Neoadjuvant Short-course Radiotherapy Followed by a Combination of Disitamab Vedotin, Sintilimab, and Capecitabine in Locally Advanced HER2-expressing Rectal Cance

Neoadjuvant Short-course Radiotherapy Followed by a Combination of Disitamab Vedotin, Sintilimab, and Capecitabine in Locally Advanced HER2-expressing Rectal Cance: Preliminary Results of a Prospective, Single-arm, Phase II Study.

After signing the informed consent form, patients who met the inclusion and exclusion criteria were given the full course of neoadjuvant treatment: short-term radiotherapy, followed by 6 consecutive cycles of disitamab vedotin, combined with sintilimab and capecitabine, and within 3-4 weeks after the last dose, they underwent preoperative imaging examinations to evaluate the efficacy of the neoadjuvant treatment and the possibility of total mesorectal excision. Whether adjuvant therapy was performed after surgery was determined by the investigators.

After signing the informed consent form, patients who met the inclusion and exclusion criteria were given the full course of neoadjuvant treatment: short-term radiotherapy, followed by 6 consecutive cycles of disitamab vedotin, combined with sintilimab and capecitabine, and within 3-4 weeks after the last dose, they underwent preoperative imaging examinations to evaluate the efficacy of the neoadjuvant treatment and the possibility of total mesorectal excision. Whether adjuvant therapy was performed after surgery was determined by the investigators.

Inclusion Criteria:

1. Subjects voluntarily participate in this study, are able to sign the informed consent form, and demonstrate good compliance.
2. Subjects are aged between 18 and 75 years (at the time of signing the informed consent form), regardless of gender.
3. Subjects are diagnosed with locally advanced rectal cancer by histology and/or cytology, with the lower edge of the tumor ≤10 cm from the anal verge. According to the 8th edition of the AJCC criteria, the disease is diagnosed as locally advanced. Based on endoscopic ultrasound or enhanced CT/MRI scans (combined with diagnostic laparoscopic exploration if necessary), the cTNM stage is T3 - 4N+, and the subjects agree to undergo total mesorectal excision.
4. The tumor is ≤5 cm from the anal verge and the subject has a need for anal - preservation, or pelvic MRI shows high - risk features (meeting one of the following conditions):

1) CT stage cT4a or cT4b 2) Extramural vascular invasion (EMVI+) 3) Clinical lymph node (CN) stage cN2, involving the mesenteric fascia 3)Positive lateral lymph nodes 5. Subjects have not previously received systematic treatment for the current disease, including anti - tumor radiotherapy, chemotherapy, immunotherapy, etc.

6. IHC results confirm HER2 expression (defined as IHC 1+, 2+, 3+). 7. The ECOG score is 0 - 1. 8. The estimated survival time is ≥6 months. 9. The functions of major organs are good, meeting the following criteria: 10. In the blood routine examination (without blood transfusion and without using hematopoietic stimulating factors to correct the state within 14 days): Hemoglobin (Hb) ≥90 g/L; Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Platelet (PLT) ≥80×10⁹/L.

11. In the biochemical examination: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; Total serum bilirubin (TBIL) ≤1.5×ULN; Serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance rate ≥60 mL/min.

12. In terms of coagulation function: Activated partial thromboplastin time (APTT), international normalized ratio (INR), and prothrombin time (PT) ≤1.5×ULN.

13. According to Doppler ultrasound evaluation: Left ventricular ejection fraction (LVEF) ≥50%.

14. The doctor clinically determines that the subject has sufficient organ function.

15. Subjects of child - bearing potential must use appropriate contraceptive methods during the study and within 120 days after the study ends. The serum pregnancy test should be negative within 7 days before study enrollment, and the subjects must not be lactating.

Exclusion Criteria:

1. Diagnosis of a malignant disease other than colorectal cancer within 5 years prior to the first dose (excluding radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ).
2. Tumor lesions with a bleeding tendency (e.g., presence of an active ulcerated tumor lesion with a positive fecal occult blood test, history of hematemesis or melena within 2 months before signing the informed consent form, judged by the investigator to be at risk of major gastrointestinal bleeding, etc.) or having received blood transfusion within 4 weeks before the study drug administration.
3. Inability to take oral medications.
4. Currently participating in an interventional clinical research treatment, or having received other research drugs or used research devices for treatment within 4 weeks before the first dose.
5. Previous exposure to the following therapies: anti - HER2, anti - PD - 1, anti - PD - L1, anti - PD - L2 drugs, or drugs targeting another stimulatory or co - inhibitory T - cell receptor (including but not limited to CTLA - 4, OX - 40, CD137, etc.).
6. Systemic treatment with Chinese patent medicines with anti - tumor indications or drugs with immunomodulatory effects (including thymosin, interferon, interleukin, except for local use to control pleural effusion) within 2 weeks before the first dose.
7. Occurrence of an active autoimmune disease requiring systemic treatment (e.g., use of disease - modifying drugs, glucocorticoids, or immunosuppressants) within 2 years before the first dose. Replacement therapies (e.g., thyroxine, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency) are not considered systemic treatment.
8. Receiving systemic glucocorticoid treatment (excluding nasal spray, inhaled, or other local glucocorticoids) or any other form of immunosuppressive therapy within 7 days before the first dose of the study. Note: Use of physiological doses of glucocorticoids (≤10 mg/day of prednisone or equivalent) is allowed.
9. Known allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation.
10. Known allergy to the drugs used in this study.
11. Peripheral neuropathy of grade 2 or higher.
12. Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV 1/2 antibodies).
13. Subjects with active hepatitis B or hepatitis C (positive HBsAg with HBV DNA titer above the upper limit of normal; positive HCVAb with HCV RNA titer above the upper limit of normal).
14. Vaccination with a live vaccine within 30 days before the first dose (Cycle 1, Day 1). Note: Receiving an injectable inactivated virus vaccine against seasonal influenza within 30 days before the first dose is allowed, but receiving a live attenuated influenza vaccine administered intranasally is not allowed.
15. Pregnant or lactating women.
16. Presence of any severe or uncontrollable systemic diseases, such as:

1. Significant and severely symptomatic and uncontrollable abnormalities in rhythm, conduction, or morphology on a resting electrocardiogram, such as complete left bundle - branch block, cardiac conduction block of grade II or higher, ventricular arrhythmia, or atrial fibrillation.
2. Unstable angina, congestive heart failure, chronic heart failure of New York Heart Association (NYHA) class 2 or higher.
3. Any arterial thrombosis, embolism, or ischemia (such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) within 6 months before enrollment for treatment.
4. Poor blood pressure control (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg).
5. History of non - infectious pneumonia requiring glucocorticoid treatment within 1 year before the first dose, or current presence of clinically active interstitial lung disease.
6. Active pulmonary tuberculosis.
7. Presence of an active or uncontrolled infection requiring systemic treatment.
8. Presence of clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction.
9. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis.
10. Poorly controlled diabetes (fasting blood glucose (FBG) > 10 mmol/L).
11. Urine routine indicating urine protein ≥ ++ and confirmed 24 - hour urine protein quantification > 1.0 g.
12. Patients with mental disorders who are unable to cooperate with treatment. 17. History, evidence of disease, treatment, or abnormal laboratory test values that may interfere with the test results or prevent the subject from participating in the study throughout, or other situations considered by the investigator as unsuitable for enrollment. The investigator believes that there are other potential risks that make the subject unsuitable for this study.