Tafolecimab Combined With Sintilimab and SOX in the Treatment of pMMR/MSS Gastric Cancer

Efficacy and Safety of a PCSK9 Inhibitor (Tafolecimab) Combined With Sintilimab and SOX in the Treatment of pMMR/MSS Gastric Cancer: A Multicenter, Prospective, Single-Arm Exploratory Study

Background:

Gastric cancer remains a significant health burden globally, particularly in China, where the majority of patients present with advanced disease at diagnosis. While immune checkpoint inhibitors (ICIs) targeting PD-1 have revolutionized treatment for various malignancies, their efficacy in proficient mismatch repair (pMMR) or microsatellite stable (MSS) gastric cancer-which constitutes over 85% of cases-remains limited. Recent Phase III trials (CheckMate 649, ATTRACTION-04, Orient-16) have demonstrated that combining PD-1 inhibitors with chemotherapy improves outcomes in advanced gastric cancer, leading to approved indications. However, the benefit in pMMR/MSS populations is modest, highlighting an urgent need for novel combination strategies to overcome immunotherapy resistance.

Preclinical research published in Nature (Liu et al., 2020) revealed that inhibiting PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9)-a key regulator of cholesterol metabolism-can potentiate immune checkpoint therapy through a novel mechanism independent of its lipid-lowering function. PCSK9 inhibition was shown to increase tumor cell surface expression of MHC class I molecules by preventing their lysosomal degradation, thereby enhancing tumor antigen presentation and promoting cytotoxic T lymphocyte infiltration. This mechanistic insight suggests that combining a PCSK9 inhibitor with PD-1 blockade could synergistically improve antitumor immunity, particularly in immunologically "cold" tumors like pMMR/MSS gastric cancer.

Tafolecimab is the first domestically developed fully humanized PCSK9 monoclonal antibody approved in China for hypercholesterolemia, with a favorable safety profile and extended half-life. Based on this strong preclinical rationale and the established efficacy of PD-1 plus chemotherapy in gastric cancer, this investigator-initiated trial aims to clinically translate the concept of PCSK9 inhibition as an immunomodulatory strategy.

Study Population:

This study will enroll 30 patients with the following key eligibility criteria:

Inclusion: Adults aged 18-75 years with histologically confirmed pMMR/MSS gastric or gastroesophageal junction adenocarcinoma; initially unresectable or advanced disease (including metastatic); ECOG performance status 0-1; measurable disease per RECIST v1.1; adequate organ function.

Exclusion: HER2-positive, EBER-positive, or CLDN18.2-positive tumors; prior systemic anticancer therapy for advanced disease; active autoimmune disease requiring immunosuppression; uncontrolled intercurrent illness; LDL-C <30 mg/dL; history of PCSK9 inhibitor allergy; prior exposure to anti-PD-1/PD-L1 or PCSK9-targeted therapies.

Study Objectives:

This is a multicenter, prospective, single-arm exploratory trial with a safety run-in phase (first 6 patients monitored for dose-limiting toxicities). The treatment regimen consists of:

Sintilimab (PD-1 inhibitor): 200 mg IV, day 1, every 3 weeks (Q3W) Tafolecimab (PCSK9 inhibitor): 300 mg subcutaneous injection, day 1, Q3W (dose reduction to 150 mg if DLTs occur) SOX chemotherapy: Oxaliplatin 130 mg/m² IV, day 1 + S-1 40 mg/m² orally twice daily, days 1-14, Q3W cycles Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.

Primary Endpoint:

Objective Response Rate (ORR) assessed by RECIST v1.1

Secondary Endpoints:

Progression-Free Survival (PFS) Disease Control Rate (DCR) Conversion surgery rate and R0 resection rate Pathological Complete Response (pCR) and Major Pathological Response (MPR) rates in resected patients Overall Survival (OS) Safety and tolerability (incidence of TRAEs, ≥Grade 3 AEs, irAEs per CTCAE v5.0)

Exploratory Endpoints:

Association between tumor biomarkers (including PD-L1 CPS, H. pylori infection status, and tumor PCSK9 expression) and treatment efficacy Multi-omics analyses using paired pre- and post-treatment tumor tissue, peripheral blood, and fecal samples

Sample Size and Duration:

A fixed sample size of 30 patients will be recruited over approximately 12 months, with survival follow-up extending to 36 months. This exploratory study is designed to generate preliminary efficacy and safety signals to inform future larger-scale investigations. The safety run-in design ensures close monitoring for potential additive toxicities, particularly given the novel combination of PCSK9 inhibition with immunotherapy and chemotherapy.

Inclusion Criteria:

1. Fully understood the study and voluntarily signed the Informed Consent Form (ICF);

2. Aged 18-75 years, male or female;

3. Histopathologically confirmed pMMR/MSS type gastric/gastroesophageal junction adenocarcinoma;

4. Initially unresectable, advanced gastric/gastroesophageal junction adenocarcinoma;

5. ECOG performance status 0-1;

6. Life expectancy exceeding 3 months;

7. Presence of measurable disease as confirmed by the investigator according to RECIST 1.1 criteria;

8. Patients currently taking statin lipid-lowering medications must discontinue for ≥4 days before enrollment in this study;

9. Adequate major organ function meeting the following requirements (laboratory values must meet the following criteria within 7 days before enrollment):

   • Hematology (no transfusion, no granulocyte colony-stimulating factor [G-CSF], no medication correction within 14 days before screening):
   • Neutrophils ≥ 1.5 × 10⁹/L;
   • Platelets ≥ 75 × 10⁹/L;
   • Hemoglobin ≥ 90 g/L;
   • Biochemistry (no albumin infusion within 14 days before screening):
   • Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or creatinine clearance > 50 mL/min;
   • Serum total bilirubin ≤ 1.5 × ULN (subjects with Gilbert's syndrome are allowed total bilirubin ≤ 3 × ULN);
   • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN; for subjects with liver metastases, ALT and AST ≤ 5 × ULN;

   Coagulation function:

   - International Normalized Ratio (INR) ≤ 2.3 or Prothrombin Time (PT) exceeding normal control by ≤ 6 seconds;

10. No severe concomitant diseases leading to a life expectancy < 5 years;

11. Agree to provide blood and tissue samples for molecular biology testing;

12. For patients with active Hepatitis B Virus (HBV) infection: HBV-DNA must be < 500 IU/mL (if the study center only uses copy/mL units, must be < 2500 copies/mL), and willing to receive antiviral therapy throughout the study period; Hepatitis C Virus (HCV) RNA-positive patients must receive antiviral therapy according to local standard treatment guidelines and have liver function elevations within CTCAE Grade 1;

13. Within 28 days before enrollment, females of childbearing potential must have a confirmed negative serum pregnancy test and agree to use effective contraception during study drug administration and for 60 days after the last dose. For this protocol, females of childbearing potential are defined as sexually mature women who: 1) have not undergone hysterectomy or bilateral oophorectomy; 2) have not been naturally postmenopausal for at least 24 consecutive months (cancer treatment-induced amenorrhea does not rule out childbearing potential) (i.e., have had menstruation at any time in the preceding 24 consecutive months). Male subjects' female partners of childbearing potential should also follow the above contraceptive requirements.

Exclusion Criteria:

1. HER2 positive (IHC 3+, or IHC 2+ with positive in situ hybridization);
2. EBER positive;
3. CLDN18.2 positive (≥ 75% of tumor cells with membranous staining of IHC intensity 2+/3+);
4. Currently participating in other interventional clinical studies;
5. Low-density lipoprotein cholesterol (LDL-C) controlled below 30 mg/dL (≈ 0.78 mmol/L);
6. History of allergic reaction to PCSK9 inhibitors;
7. Concurrent other active malignancy within the last 5 years besides gastric/gastroesophageal junction adenocarcinoma that has not recovered; Patients preparing for or having previously received organ or allogeneic bone marrow transplantation;
8. Received major surgery (excluding diagnostic) within 4 weeks before start of study treatment or expected to require major surgery during the study (excluding radical gastrectomy);
9. Currently have interstitial pneumonia or interstitial lung disease, or a history of interstitial pneumonia or interstitial lung disease requiring steroid therapy, or other pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), pneumoconiosis, drug-related pneumonia, idiopathic pneumonia that might interfere with the judgment and management of immune-related pulmonary toxicity, or evidence of active pneumonitis on chest computed tomography (CT) scan during the screening period, or severely impaired pulmonary function.Subjects with radiation pneumonitis in the radiation field are allowed; active tuberculosis;

11. Presence of active autoimmune disease or a history of autoimmune disease that may recur (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [subjects controlled by hormone replacement therapy alone can be included]); subjects with skin diseases not requiring systemic treatment such as vitiligo, psoriasis, alopecia, controlled Type I diabetes mellitus receiving insulin therapy, or childhood asthma that has completely resolved and requires no intervention in adulthood can be included; asthma patients requiring bronchodilators for medical intervention cannot be included; 12. History of uncontrolled epilepsy, central nervous system disease, or mental disorders, judged by the investigator as to whether clinical severity interferes with signing informed consent or affects patient compliance with medication; 13. Clinically significant (i.e., active) heart disease, such as symptomatic coronary artery disease, New York Heart Association (NYHA) Class II or more severe congestive heart failure, or severe arrhythmia requiring medical intervention, or history of myocardial infarction within the last 12 months; 14. Severe uncontrolled recurrent infections, or other severe uncontrolled concomitant diseases; 15. Allergy or contraindication to the components of the study drugs (PCSK9 inhibitor, PD-1 monoclonal antibody, or chemotherapeutic agents); 16. Prior receipt of any anti-tumor therapy for gastric/gastroesophageal junction adenocarcinoma, including radiotherapy, chemotherapy, systemic therapy, etc.; 17. Use of immunosuppressants or systemic hormone therapy for immunosuppressive purposes (dose > 10 mg/day prednisone or equivalent) within 14 days before the start of study treatment; 18. Patients with congenital or acquired immunodeficiency (e.g., HIV infection); 19. Co-infection with Hepatitis B and Hepatitis C; 20. Prior receipt of other anti-PD-1 antibody therapy or other immunotherapy targeting PD-1/PD-L1, or prior receipt of PCSK9 monoclonal antibody therapy; 21. Receipt of live attenuated vaccine within 28 days before start of study treatment, or expected need for such vaccination during PD-1 monoclonal antibody treatment or within 60 days after the last dose of PD-1 monoclonal antibody; 22. Receipt of investigational drug (i.e., participating in another trial), anti-tumor cytotoxic drug therapy, biological drug therapy (e.g., monoclonal antibodies), immunotherapy (e.g., interleukin-2 or interferon) within 4 weeks before study enrollment; 23. Judged by the investigator, patients have other factors that may affect the study results or lead to premature termination of the study, such as alcoholism, drug abuse, other severe diseases (including mental illness) requiring concurrent treatment, severe laboratory abnormalities, family or social factors, etc., that might affect subject safety or compliance; 24. Subjects with active tuberculosis (TB), receiving anti-tuberculosis treatment, or having received anti-tuberculosis treatment within 1 year before screening; 25. Pregnant or breastfeeding women.