This study will evaluate the effectiveness and safety of HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG regimen) as conversion therapy for patients with locally advanced pancreatic cancer.

Participants will undergo regular assessments, including imaging scans and CA19-9 biomarker tests. If disease recurrence is suspected, unscheduled evaluations may be performed. For participants who discontinue treatment due to reasons other than disease progression (e.g., toxicity), tumor assessments will continue as scheduled until progression, loss to follow-up, death, consent withdrawal, or study termination.

After the final treatment, participants will enter a survival follow-up phase. Investigators will contact the participants or their families approximately every month (±7 days) to collect information on survival status (date and cause of death) and any subsequent anti-cancer treatments until death, loss to follow-up, study termination, or other study endpoints are met. All follow-up information will be documented in the medical records.

Study Objectives

Primary Objective:

● To evaluate the efficacy of HRS-4642 combined with AG (nab-paclitaxel and gemcitabine) as conversion therapy in patients with locally advanced pancreatic cancer, as measured by Objective Response Rate (ORR).

Secondary Objectives:

• To evaluate the efficacy of HRS-4642 combined with AG as conversion therapy by assessing surgical conversion rate, Disease Control Rate (DCR), CA19-9 response rate, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and 1-year OS rate.
• To evaluate the safety profile of HRS-4642 combined with AG as conversion therapy.
• To assess changes in health-related quality of life from baseline using the EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires in all participants.

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for this study:

1. Age ≥18 years and ≤75 years, regardless of gender.

2. Histologically or cytologically confirmed pancreatic ductal adenocarcinoma.

3. Radiologically confirmed locally advanced disease, defined as:

   1. No distant metastasis.
   2. Pancreatic head/uncinate process tumors: Tumor contact with the superior mesenteric artery (SMA) >180°.
   3. Pancreatic body/tail tumors: Tumor contact with the SMA or celiac artery >180°; or contact with the celiac artery with aortic invasion; or tumor invasion of the jejunal branches of the SMA.
   4. Inability to safely reconstruct the portal vein-superior mesenteric vein due to tumor invasion, venous occlusion, or extensive involvement of the jejunal branches of the superior mesenteric vein.

4. KRAS G12D mutation confirmed by tissue histology or peripheral blood testing.

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

6. No prior antitumor therapy (including radiotherapy, chemotherapy, targeted therapy, or immunotherapy).

7. At least one radiologically measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

8. If biliary obstruction is present, it must have been relieved prior to study entry, and the expected survival time is >3 months.

9. Signed written informed consent obtained before performing any study-related procedures.

10. Adequate organ function meeting the following criteria (without corrective treatment with blood components or growth factors within 14 days prior to the first dose), with test results completed within 7 days before initiation of study treatment:

    1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L.
    2. White blood cell (WBC) count ≥3.0 × 10^9/L.
    3. Platelets ≥100 × 10^9/L.
    4. Hemoglobin >9 g/dL.
    5. Albumin ≥3.0 g/dL.
    6. Total bilirubin ≤1.5 × upper limit of normal (ULN).
    7. Prothrombin time and activated partial thromboplastin time ≤1.5 × ULN.
    8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
    9. Serum creatinine ≤1.5 × ULN or creatinine clearance (calculated using Cockcroft-Gault formula) ≥50 mL/min.
    10. Electrocardiogram: QTcF interval ≤450 msec for males and ≤470 msec for females.

11. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose and must not be lactating. Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use effective contraception from the time of signing the informed consent form until 180 days after the last dose of the study drug (whichever is later). A female is considered not of childbearing potential if postmenopausal for at least 1 year, or surgically sterilized (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

Exclusion Criteria:

Participants will be excluded from the study if they meet any of the following criteria:

1. Presence of portal hypertension or cavernous transformation of the portal vein; tumor involvement of the gastrointestinal tract causing gastrointestinal bleeding; tumor leading to intra-abdominal fistula or abscess; tumor encasement of the celiac artery or superior mesenteric artery (SMA) with significant vascular wall involvement (moth-eaten appearance).

2. Diagnosis of malignancies other than pancreatic cancer within 5 years prior to the first dose (excluding radically treated skin basal cell carcinoma, squamous cell carcinoma, and/or carcinoma in situ).

3. History of active autoimmune disease requiring systemic therapy (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic therapy.

4. Current use of systemic corticosteroid therapy (excluding topical, inhaled, nasal, or intra-articular corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first study dose. Note: Use of physiologic doses of corticosteroids (≤10 mg/day prednisone or equivalent) is permitted.

5. Known history of allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.

6. History of allergy or hypersensitivity considered clinically significant by the investigator.

7. Presence of clinically significant acute or chronic pancreatitis.

8. History of drug abuse, chronic alcoholism, or infectious diseases such as AIDS (i.e., HIV-1/2 antibody positive).

9. Uncontrolled active hepatitis B (defined as HBsAg positive with HBV-DNA level above the upper limit of normal at the local laboratory). Note: Participants with hepatitis B meeting the following criteria may be enrolled: 1) HBV viral load <10,000 copies/mL (2,000 IU/mL) prior to the first dose, and the participant should receive anti-HBV therapy throughout the study drug treatment period to prevent reactivation; 2) Participants who are anti-HBc positive, HBsAg negative, anti-HBs negative, and with negative HBV viral load do not require prophylactic anti-HV therapy but require close monitoring for reactivation.

10. Active hepatitis C virus (HCV) infection (HCV antibody positive and HCV-RNA level above the lower limit of detection).

11. Administration of a live attenuated vaccine within 28 days prior to the first study dose or anticipated need for a live attenuated vaccine during the study treatment period. Note: Administration of inactivated seasonal influenza vaccine within 28 days prior to the first dose is permitted; however, live attenuated intranasal influenza vaccines are not allowed.

12. Major surgery (other than diagnostic biopsy) within 28 days prior to the first dose; minor traumatic surgery (biopsy, endoscopy, and drainage) within 7 days prior to the first dose; presence of non-healing wounds, untreated fractures.

13. Presence of any severe or uncontrolled systemic disease, for example:

    1. Resting ECG showing significant uncontrolled abnormalities in rhythm, conduction, or morphology, such as complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmia, or atrial fibrillation.
    2. Unstable angina, congestive heart failure, chronic heart failure of New York Heart Association (NYHA) class ≥II.
    3. History of any arterial thrombotic, embolic, or ischemic event within 6 months prior to enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
    4. Poorly controlled blood pressure (systolic >150 mmHg or diastolic >100 mmHg).
    5. History of non-infectious interstitial lung disease requiring glucocorticoid therapy within 1 year prior to the first dose, or current clinically active interstitial lung disease.
    6. Active tuberculosis.
    7. Active or uncontrolled infection requiring systemic therapy.
    8. Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction.
    9. Liver disease such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis.
    10. Low-density lipoprotein cholesterol (LDL-C) >3.4 mmol/L or severe hypertriglyceridemia (>5.7 mmol/L).
    11. Carotid ultrasound showing stenosis ≥50% or the presence of two or more high-risk characteristic plaques.

14. History of severe infection within 28 days prior to the first dose, including but not limited to infection complications requiring hospitalization, bacteremia, or severe pneumonia; or active infection requiring therapeutic intravenous antibiotics within 2 weeks before starting study treatment. Participants receiving prophylactic antibiotics (e.g., for urinary tract infection prevention) may be enrolled.

15. Any history, evidence of disease, treatment, or abnormal laboratory value that, in the investigator's judgment, could interfere with the trial results, prevent the participant from completing the study, indicate poor compliance, or pose potential risks making the participant unsuitable for study participation.