FAPI-Guided Radiotherapy With Cadonilimab and Standard Chemotherapy for Colorectal Peritoneal Metastasis: A Phase III Randomized Controlled Trial (TORHC-PM02)

• Second-Line Chemotherapy (Drug): All chemotherapy agents are given by intravenous infusion every 2 weeks with oxaliplatin, leucovorin and continuous infusion fluorouracil, or irinotecan, leucovorin and continuous infusion fluorouracil. Targeted agents bevacizumab or cetuximab can be added per investigator's clinical judgment. Dose adjustments are allowed for myelosuppression, gastrointestinal or other toxicities.
• Radiation Therapy (Radiation): Radiation target volumes are contoured on fused FAPI PET/CT images for peritoneal masses ≥1 cm. Fraction doses range from 5 Gy to 25 Gy over 5 fractions, modified to meet small intestine organ-at-risk constraints. Radiation is delivered within the first 8 weeks of combined chemoimmunotherapy treatment.
• Cadonilimab (AK104) (Drug): Cadonilimab is a PD-1/CTLA-4 dual-target biologic agent. The fixed dose of 6 mg/kg is infused intravenously once every 2 weeks alongside chemotherapy. Dose delay or permanent discontinuation will be applied for grade 3-4 immune-related adverse events that do not improve with immunosuppressive treatment.

Primary outcomes

• Progression-Free Survival (PFS) [Up to 36 months after randomization]: Time from randomization to first documentation of tumor progression (including enlargement of target lesions, new distant metastases, or new onset of ascites) or death from any cause, whichever occurs first, assessed per RECIST v1.1.

Secondary outcomes

• Overall Survival (OS) [OS is defined from randomization until death from any cause up to 36 months.]: Survival duration from randomization until death from any cause.
• Objective Response Rate (ORR) [The best overall tumor response will be assessed every 8 weeks after the participant begins study treatment by scheduled MDT assessment through study completion, up to 36 months.]: The best overall tumor response rate, defined as the proportion of participants achieving confirmed complete response or partial response assessed via imaging based on RECIST 1.1 criteria and verified by multidisciplinary team review.
• Disease Control Rate (DCR) [The best overall disease control rate will be assessed every 8 weeks after the participant begins study treatment by scheduled MDT assessment through study completion, up to 36 months.]: The best overall disease control rate, defined as the proportion of participants with confirmed complete response, partial response or stable disease assessed via imaging based on RECIST 1.1 criteria and verified by multidisciplinary team review.
• Treatment-related adverse events [Side effects will be recorded from the participant's first study treatment dose with radiotherapy and system treatment every cycle to 30 days after their final study treatment dose through study completion, up to 36 months.]: Incidence and severity of treatment side effects graded by NCI CTCAE v6.0.
• Quality of life( QoL) [At baseline and radiotherapy period will be reorded once, at system treatments QoL will be reported and recorded every 8 weeks regularly during the treatment through study completion, up to 36 months.]: Patient self-assessment via EORTC QLQ-C30 questionnaire to monitor changes in quality of life throughout treatment.

Other outcomes

• Change in Peritoneal Cancer Index (PCI) [At baseline and every 8 weeks fixed assessment time points during treatment by scheduled MDT assessment through study completion, up to 36 months.]: PCI score reflecting peritoneal tumor burden is measured on FAPI PET/CT images to observe tumor load variations.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. Histopathologically confirmed colorectal adenocarcinoma.
2. Tumors confirmed pMMR by immunohistochemistry or MSI-L/MSS via gene sequencing.
3. Metastases limited to peritoneum only, no metastases in other organs.
4. No moderate or massive ascites; only trivial physiological effusion without drainage requirement.
5. No symptomatic intestinal obstruction and no obstructive signs on imaging; patients can take food normally.
6. Baseline CT/MRI confirms peritoneal metastases.
7. Positive baseline FAPI PET/CT: at least one peritoneal mass lesion with long diameter ≥1 cm and markedly elevated SUVmax suitable for radiotherapy contouring.
8. At least one measurable lesion per RECIST v1.1 criteria.
9. Progression after first-line standard systemic therapy (FOLFOX/XELOX ± targeted agents); no prior second-line treatment received.
10. Peritoneal recurrence within 1 year after adjuvant fluoropyrimidine-based chemotherapy.
11. No moderate or massive ascites; only trivial physiological effusion without drainage requirement.
12. Voluntarily sign written informed consent and comply with scheduled study visits and treatment procedures.

Exclusion Criteria:

1. Prior exposure to any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or other agents targeting T-cell co-stimulatory/checkpoint pathways.
2. Moderate or massive ascites requiring clinical intervention.
3. Partial or complete symptomatic intestinal obstruction.
4. Pregnant or breastfeeding women.
5. History of high-dose abdominal radiotherapy that prevents re-irradiation.
6. Diffuse miliary peritoneal metastases on FAPI PET/CT without definable target volume for radiotherapy.
7. Active autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, etc.); systemic corticosteroids or other immunosuppressants required within 14 days before enrollment; severe underlying vital organ disease judged unsuitable for immunotherapy by investigators.
8. Poor compliance or other conditions judged inappropriate for study participation by investigators.