Total neoadjuvant therapy with FOLFOX plus bevacizumab and short-course radiotherapy for Ras mutant, high-risk, locally advanced rectal cancer: The TRAINER trial.

133 Background: Total neoadjuvant therapy (TNT) intensified by the combination of targeted therapy or immunotherapy is warranted to achieve satisfying local and systemic control for high-risk locally advanced rectal cancer (LARC). Our study aimed to explore the efficacy and safety of a FOLFOX-based TNT regimen plus bevacizumab and short-course radiotherapy (SCRT) in Ras-mutant high-risk LARC patients. Methods: In this single-arm, single-center, phase II trial, LARC patients with at least one risk factor (cT3c-4, mesorectal fascia positive, cN2, lateral lymph node involvement, and extramural venous invasion positive) were recruited and only Ras-mutant patients were included. Four cycles of FOLFOX plus bevacizumab were arranged as induction chemotherapy followed by SCRT (25Gy/5Fx) and two cycles of FOLFOX as consolidation chemotherapy. Surgery was performed 8 weeks after completion of radiotherapy. After surgery, high-risk stage III patients (T4 or N2) were recommended to receive an extra 6 cycles of FOLFOX as adjuvant chemotherapy, while low-risk stage III patients were scheduled for regular follow-up. Patients with clinical complete response(cCR) were allowed to choose the “Watch & Wait” (W&W) strategy instead of surgery. The primary endpoint was the complete response (CR) rate, defined as the total rate of cCR plus pathological complete response (pCR). Secondary endpoints included adverse events of TNT, postoperative complications, 2-year disease-free survival, and overall survival. Results: Between April 2, 2021, and March 12, 2024, 47 of 51 enrolled patients were eligible for treatment. All patients completed the prescribed TNT cycles, and six (12.8%) of them had dose reduction. The CR was achieved in 18 (38.3%) patients, including 14 (29.8%) pCR. No grade IV-V toxicity was observed and the incidence of grade III toxicities was 34.0%. Four patients (8.5%) achieved cCR and chose the W&W strategy. The other 43 patients underwent curative surgery and anal preservation was achieved in 39 (90.7%) patients. Seven patients (16.3%) experienced postoperative complications, including four (9.3%) cases of anastomotic leakage. Conclusions: The intensified TNT regimen combined with bevacizumab achieved a satisfying CR rate with acceptable toxicities and complications for Ras-mutant high-risk LARC patients. Long-term survival data of this cohort are needed to validate the efficacy of this regimen further. Clinical trial information: NCT04923620 .