Neoadjuvant Immunotherapy ± Radiotherapy in MSI-H/dMMR Locally Advanced Colorectal Cancer (TORCH-OPTIMA)

A Phase II Randomized Controlled Trial of Neoadjuvant Immunotherapy With or Without Radiotherapy in Locally Advanced Microsatellite Instability-High/Mismatch Repair-Deficient Colorectal Cancer

This phase II clinical trial evaluates the efficacy and safety of three neoadjuvant regimens in patients with locally advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC): 1) Regimen A: Dual immune checkpoint blockade with nivolumab plus ipilimumab. 2) Regimen B: Nivolumab plus radiotherapy. 3) Regimen C: Nivolumab monotherapy. The primary objectives are to determine whether: 1) Dual immune checkpoint blockade (Regimen A) is superior to nivolumab monotherapy (Regimen C); and 2) Immunotherapy plus radiotherapy (Regimen B) is superior to nivolumab monotherapy (Regimen C). Methods: Participants will be randomized in a 1:1:1 ratio to one of the three arms. For patients with resectable tumors, surgical resection will be performed. In patients with low rectal cancer and poor prospects for sphincter preservation, a watch-and-wait (WW) strategy is an option if a clinical complete response (CR) is achieved following neoadjuvant therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer (MSI-H)
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab (1mg/kg); Procedure: Radical surgery; Other: Watch & wait; Radiation: PULSAR

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Menglong Zhou, MD; Phone Number: 86+18121299608; Email: mrzhouml@163.com

Study Locations

• China
  • Shanghai, China
    • Fudan University Shanghai Cancer Center
    • Contact: Menglong Zhou, MD; Phone Number: 86-18121299608; Email: mrzhouml@163.com
    • Principal Investigator: Zhen Zhang, MD
    • Principal Investigator: Sanjun Cai, MD
    • Sub-Investigator: Fangqi Liu, MD
    • Sub-Investigator: Fan Xia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histopathologically confirmed primary colorectal adenocarcinoma.
2. Radiographic assessment showed a stage II-III based on AJCC Stage 8th ed.
3. At least 18 years old.
4. MSI-H or dMMR.
5. The Eastern Cooperative Oncology Group performance status (ECOG PS) score is 0 or 1.
6. Physical state or organ function can tolerate the planned treatment of the study protocol.
7. Agreed to sign written informed consent before recruitment.

Exclusion Criteria:

1. Previously received any antitumor therapy for the disease under study, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.
2. Pregnancy or breastfeeding women.
3. History of other malignancies within 5 years.
4. Serious medical illness, such as severe mental disorders, cardiac disease, uncontrolled infection, etc.
5. Immunodeficiency disease or long-term using of immunosuppressive agents.
6. Allergic to any component of the therapy.
7. Any other condition or disease that is not suitable to take the therapy included in the protocol.
8. Concurrent participation in another clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study.
9. Received any investigational drug or device treatment within 4 weeks prior to initial administration of the investigational drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: anti-PD-1 plus anti-CTLA-4; Arm A: Nivolumab 240 mg every 2 weeks (6 doses) plus ipilimumab 1 mg/kg every 3 weeks (4 doses).	Drug: Nivolumab; Nivolumab 240 mg every 2 weeks; Drug: Ipilimumab (1mg/kg); Ipilimumab 1 mg/kg every 3 weeks; Procedure: Radical surgery; Surgical resection will be performed in resectable cases.; Other: Watch & wait; For patients with low rectal cancer who are unable to preserve the anal sphincter, a watch-and-wait (WW) strategy can be considered if a clinical complete response (CR) is achieved.
Experimental: anti-PD-1 plus radiotherapy; Arm B: Radiotherapy (5 Gy per fraction, total 4 fractions, delivered every 3 weeks) to the primary lesion plus nivolumab 240 mg every 2 weeks (6 doses).	Drug: Nivolumab; Nivolumab 240 mg every 2 weeks; Procedure: Radical surgery; Surgical resection will be performed in resectable cases.; Other: Watch & wait; For patients with low rectal cancer who are unable to preserve the anal sphincter, a watch-and-wait (WW) strategy can be considered if a clinical complete response (CR) is achieved.; Radiation: PULSAR; Irradiation targeted to the primary lesion (5 Gy per fraction, total 4 fractions, delivered every 3 weeks).
Active Comparator: anti-PD-1 monotherapy; Arm C: Nivolumab 240 mg every 2 weeks (6 doses).	Drug: Nivolumab; Nivolumab 240 mg every 2 weeks; Procedure: Radical surgery; Surgical resection will be performed in resectable cases.; Other: Watch & wait; For patients with low rectal cancer who are unable to preserve the anal sphincter, a watch-and-wait (WW) strategy can be considered if a clinical complete response (CR) is achieved.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete regression (CR) rate	Proportion of patients achieving either clinical CR (and undergoing WW) or pathological CR (confirmed by pathology) among all evaluable patients.	1 month after surgery or the completion of neoadjuvant therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicities	Number of participants with treatment-related adverse events (TrAEs) reported between the first dose and 28 days after the last dose of study therapy as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.	From the time of enrollment, assessed up to 28 days after the last dose of study therapy
Surgical mortality	Death from any cause within 30 days of the date of surgery will be considered a surgical mortality death.	During or one month after surgery
Overall survival (OS)	OS is defined as the time interval from enrollment to death of any reason or censoring.	36 months after the enrollment of the last subject
Surgical morbidity	Surgery related adverse events (SRAEs) refer to complications which happen during or one month after surgery. Severe complications after surgery will be documented and classified by Clavien-Dindo classification, such as abdominal or GI tract bleeding, anastomotic fistula, pancreatic fistula of grade B or above, and incision complications (infection, bleeding, rupture).	During or one month after surgery
R0 resection rate	Proportion of patients who achieve R0 resection.	1 month after surgery
Objective response rate (ORR)	Proportion of patients with complete response (CR) or partial response (PR) to preoperative multimodal therapy. ORR will be evaluated using RESIST1.1 by CT/MRI of the chest, abdomen, and pelvis.	6 months after the enrollment of the last subject
Event-free survival (EFS)	The EFS was defined as the time from randomization to the first determination of inoperable disease progression, postoperative local recurrence or distant metastasis, tumor regrowth, or death from any cause, whichever occurs first.	36 months after the enrollment of the last subject

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2034

Study Registration Dates

• First Submitted: February 1, 2026
• First Submitted That Met QC Criteria: February 7, 2026
• First Posted (Actual): February 11, 2026

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 7, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: colorectal cancer; immunotherapy; radiotherapy; neoadjuvant therapy; locally advanced; microsatellite instability high; mismatch repair-deficient
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Turcot syndrome; Amino Acids, Peptides, and Proteins; Proteins; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Polysaccharides; Glucans; Dextrans; Nivolumab; Ipilimumab; DEAE-Dextran
• Other Study ID Numbers: FDRT-2025-592-4741

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No