SCALE-1: Safety and efficacy of short course neoadjuvant chemo-radiotherapy plus toripalimab for locally advanced resectable squamous cell carcinoma of esophagus.
Authors: Jiang Ning , Jiang Ming , Zhu Xiangzhi , Ren Binhui , Zhang Jingyuan , Guo Zhen , Wu Yinan , Song Xue , Zhao Lijun , Kong Cheng , Zong Dan , Cao Guochun , Qian Pudong , Zhao Yang , Li Si , Luo Shifu 
Published: June 2022

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Background: Adding PD-1 inhibitors to neoadjuvant chemoradiotherapy have shown promising results in treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, there is a need to explore more effective and safe treatment doses and schedules. The aim of this single arm phase Ib trial is to determine the safety and efficacy of short course neoadjuvant chemo-radiotherapy plus toripalimab following by esophagectomy in patients with locally advanced resectable ESCC. Methods: Patients (pts) with histopathologically confirmed thoracic ESCC, diagnosed as clinical stage of cT3-4aN0M0/cT1-4aN+M0 per AJCC 8th and ECOG PS of 0-1 were eligible. Toripalimab (240mg) was given with paclitaxel (135 mg/m2) and carboplatin (AUC=5) on D1 every 3 weeks for two cycles. Short course neoadjuvant radiotherapy (3000 cGy in 12 fractions on 5 days per week) was administered from D3 to D18. Esophagectomy was scheduled 4 to 6 weeks after the completion of neoadjuvant therapy. Target total enrollment was 20 pts. The primary endpoint was treatment safety. Pre- and post-treatment specimens were collected for PD-L1 expression assay and gene expression profiles (GEPs) analysis using the nCounter platform. Results: From Jan 29, 2021 to Nov 3, 2021, 26 patients were screened and 23 met the inclusion criteria. The majority of them were diagnosed with clinical stage of cT3-T4 (95.6%), cN1-2 (62.5%), and cTNM III-IVA (78.2%). All 23 pts finished neoadjuvant radiotherapy, while two of them didn’t receive or received reduced dose of the second cycle chemotherapy or toripalimab due to toxicity. Notable grade 3 or higher AEs included leukopenia (n=21), neutropenia (n=21), anorexia (n=19) and nausea (n=18). No treatment related oesophagitis, pneumonia and gastrointestinal hemorrhage above Grade 3 were observed. 20 pts underwent surgery after a median of 7 weeks post neoadjuvant therapy. Reasons for not undergoing surgery were patients’ choice (n=2) and tuberculosis reactivation (n=1). 3 pts with Grade III surgical complications were observed during the perioperative period. 11/20 (55%) complete pathological responses (ypT0N0) were observed, 16/20 (80%) pts were major pathologic response (MPR) and the remaining 4 pts achieved partial response. Pre-treatment GEP analysis revealed significantly higher expression levels of CXCL10, CXCL11, OAS2, and lower level of CD209 and KLRB1 in pCR (n=6) than in Non-pCR group (n=4). Moreover, pCR group showed a trend of upregulated signatures of tumor infiltrating leukocytes, cytolytic activity, cytotoxic T cell, T cell markers and Teff score (P= 0.062) after treatment. Conclusions: Combining short course nCRT with toripalimab is feasible and effective in patients with locally advanced resectable ESCC, and might be a promising approach for neoadjuvant treatment. Clinical trial information: ChCTR2100045104.