SCALE-2: A phase 2 trial evaluating neoadjuvant short-course radiotherapy combined with chemotherapy and toripalimab in resectable locally advanced esophageal squamous cell carcinoma.

4092 Background: The SCALE-1 Phase Ib trial demonstrated that short-course neoadjuvant radiotherapy combined with toripalimab and chemotherapy, followed by esophagectomy, exhibited manageable toxicity and promising efficacy in patients (pts) with resectable locally advanced ESCC (RLaESCC). This Phase II trial aims to further valuate efficacy and safety of this novel short-course regimen in a larger cohort. Methods: RLaESCC pts with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m 2 ), carboplatin (AUC=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy/12f; 5 days per week) was administered between the two doses of neoadjuvant immune-chemotherapy. Compared to SCALE-1, high-risk nodal regions were selectively included in the irradiation volume. Weekly weight changes were used to assess preoperative waiting time. Esophagectomies were scheduled 8-10 weeks after completing neoadjuvant treatment. The primary endpoint was pathological complete response (pCR) rate, with secondary endpoints included disease free survival (DFS), overall survival (OS) and safety. Results: From April 28, 2024 to February 26, 2025, 63 pts were enrolled (intention-to-treat population, ITT), with stage distribution:I (3.2%), II (14.3%), III (63.5%) and IVA (19%). Following the exclusion of 3 pts who refused surgery, pathological assessment of the surgical specimens revealed that 56.7% (34/60) pts achieved pCR (ypT0N0 or ypTisN0) and 91.7% (55/60) achieved MPR. The median number of resected lymph nodes was 19 (range: 6–45). At a median follow-up of 23.9 months (cutoff date: Jan 19, 2026), median OS and DFS were not reached. In the ITT population, the 2-year OS and DFS rates were 90.4% (95% Cl: 82.4-98.4%) and 81.5% (95% Cl: 70.5-92.5%), respectively. Postoperative complications occurred in 45% (27) pts, with 18.3%(11) experiencing Grade ≥3 events. The most frequent Grade 3 and above complications were anastomotic leakage (n=4) (with or without pleural effusion or hemothorax) and airway mucus obstruction (n=4). Moreover, one case of postoperative delirium was observed (Grade IV), and one patient died of septic shock secondary to an anastomotic leak. All 63 pts completed neoadjuvant radiotherapy. However, 2 pts discontinued the second dose of toripalimab, and 16 pts required dose reductions during the second cycle of neoadjuvant chemotherapy. The most frequent grade 3/4 adverse events were neutropenia (n=27, 42.9%) and leukopenia (n=21, 33.3%). Notably, no grade 3 esophagitis or pneumonitis occurred. Conclusions: The SCALE regimen demonstrated potent antitumor activity, achieving 56.7% pCR and 91.7% MPR. Favorable 2-year OS and DFS further highlight its potential to improve long-term outcomes for RLaESCC pts. Clinical trial information: NCT05424432 .