sotigalimab combined with NCRT for esophageal or GEJ cancers was generally well tolerated and achieved path CR rates that compare favorably with historical data and are promising for this treatment strategy. Clinical trial information: NCT03165994. SIGNIFICANCE: The current study represents the first report to evaluate a CD40 agonist antibody in combination with concurrent chemoradiation in the neoadjuvant setting for patients with esophageal/GEJ cancers. This novel strategy was both safe and feasible, producing encouraging path CR rates that compare favorably with historical data. Our findings support the further evaluation of how immune-based therapies may be incorporated into perioperative treatment paradigms for upper gastrointestinal malignancies.