Prediction for major pathologic response after neoadjuvant tislelizumab combined with chemotherapy in patients with locally advanced esophageal squamous cell carcinoma by RNA sequencing: A single-arm, phase II trial.

Abstract

4078 Background: Although neoadjuvant chemoradiotherapy is evolved into standard-of-care treatment in locally advanced esophageal cancer (EC) patients (pts), nearly half of pts experience relapse and death within 5 years. It is therefore important to establish novel and effective treatment strategies for further improve survival. With successful treatment of unresectable esophageal squamous cell carcinoma (ESCC) with PD-1/PD-L1 inhibitors, which are expected to provide better benefits in resectable ESCC preoperatively. However, owing to lack effective predictors in MPR in neoadjuvant immunotherapy, efficacy of treatment is unsatisfactory. In this study we sought to explore potential biomarkers in treatment of locally advanced ESCC with tislelizumab combined with chemotherapy preoperatively. Methods: In this single centre, perspective, single arm study, 62 locally advanced (stage II-IVA) ESCC pts were enrolled from January 2023 to December. Pts received tislelizumab (200mg/ d1 Q3W) and chemotherapy (Albumin Paclitaxel 240 mg/m2, Carboplatin: AUC=5 Q3W, d1 or Nedaplatin: 70mg d1 Q3W). Minimally invasive esophagectomy was performed within 4-6 weeks after preoperative therapy. The primary endpoint was MPR rate and secondary endpoints were R0 resection rates and adverse events (AEs). Exploratory biomarker analysis was performed on tumor biopsy before neoadjuvant therapy. Results: 62 pts were enrolled who received all cycles of tislelizumab plus chemotherapy and 84% (52/62) of whom proceeded to surgery. Grade I AEs were observed in 57 (91.3%) pts and most common of which was anemia (49/62, 79%). 19 (30.6%) pts had grade II and 4 (6.4%) had grade III AEs. No higher AEs was observed. Reasons for not undergoing surgery was patient refusal (10/62, 16.1%). No perioperative death was observed. MPR, pCR and R0 resection rate were (55.8%), (23.1%) and (100%), respectively. The mediate follow-up time was 7.4 (1.7-12.6) months and no relapse was found before the last follow-up.10 pts underwent RNA-sequencing, of which 5 achieved MPR and 5 were not. Compared to MPR pts, 393 upregulated and 1950 downregulated genes were found in non-MPR patients. Additionally, it was indicated that immunomodulatory, keratinocyte differentiation and calcium signaling pathway may correlate with MPR status by GSEA, GO and KEGG analysis. Moreover, some hub genes, such as IL6, MMP1, SPPR3, CRNN, were identified to be associate with non-MPR after neoadjuvant therapy. Conclusions: Our results indicated that tislelizumab combined with chemotherapy is a feasibility and effective neoadjuvant treatment option for locally advanced ESCC. In addition, some hub genes were found to be associated with non-MPR after neoadjuvant therapy. Further experimental studies are needed to investigate these findings. Clinical trial information: NCT05880082 .