A multicenter single-arm phase II study examining the efficacy of TNT for locally advanced rectal cancer: ENSEMBLE-2.
Authors: Koji Ando, Yoshinori Kagawa, Mamoru Uemura, Jun Watanabe, Masaaki Miyo, Yasunori Emi, Nobuhisa Matsuhashi, Naoki Izawa, Osamu Muto, Tatsuya Kinjo, Yujiro Nishizawa, Tsuyoshi Hata, Yusuke Suwa, Takuya Honboh, Jesse Yu Tajima, Yu Sunakawa, Koji Oba, Ichiro Takemasa, Eiji Oki
Journal: Journal of Clinical Oncology (2024)

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.