Short-course radiotherapy (SCRT) followed by immunochemotherapy plus fruquintinib as the total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study (UNION TNT).

128 Background: The phase III trial (UNION) evaluating SCRT followed by immunochemotherapy in patients (pts) with LARC has reported a pathological complete response (pCR) rate of 39.8%. The phase II UNION TNT study aimed to assess the benefit of adding fruquintinib (VEGFR-1, -2, and -3 inhibitor) to the immunotherapy-based TNT in high risk LARC. Here we reported the updated results. Methods: Eligible pts with high risk LARC were enrolled. Six pts in the safety run-in received SCRT followed by six cycles of fruquintinib 3mg/d, d1-14, q3w as starting dose with fixed doses of adebrelimab (1200mg, d1, q3w) and CAPOX (q3w). Further 39 pts would be enrolled in dose expansion period. Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year EFS rate, OS, R0 resection rate and safety. Results: As of August 29, 2025, 45 pts were enrolled (51% clinical T4 stage, 44% clinical N2 stage, 82% EMVI positive, 71% MRF positive, 49% tumor located ≤5cm from the anal verge). Among the 41 pts evaluable for efficacy, all received the full dose of radiotherapy and 26 pts (63%) completed at least 6 cycles of combined regimen. 7 pts achieved cCR and were offered watch-and-wait. Of the remaining 34 pts without cCR，33 pts underwent total mesorectal excision (TME), 57.6% (19/33) pts achieved pCR and R0 resection rate was 100%. Out of 33 patients who underwent TME, 33.3% (11 pts) experienced surgical complications. The overall CR rate was 63.4%, demonstrating a notable increase when comparing with historical CR rates (12.3-56.5%) achieved by conventional chemoradiotherapy-based or immunotherapy-based TNT. 3-year EFS rate and OS continue to mature. The most frequent grade 3 to 4 TEASs during TNT treatment were lymphocyte count decreased (46.3%), leukopenia (9.8%) and AST elevation (7.3%). 4 pts experienced SAEs of intestinal perforation, while all of them achieved pCR. Grade 3 complications according to Clavien-Dindo classification were reported in 4 pts, including one intestinal obstruction, one extremity vein thrombosis, and two anastomotic fistulas. Conclusions: The new UNION TNT regimen with acceptable toxicity remarkably improved CR rate in high risk LARC compared with historical benchmark. Clinical trial information: NCT06234007 .