A multicenter single-arm phase II study examining the efficacy of TNT for locally advanced rectal cancer: ENSEMBLE-2.

3601 Background: Recent studies have highlighted the efficacy of Total Neoadjuvant Therapy (TNT) in improving long-term outcomes by controlling both local and distant metastases. We previously reported the results of the multicenter Phase II trial ENSEMBLE-1, which evaluated TNT using short-term radiotherapy (5x5Gy) and systemic chemotherapy (CAPOX 6 courses) at ASCO-GI 2024. Building upon this, we conducted the ENSEMBLE-2 trial, a multicenter single-arm Phase II trial exploring TNT with chemoradiotherapy plus systemic chemotherapy. Subjects: The main eligibility criteria included individuals aged 20 or older with locally advanced rectal cancer, located within 12 cm from the anal verge, diagnosed as cT3-4N0M0 or TanyN+M0, and amenable to curative resection. Methods: The protocol treatment (PRT) consisted of chemoradiotherapy (CRT: 50.4Gy + concurrent capecitabine) followed by CAPOX for 4 courses and total mesorectal excision (TME). In cases of clinical complete response (cCR) after preoperative treatment, non-operative management (NOM) was allowed. The primary endpoint was the proportion of patients achieving pathologic complete response (pCR) assessed at participating medical institutions. With an expected pCR rate of 30% and a ±15% precision based on the modified Wald method; the planned registration number was set at 27 patients. Results: A total of 28 patients were enrolled. Demographics included gender (male: female 19: 9), median age at 69.5 years (41-79 years), predominant site (upper rectum: lower rectum 5: 23), cT factors (T3:T4a 24:4), and cN factors (N0:N1:N2 15:8:5). Completion rates were 100% for CRT, 92.9% for CAPOX, and 75.0% for PRT. TME was performed in 21 patients, while NOM was chosen in 6 patients (5 cCR, 1 nCR by patient preference) and one patient quit the follow-up after TNT. No disease progression was observed during PRT. Surgical procedures for TME were LAR:ISR:APR/Hartmann (10:5:6). There were no postoperative complications of Grade IIIb or higher (Clavien-Dindo classification). Histological efficacy was graded as 1:2:3 (9:7:5). The pCR rate, calculated as a proportion of surgical cases, was 23.8% (5/21 cases, 90% CI: 11.8%-41.8%). The NOM rate with pCR+cCR was 35.7% (10/28 cases, 90% CI: 22.6%-51.3%). There were no treatment-related deaths, and Grade 3 or higher adverse events included diarrhea (7.1%), leukopenia (7.1%), and neutropenia (3.6%). The median follow-up period was 14.8 months, with 3 patients of recurrence and 12-month recurrence-free survival rate was 92% (95% CI: 71.6%-97.9%). Conclusions: TNT comprising chemoradiotherapy and CAPOX4 showed the expected efficacy, including a transitioning to NOM, and was deemed a safe treatment option. Future studies will compare these results to the ENSEMBLE-1 trial, assessing long-term outcomes, and explore the correlation with minimal residual disease. Clinical trial information: jRCTs071210143.