Neoadjuvant Radiotherapy for Rectal Adenocarcinoma With Capecitabine Versus TAS-102 (Neo-REACT): A Multi-center, Randomized, Phase III Trial

Neoadjuvant fluoropyrimidine-based chemoradiotherapy (nCRT) followed by TME is the standard care for LARC. However, the tumor responses to nCRT cover a wide spectrum and the complete pathologic response rate varies from 8% to 20%. The low rate of pCR after neoadjuvant therapy could not satisfy patients with distal rectal cancer who want to keep anal function. Therefore, currently, the addition of other agents to 5-FU or capecitabine as components of the multimodality treatment for LARC outside of clinical trials is not recommended in clinical practice. TAS-102 is a new oral anti-tumor oral formulation of nucleoside analogue, FTD, and a thymidine phosphorylase inhibitor, TPI. TPI improves the bioavailability and ensures sufficient blood concentrations of FDT. Previous studies have shown that TAS-102 has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Also, a phase 2 trials conducted by our team have demonstrated that neoaduvant TAS-102 concurrent with long-course radiotherapy could lead to a high pCR rate of 32% with acceptable toxicity for LARC patients. Herein, we will conduct this multicenter, randomized controlled, phase III trial to explore the safety and efficacy benefit of TAS-102 concurrent with long-course radiotherapy for LARC.

Inclusion criteria

• Patients aged between 18 and 75 years of either sex.
• Histologically confirmed rectal adenocarcinoma with the following conditions:

• Clinical stage II (T3-4, N-) or III (any T, N+) as determined by MRI.
• The tumor is located within 12 cm from the anal margin, with at least one high-risk factors (ie, extramural vascular invasion [EMVI+], mesorectal fascia involved [MRF+], cT4, cN2, lateral lymph nodes, tumor deposit, or tumor located in the lower rectum [≤5 cm from the anal verge]).
• No other types of rectal cancer (e.g., sarcoma, lymphoma, carcinoid, squamous cell carcinoma) or synchronous colon cancer.
• Presence of measurable lesions that meet RECIST v1.1 criteria for evaluation.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Estimated life expectancy > 6 months.

Exclusion criteria

• Patients of dMMR or MSI-H status.
• Unexplained myelosuppression.
• Evidence of distant metastasis and inguinal lymph node metastasis based on comprehensive chest and abdominal CT or whole-body PET-CT scans. Retroperitoneal lymph nodes above the iliac vessel bifurcation are considered distant metastasis.
• Active autoimmune disease or history of autoimmune disease.
• Uncontrolled cardiac symptoms or diseases.
• History of other malignancies, except for cured basal cell carcinoma of the skin and cervical carcinoma in situ.