Short-course radiotherapy followed by ivonescimab and CAPOX as neoadjuvant therapy for locally advanced rectal cancer: A single-arm, phase II trial.

Abstract

e15652 Background: Short-course radiotherapy (SCRT) combined with chemotherapy as neoadjuvant therapy has been proven to increase the pathological complete response (pCR) rate for locally advanced rectal cancer (LARC). Radiotherapy and immunotherapy exhibit a synergistic effect. Ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, has the potential to produce synergistic anti-tumor effects. This study aimed to evaluate the efficacy and safety of SCRT followed by Ivonescimab and CAPOX as neoadjuvant therapy in LARC patients. Methods: In this single-arm, single-center, phase II trial, LARC patients who met at least one of the following high-risk criteria—cT4, cN2, EMVI (+), MRF (+) or lateral lymph node (+) —were enrolled. All patients should have a tumor inferior margin ≤10 cm above the anal verge, and received SCRT followed by 6 cycles of Ivonescimab (20mg/kg or 10mg/kg, Q3W) and CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14; oxaliplatin: 130mg/m2, ivgtt, d1; Q3W). Surgery was performed 1 week after the completion of neoadjuvant therapy. The primary endpoint was the pCR rate, while the secondary endpoints include 3-years Event-Free Survival rate, R0 resection rate, quality of life, overall survival and safety. Results: As of December 25, 2025, a total of 49 patients were enrolled. Among these patients, 33(67.3%) were male, with a mean age of 59 years (range, 37-73). 25(51.0%) patients had cT4 disease, and 22(44.9%) had cN2. The rates of CRM (+), MRF (+) and EMVI (+) were 67.3%, 63.3% and 67.3%, respectively. Tumor response was evaluable in 42 patients, among whom 39 underwent surgical resection. The pCR rates were 48.7% (19/39), while the complete response rates (pCR + cCR) were 47.6% (20/42). All surgical procedures achieved R0 resection. During the neoadjuvant treatment period, treatment-related adverse events (TRAEs) of any grade occurred in all patients (100%). The most common TRAEs were lymphocyte count decreased (100%), anemia (93.9%), weight loss (73.5%), and anorexia (73.5%). Grade ≥3 TRAEs were observed in 67.3% of patients, with the most common being lymphocyte count decreased (46.9%), anemia (22.4%), and weight loss (16.3%). Conclusions: SCRT followed by Ivonescimab and CAPOX as neoadjuvant therapy in LARC patients seems to demonstrate safety and promising efficacy. Clinical trial information: NCT06802666 . Surgical and post-operative pathological outcomes. Surgical population N=39 Pathological complete response (ypT0N0), n(%) 19(48.7) Tumor regression grading, n (%) 0 19(48.7) 1 12(30.8) 2 7(17.9) 3 1(2.6) Pathological tumor stage, n (%) ypT0 19(48.7) ypTis 1(2.6) ypT1 3(7.7) ypT2 5(12.8) ypT3 10(25.6) ypT4 1(2.6) Pathological node stage, n (%) ypN0 35(89.7) ypN1 3(7.7) ypN2 1(2.6) Surgical resection status, n (%) R0 39(100)