Neoadjuvant fluoropyrimidine-based chemoradiotherapy followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer (LARC); however, pathologic complete response (pCR) rates are low. Trifluridine/tipiracil (TAS-102) is a new oral anti-tumor oral formulation of nucleoside analogue, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI). 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.

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:

1. Patients aged between 18 and 75 years of either sex.

2. Histologically confirmed rectal adenocarcinoma with the following conditions:

   1. Clinical stage II (T3-4, N-) or III (any T, N+) as determined by MRI.
   2. 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]).

3. No other types of rectal cancer (e.g., sarcoma, lymphoma, carcinoid, squamous cell carcinoma) or synchronous colon cancer.

4. Presence of measurable lesions that meet RECIST v1.1 criteria for evaluation.

5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

6. Estimated life expectancy > 6 months.

Exclusion Criteria:

1. Patients of dMMR or MSI-H status.
2. Unexplained myelosuppression.
3. 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.
4. Active autoimmune disease or history of autoimmune disease.
5. Uncontrolled cardiac symptoms or diseases.
6. History of other malignancies, except for cured basal cell carcinoma of the skin and cervical carcinoma in situ.