LB4 - Total Neoadjuvant Therapy With mFOLFOX6 Plus Bevacizumab and Short-course Radiotherapy for Ras-mutant, High-risk Locally Advanced Rectal Cancer: The TRAINER Trial

Purpose/Background: Total neoadjuvant therapy (TNT) intensified by targeted therapy might improve local and systemic control for high-risk locally advanced rectal cancer (LARC). Our study aimed to explore the efficacy and safety of a modified FOLFOX6 (mFOLFOX6)-based TNT regimen plus bevacizumab in Ras-mutant high-risk LARC patients.

Methods/Interventions: TRAINER-B was a single-arm, phase II trial, enrolling RAS-mutant LARC patients with at least one high-risk factor (cT3c-4, cN2, mesorectal fascia involvement, lateral lymph node involvement, and/or extramural venous involvement) between April 2021 and March 2024. Data were analyzed between August 2024 and November 2024. Four cycles of mFOLFOX6 plus bevacizumab were administered as induction chemotherapy, followed by SCRT (25Gy/5Fx) and two cycles of mFOLFOX6 as consolidation chemotherapy. Surgery was planned 8 weeks after completion of radiotherapy. After surgery, high-risk stage III patients (ypT4 or ypN2) were recommended to receive an extra six cycles of mFOLFOX6 as adjuvant chemotherapy. Patients with clinical complete response (cCR) were allowed to choose the “Watch & Wait” (W&W) strategy. The primary endpoint was the complete response (CR) rate. The secondary endpoints included patient compliance and safety, pathological outcomes, and survival data.

Results/Outcomes: Of 47 patients analyzed, 17 (36.2%) were female, and the median (IQR) age was 59 (51-68) years. The CR was achieved in 18 (38.3%) patients, including 14 (29.8%) pCR and four (8.5%) cCR. The prevalence of grade III toxicities was 34.0% whereas no grade IV-V toxicity was observed. 43 patients underwent curative surgery, and sphincter preservation was accomplished in 39 (90.7%) patients. Seven patients (16.3%) experienced Clavian-Dindo I-II postoperative complications, including four (9.3%) anastomotic leaks.

Conclusion/Discussion: The intensified TNT regimen plus bevacizumab achieved a satisfactory CR rate with acceptable toxicities and complications for RAS-mutant high-risk LARC patients. Long-term survival data are needed to validate the efficacy of this regimen.

Trial profile
MRF = mesorectal fascia; EMVI = extramural venous invasion; mFOLFOX6 consists of fluorouracil, leucovorin, and oxaliplatin; INCT = induction chemotherapy; SCRT = short-course radiotherapy; CNCT = consolidation chemotherapy; TME = total mesorectal excision; ISR = intersphincteric resection; cCR = clinical complete response; W&W = watch and wait; IC = informed consent;

Waterfall plot of radiological change in maximum tumor diameter from baseline
Orange columns represent tumor regression evaluated after INCT, while blue columns represent tumor regression evaluated after TNT. The grey dashed line indicates a 20% cut-off ETS, the orange dashed line indicates the median DpR evaluated after INCT, and the blue dashed line indicates the median DpR evaluated after TNT. The green squares represent non-CR patients, the red squares represent pCR patients, and the purple squares represent cCR patients. INCT = introduction chemotherapy; TNT = total neoadjuvant therapy; DpR = depth of response; ETS = early tumor shrinkage; CR = complete response; pCR = pathological complete response; cCR = clinical complete response;