Application of furaquitinib combined with PD-1 monoclonal antibody in HER-2 negative advanced GC / GEJC maintenance treatment

Abstract

The invention discloses application of furaquitinib combined with a PD-1 monoclonal antibody in HER-2 negative advanced GC / GEJC maintenance treatment, and belongs to the technical field of tumor treatment. Aiming at HER2 negative advanced gastric cancer or gastroesophageal junction adenocarcinoma, disease control is realized after PD-1 monoclonal antibody combined with first-line induction treatment based on oxaliplatin for three months, and a therapeutic scheme is maintained through dechemotherapy of furaquinib combined with the PD-1 monoclonal antibody subsequently. The maintenance treatment scheme provided by the invention improves the life quality of a patient and prolongs the total lifetime while delaying disease progression, and has important clinical significance.

Description

Technical Field

[0001] The present invention belongs to the technical field of tumor treatment, and particularly relates to the application of fruquintinib combined with PD-1 monoclonal antibody in the maintenance treatment after (during) the first-line induction treatment of HER-2 negative advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC / GEJC). Background Art

[0002] Gastric cancer (GC) is the fifth most common cancer globally and the fourth leading cause of cancer-related deaths. The highest incidence and mortality rates are found in East Asian men and women, with 43.9% of gastric cancer cases and 48.6% of global deaths occurring in China. Currently, surgical resection remains the only way to cure gastric cancer. However, patients are already in the middle or advanced stage at the time of initial diagnosis and are inoperable, and even a large proportion of patients experience recurrence or metastasis after surgery. In such cases, systemic chemotherapy is the main treatment. The 5-year survival rate of advanced or metastatic gastric cancer is 5-20%, and the median overall survival (OS) is approximately 1 year. In the early 21st century, chemotherapy based on fluorouracil plus platinum was the first-line treatment for inoperable advanced or metastatic HER2-negative gastric cancer in China and globally. Over the past decade, the treatment methods for various malignancies have developed rapidly, achieving revolutionary milestones from traditional chemotherapy to molecular targeted therapy and then to immunotherapy, gradually improving the prognosis.

[0003] Immune checkpoint inhibitors, such as anti-programmed cell death protein 1 / programmed death ligand 1 (PD-1 / PD-L1) antibodies, have revolutionized the standard treatment paradigm for many types of solid tumors. Currently, the first-line standard treatment for gastric cancer has evolved from previous single chemotherapy to a new model of immunotherapy combined with chemotherapy.

[0004] Specifically, in the randomized global Phase 3 CheckMate 649 study (for patients with PD-L1, combined positive score (CPS) ≥5), nivolumab plus chemotherapy showed superior overall survival compared to chemotherapy at 12-month follow-up in gastric, gastroesophageal junction, or esophageal adenocarcinoma. Based on this study, nivolumab plus chemotherapy has been approved as first-line treatment for these patients in many countries. The ORIENT-16 study demonstrated that sintilimab plus XELOX significantly improved progression-free survival (PFS) and overall survival (OS) in the first-line overall population of advanced gastric cancer (regardless of PD-L1 expression status). The KEYNOTE-859 study evaluated 1,579 patients with locally advanced or metastatic HER2-negative gastric cancer or gastroesophageal cancer who received fluoropyrimidine- and platinum-containing dual chemotherapy plus pembrolizumab. Regarding the PD-L1 status at baseline, 78% of patients had a PD-L1 CPS ≥1, while 35% of patients had a tumor CPS ≥10. At a median follow-up of 31.0 months, the median overall survival in the pembrolizumab plus chemotherapy group was 12.9 months, compared with 11.5 months in the chemotherapy-alone group, and the benefit of pembrolizumab was observed in all key subgroups. The median PFS was 6.9 months and 5.6 months, respectively. The RATIONALE-305 study showed that tislelizumab plus chemotherapy for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, regardless of whether the patient had a PD-L1 tumor area positivity (TAP) score ≥5% or the overall population, tislelizumab plus chemotherapy could significantly prolong the overall survival of patients with advanced gastric cancer.

[0005] Although immunotherapy with immune checkpoint inhibitors represented by PD-1 antibodies has changed the first-line treatment pattern of advanced gastric cancer, the treatment options for second-line therapy are very limited after the progression of first-line treatment. Signaling and angiogenesis mediated by vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) are involved in the pathogenesis of gastric cancer. In patients with gastric cancer, circulating VEGF levels are associated with increased tumor invasiveness and reduced survival. Anti-angiogenic therapies targeting the VEGF / VEGFR signaling pathway, whether as monotherapy or in combination regimens, have been proven effective and safe in clinical studies and practices for various tumors such as gastric cancer, liver cancer, and colorectal cancer, and have become an important strategy for systemic treatment of advanced digestive tract tumors. Ramucirumab is a human IgG1 monoclonal antibody targeting VEGFR2. The success of the previous RAINBOW study has made ramucirumab plus paclitaxel the second-line standard treatment regimen for patients with advanced gastric cancer in many countries and regions.

[0006] The results of the phase III ARMANI study were reported at the ESMO 2024 and ASCO 2024 annual meetings. This trial was a multicenter trial conducted in Italy, which evaluated whether maintenance therapy with paclitaxel combined with ramucirumab was superior to continued first-line chemotherapy based on oxaliplatin as maintenance therapy for patients with HER2-negative advanced gastric cancer or gastroesophageal junction cancer. Among patients with advanced HER2-negative gastric cancer or gastroesophageal junction (GEJ) cancer who achieved disease control after 3 months of induction therapy with FOLFOX or CAPOX, compared with continued use of FOLFOX, ramucirumab combined with paclitaxel could improve PFS (3.5 months in the control group and 6.6 months in the experimental group) and OS (10.4 months in the control group and 12.6 months in the experimental group) outcomes. According to the results of the ARMANI trial, ramucirumab combined with paclitaxel may be a new standard post-induction treatment strategy, and switching to consolidation maintenance therapy can extend the benefits of the initial strategy and delay disease progression.

[0007] According to the above sorting of tumor treatment regimens, it can be found that whether it is first-line, second-line treatment or maintenance treatment, the treatment strategy is still mainly chemotherapy. Since the publication of the first article on paclitaxel maintenance therapy in the Journal of Clinical Oncology in 2005, maintenance therapy has always been a research hotspot in the field of tumor treatment. Especially after the results of the JMEN study were announced, maintenance therapy took a turn for the better, and pemetrexed also became an option for those who did not progress in first-line treatment and entered the NCCN treatment guidelines. Theoretically, for those who achieve disease control in first-line treatment, giving a drug for maintenance that has no cross-resistance with the previous treatment and is highly effective and low-toxic can delay the time of disease progression, improve the quality of life of patients, extend the overall survival period, and at the same time increase the opportunity for patients to receive subsequent treatment. Summary of the Invention

[0008] Based on the above background, the present invention provides a de-chemotherapy maintenance treatment plan for HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma, which is given fruquintinib combined with a PD-1 monoclonal antibody after disease control is achieved 3 months after first-line treatment with a PD-1 monoclonal antibody combined with oxaliplatin (CAPOX / SOX / FOLFOX) as the basis. One object of the present invention is to evaluate the effectiveness and safety of anti-angiogenic combined with immunotherapy in the maintenance treatment plan after effective first-line induction treatment for HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma; in addition, the object of the present invention also lies in exploring the tumor evolution law driven by chemotherapy pressure and the related molecular mechanism of anti-angiogenic combined with immunotherapy for first-line maintenance treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma.

[0009] The present invention includes the following technical solutions:

[0010] In a first aspect, the present invention provides the use of an immune checkpoint inhibitor in combination with a VEGFR inhibitor in the preparation of a medicament for maintenance treatment of cancer patients, where the cancer patients are those with HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma who have achieved disease control after 3 months of first-line induction treatment.

[0011] The immune checkpoint inhibitor is selected from at least one of the following:

[0012] (1) Anti-PD-1 antibodies, such as nivolumab, pembrolizumab, cemiplimab, sintilimab, tislelizumab or their biosimilars;

[0013] (2) Anti-PD-L1 antibodies, such as avelumab, atezolizumab, durvalumab, CX-072 or their biosimilars;

[0014] (3) Anti-PD-L2 antibodies;

[0015] (4) Anti-CTLA-4 antibodies, such as ipilimumab, QL1706 or their biosimilars.

[0016] In some embodiments of the present invention, the anti-PD-1 antibody is selected from nivolumab, pembrolizumab, sintilimab or tislelizumab.

[0017] Preferably, the dose of the anti-PD-1 antibody is 200 - 600 mg, such as 200 mg, 300 mg, 360 mg, 400 mg or 600 mg; the dosing frequency is selected from once a week, once every two weeks, once every three weeks or once every four weeks.

[0018] In the most preferred embodiment of the present invention, the dose of the anti-PD-1 antibody is nivolumab 240 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, and the dosing frequency is once every three weeks.

[0019] The VEGFR inhibitor also includes a VEGF inhibitor, and the VEGFR inhibitor and / or VEGF inhibitor is selected from at least one of the following or its pharmaceutically acceptable salts: fruquintinib, apatinib, tafatinib, canertinib, anlotinib, delitinib, cediranib, sirolimus, dovitinib, donafenib, famitinib, teratinib, axitinib, sorafenib, metatinib, regorafenib, pazopanib, ningetinib or sunitinib.

[0020] The pharmaceutically acceptable salts described in the present invention are selected from methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate or phosphate.

[0021] In a specific embodiment of the present invention, the VEGFR inhibitor and / or VEGF inhibitor is fruquintinib. Fruquintinib is a highly selective small molecule inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3, and has a significant strong inhibitory effect on VEGFR-3. It was approved by the China National Medical Products Administration in 2018 and approved by the US Food and Drug Administration in 2023 for the third-line treatment of metastatic colorectal cancer.

[0022] Preferably, the dose of fruquintinib is 1-10 mg, such as 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg; the dosing frequency is selected from once a day, once every two days or once every three days.

[0023] In the most preferred embodiment of the present invention, the dosing dose of fruquintinib is 3 mg, and the dosing frequency is once a day.

[0024] In a specific embodiment of the present invention, the maintenance treatment plan is as follows:

[0025] Fruquintinib (3 mg orally, once a day, stop for 1 week after 3 weeks of oral administration), PD-1 monoclonal antibody (nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), and the treatment cycle is 21 days (3 weeks).

[0026] The first-line induction treatment is the clinical first-line treatment strategy for HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma known to those skilled in the art.

[0027] Preferably, the first-line induction treatment described in the present invention includes administering:

[0028] (1) A chemotherapeutic agent; and

[0029] (2) An immune checkpoint inhibitor.

[0030] The chemotherapeutic agent is a combination of oxaliplatin and capecitabine, or a combination of oxaliplatin and tegafur, or a combination of oxaliplatin, fluorouracil and calcium folinate.

[0031] The immune checkpoint inhibitor is an anti-PD-1 antibody, such as nivolumab, pembrolizumab, cemiplimab, sintilimab, tislelizumab or a biosimilar thereof.

[0032] In a specific embodiment of the present invention, the first-line induction treatment method is selected from any one of the following regimens:

[0033] (1) Oxaliplatin (130 mg / m2 , intravenous injection, D1), capecitabine (1000 mg / m 2 , twice daily, stop for 1 week after 2 weeks of treatment) or tegafur (for body surface area < 1.25, 40 mg morning and evening; for body surface area ≥ 1.25 and < 1.5, 50 mg morning and evening; for body surface area ≥ 1.5, 60 mg morning and evening, stop for 1 week after 2 weeks of treatment); PD-1 monoclonal antibody (nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), and the treatment cycle is 21 days (3 weeks);

[0034] (2) Oxaliplatin (85 mg / m 2 , intravenous injection, D1), fluorouracil (2400 mg / m 2 , maintained by microinfusion pump for 46 h), fluorouracil (400 mg / m 2 , intravenous bolus injection, D1), calcium folinate (400 mg / m 2 , intravenous injection, D1), PD-1 monoclonal antibody (nivolumab 240 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), and the treatment cycle is 14 days (2 weeks).

[0035] In a second aspect, the present invention provides a maintenance treatment method for cancer patients, where the cancer patients are those with HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma who achieve disease control after 3 months of first-line treatment. The method is characterized in that the method includes:

[0036] (1) Immunotherapy; and / or

[0037] (2) Anti-angiogenic therapy.

[0038] The immunotherapy includes administering an immune checkpoint inhibitor to the patient, and the immune checkpoint inhibitor is selected from at least one of the following:

[0039] (1) Anti-PD-1 antibodies, such as nivolumab, pembrolizumab, cemiplimab, sintilimab, tislelizumab or their biosimilars;

[0040] (2) Anti-PD-L1 antibodies, such as avelumab, atezolizumab, durvalumab, CX-072 or their biosimilars;

[0041] (3) Anti-PD-L2 antibodies;

[0042] (4) Anti-CTLA-4 antibodies, such as ipilimumab, QL1706 or their biosimilars.

[0043] The anti-angiogenic therapy includes administering a VEGFR inhibitor and / or a VEGF inhibitor to the patient, and the VEGFR inhibitor and / or VEGF inhibitor is selected from at least one of the following or a pharmaceutically acceptable salt thereof: fruquintinib, apatinib, tafatinib, canertinib, anlotinib, delitinib, cediranib, sotorasib, dovitinib, donafenib, famitinib, teratinib, axitinib, sorafenib, metatinib, regorafenib, pazopanib, ningetinib or sunitinib.

[0044] Preferably, the maintenance treatment method for the cancer patient includes administering:

[0045] (1) an anti-PD-1 antibody; and

[0046] (2) a VEGFR inhibitor.

[0047] The anti-PD-1 antibody is selected from nivolumab, pembrolizumab, sintilimab or tislelizumab; the VEGFR inhibitor is fruquintinib.

[0048] Preferably, the dose of the anti-PD-1 antibody is 200 - 600 mg, such as 200 mg, 300 mg, 360 mg, 400 mg or 600 mg; the dosing frequency is selected from once a week, once every two weeks, once every three weeks or once every four weeks.

[0049] In the most preferred embodiment of the present invention, the dose of the anti-PD-1 antibody is nivolumab 240 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, and the dosing frequency is once every three weeks.

[0050] Preferably, the dose of the fruquintinib is 1 - 10 mg, such as 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg; the dosing frequency is selected from once a day, once every two days or once every three days.

[0051] In the most preferred embodiment of the present invention, the dosing dose of the fruquintinib is 3 mg, and the dosing frequency is once a day.

[0052] In a specific embodiment of the present invention, the maintenance treatment regimen is as follows:

[0053] Fruquintinib (3 mg orally, once a day, stop for 1 week after oral administration for 3 weeks), PD-1 monoclonal antibody (nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), and the treatment cycle is 21 days (3 weeks).

[0054] In the present invention, when an anti-PD-1 antibody and a VEGFR inhibitor are combined for maintenance treatment of patients with HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma, there is no restriction on the administration sequence of the two. The anti-PD-1 antibody can be administered first and then the VEGFR inhibitor, or the VEGFR inhibitor can be administered first and then the anti-PD-1 antibody.

[0055] In a third aspect, the present invention provides a method for treating a cancer patient, where the cancer patient is a patient with HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma, and the method includes:

[0056] (1) administering a chemotherapeutic agent and an immune checkpoint inhibitor to the patient for first-line induction treatment;

[0057] (2) administering a VEGFR inhibitor and an immune checkpoint inhibitor to the patient who has achieved disease control after first-line induction treatment for maintenance treatment.

[0058] For HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma, after disease control is achieved 3 months after first-line treatment with a PD-1 monoclonal antibody combined with an oxaliplatin (CAPOX / SOX / FOLFOX)-based regimen, a de-chemo maintenance treatment regimen of fruquintinib combined with a PD-1 monoclonal antibody is subsequently given. The maintenance treatment regimen provided by the present invention delays disease progression, improves the quality of life of patients, and prolongs the overall survival period, and has important clinical significance. Detailed Embodiments

[0059] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only partial embodiments of the present invention, rather than all. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0060] Glossary

[0061] The term "first-line induction treatment" refers to the first-round treatment after diagnosis. At this time, the treatment regimen has the best effect and the least side effects, and is also called basic treatment or therapy. The purpose of first-line treatment is to cure cancer if possible.

[0062] The term "second-line treatment" refers to the situation where, after first-line treatment, the patient's tumor progresses again and is resistant to the first-line treatment regimen, and a regimen with a different anti-cancer mechanism needs to be replaced.

[0063] The term "third-line treatment" refers to the treatment of changing to another regimen again after the failure of second-line treatment.

[0064] The term "administer" refers to physically introducing a composition comprising a therapeutic agent (e.g., a monoclonal antibody) to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Preferred routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion.

[0065] The term "subject" includes any human or non-human animal, and the terms "subject" and "patient" are used interchangeably herein. The term "non-human animal" includes, but is not limited to, vertebrates. Among animals, mammals are preferred, and most preferably valuable and precious animals. In a specific aspect, the subject is a human. Thus, the present disclosure is applicable to clinical, veterinary and research uses.

[0066] The term "treatment" refers to any type of intervention or treatment performed on a subject, or the administration of an active agent to a subject, with the aim of reversing, alleviating, improving, inhibiting or slowing down or preventing the progression, development, severity or recurrence of symptoms, complications, diseases or biochemical markers associated with a disease or enhancing overall survival. Treatment can be directed at subjects suffering from a disease or subjects not suffering from a disease.

[0067] The clinical study involved in the present invention has been approved by the Ethics Committee for Human Subjects of Zhongshan Hospital, Fudan University. The research protocol follows the guidelines established by the Declaration of Helsinki and written informed consent has been obtained from all subjects.

[0068] Study Objectives

[0069] To evaluate the efficacy and safety of fruquintinib combined with PD-1 monoclonal antibody as a maintenance treatment regimen after effective first-line induction treatment for gastric cancer or gastroesophageal junction adenocarcinoma.

[0070] Study Endpoints

[0071] Primary Endpoint:

[0072] The 12-month progression-free survival (PFS) rate of HER-2 negative advanced gastric cancer or gastroesophageal junction adenocarcinoma patients who receive fruquintinib combined with PD-1 monoclonal antibody for maintenance treatment after effective first-line induction treatment.

[0073] Secondary Endpoints:

[0074] The 1-year / 2-year overall survival (OS) rate

[0075] The incidence of treatment-emergent adverse events (TEAE)

[0076] Exploratory Endpoints:

[0077] To explore the tumor evolution law driven by chemotherapy pressure and the related molecular mechanisms of the anti-angiogenic combined with immunotherapy for first-line maintenance treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma

[0078] Inclusion Criteria:

[0079] (1) Voluntarily participate in the clinical trial and sign the informed consent form, with good compliance;

[0080] (2) Age ≥ 18 years old, Eastern Cooperative Oncology Group (ECOG) score 0 - 1, expected survival time ≥ 3 months;

[0081] (3) Histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic gastric cancer or gastroesophageal junction adenocarcinoma;

[0082] (4) According to the RECIST v1.1 standard, there must be measurable lesions;

[0083] (5) Tumor tissue specimen detection shows microsatellite stable (MSS) or mismatch repair deficiency-free (pMMR), HER2 negative;

[0084] (6) Sufficient organ function, including hematology: WBC ≥ 3.0×10 9 / L; NE ≥ 1.5×10 9 / L; Hb ≥ 90 g / L; PLT ≥ 100×10 9 / L, liver function (bilirubin ≤ 1.5 times the upper limit of normal value, AST and ALT ≤ 2.5 times the upper limit of normal value) and renal function (serum creatinine ≤ 1.5 times the upper limit of normal value, or creatinine clearance rate ≥ 50 ml / min, urine protein ≤ 2+, or 24-hour urine protein ≤ 2000 mg), international normalized ratio (INR) ≤ 1.5, prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 times ULN;

[0085] (7) Subjects (female patients of childbearing age or male patients of childbearing age) must take effective contraceptive measures during the entire treatment process and within 6 months after treatment.

[0086] Exclusion Criteria:

[0087] (1) Participated in other drug clinical trials within 4 weeks before randomization;

[0088] (2) Had other malignancies within the past 5 years, except for cured basal cell carcinoma of the skin, papillary thyroid carcinoma, superficial bladder cancer, ductal carcinoma in situ of the breast, and cervical carcinoma in situ;

[0089] (3) History of severe heart disease, such as: history of symptomatic congestive heart failure (CHF) ≥ grade 2 (NCI-CTCAE 5.0), heart failure of New York Heart Association (NYHA) ≥ grade 2, history of transmural myocardial infarction, unstable angina, poorly controlled arrhythmia, etc.;

[0090] (4) Hypertension that cannot be well controlled by two antihypertensive drugs (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) and type 2 diabetes that cannot be controlled by hypoglycemic treatment (fasting blood glucose ≥ 8.9 mmol / L);

[0091] (5) Active autoimmune and inflammatory diseases, such as: systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease, Hashimoto's thyroiditis, etc. Type 1 diabetes, hypothyroidism that can be controlled only by replacement therapy, skin diseases that do not require systemic treatment (such as vitiligo, psoriasis) can be included in the trial;

[0092] (6) Inadequately treated central nervous system (CNS) metastases, or the presence of uncontrolled or symptomatic active CNS metastases, which can manifest as the appearance of clinical symptoms, cerebral edema, spinal cord compression, carcinomatous meningitis, leptomeningeal disease, and / or rapid progression. For CNS metastases that have been adequately treated and the neurological symptoms can return to baseline levels at least 4 weeks before randomization (except for residual signs or symptoms related to CNS treatment), they can be enrolled in the study. In addition, the subject must discontinue corticosteroids or receive a stable dose of prednisone ≤ 10 mg / d or a gradually decreasing dose (or other corticosteroids of equivalent dose) at least 4 weeks before randomization;

[0093] (7) Pleural effusion or ascites that cannot be controlled after treatment such as puncture and drainage within 14 days before randomization; pericardial effusion with clinical symptoms or moderate or more;

[0094] (8) Administration of live vaccines or attenuated live vaccines within 30 days before randomization;

[0095] (9) Major surgery within 28 days before randomization or minor non-study-related surgery within 7 days before randomization;

[0096] (10) Bleeding symptoms with significant clinical significance or clear bleeding tendency within 3 months before randomization; gastrointestinal perforation and / or gastrointestinal fistula within 6 months before randomization; arterial / venous thromboembolic events within 6 months before randomization, such as cerebrovascular accidents (including transient ischemic attacks, cerebral infarctions), deep vein thrombosis, and pulmonary embolism, etc. (except for those whose symptoms disappeared after gastrectomy for gastric cancer bleeding / perforation);

[0097] (11) Occurrence of major vascular diseases within 6 months before the start of study treatment (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis);

[0098] (12) Severe, unhealed or dehisced wounds, as well as active ulcers or untreated fractures;

[0099] (13) Having a history of severe immediate hypersensitivity reactions;

[0100] (14) Having clinically significant pulmonary fibrosis or interstitial pneumonia as judged by the researcher; Having active pulmonary infection before injection and requiring anti-infective treatment;

[0101] (15) Having active infections including tuberculosis (medical history record, judged by the researcher and radiological examination, as well as local laboratory tests), hepatitis B (positive for hepatitis B surface antigen and HBV DNA exceeding the upper limit of the normal value of the research center), hepatitis C (positive for HCV antibody and positive for HVC RNA), HIV (positive for HIV antibody), Treponema pallidum, etc.;

[0102] (16) Having active gastrointestinal bleeding or hemoptysis, etc.;

[0103] (17) Having a history of alcohol or psychotropic substance abuse and being unable to abstain or having a history of mental disorders;

[0104] (18) Known to be allergic to the study drug or any of its excipients; or having had a severe allergic reaction to other monoclonal antibodies;

[0105] (19) Systemically using antibiotics for ≥7 days within 4 weeks before randomization, or having an unexplained fever >38.5°C during the screening period / before the first dose (as judged by the researcher, patients with fever caused by tumor reasons can be included);

[0106] (20) Having a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;

[0107] (21) Those who are unable to take oral medications;

[0108] (22) Having other severe physical or mental diseases or abnormal laboratory tests, which may increase the risk of participating in the study, or interfere with the study results, and patients who the researcher deems unfit to participate in this study.

[0109] Withdrawal criteria:

[0110] (1) The subject can withdraw from the study at any time according to their own will, that is, withdraw the informed consent form;

[0111] (2) Disease progression judged by the RECIST 1.1 standard;

[0112] (3) Unable to tolerate adverse reactions;

[0113] (4) The subject is lost to follow-up;

[0114] (5) Due to other safety, behavioral or management reasons of the subject, the researcher can require the subject to withdraw from the study at any time during the study as judged.

[0115] Dosage:

[0116] (1) First-line induction therapy (oxaliplatin-based chemotherapy (CAPOX / SOX / FOLFOX) and PD-1 monoclonal antibody treatment regimen)

[0117] Oxaliplatin (130 mg / m 2 , intravenous injection, D1), capecitabine (1000 mg / m 2 , twice a day, stop for 1 week after 2 weeks of treatment) or tegafur (40 mg morning and evening for body surface area < 1.25, 50 mg morning and evening for body surface area ≥ 1.25 and < 1.5, 60 mg morning and evening for body surface area ≥ 1.5, stop for 1 week after 2 weeks of treatment); PD-1 monoclonal antibody (nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), treatment cycle is 21 days (3 weeks);

[0118] Oxaliplatin (85 mg / m 2 , intravenous injection, D1), fluorouracil (2400 mg / m 2 , microinfusion pump maintenance for 46 h), fluorouracil (400 mg / m 2 , intravenous bolus injection, D1), leucovorin calcium (400 mg / m 2 , intravenous injection, D1), PD-1 monoclonal antibody (nivolumab 240 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), treatment cycle is 14 days (2 weeks).

[0119] (2) Maintenance therapy (maintenance treatment regimen of fruquintinib and PD-1 monoclonal antibody)

[0120] Fruquintinib (3 mg orally, once a day, stop for 1 week after 3 weeks of oral administration), PD-1 monoclonal antibody (nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1), treatment cycle is 21 days (3 weeks).

[0121] Efficacy evaluation:

[0122] Eligible subjects who achieved complete remission (CR), partial remission (PR) or stable disease (SD) after 3 months (12 weeks) of initial oxaliplatin-based chemotherapy combined with PD-1 monoclonal antibody treatment continued to receive maintenance treatment with furiquintinib and PD-1 monoclonal antibody according to the study protocol, and patients with progressive disease (PD) withdrew from the study. Reasons for discontinuation of treatment included intolerable toxicity, PD, investigator's judgment or patient withdrawal of informed consent. Investigators used enhanced CT to assess tumor response every 6 weeks during oxaliplatin-based chemotherapy combined with PD-1 monoclonal antibody treatment. Maintenance treatment with furiquintinib and PD-1 monoclonal antibody was evaluated every 6 weeks. Imaging assessment was based on RECIST 1.1 criteria.

[0123] Safety Assessment:

[0124] Adverse reactions were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, including treatment-related adverse events (AEs) and serious adverse events (SAEs). The types, frequency, and severity of abnormal changes in vital signs, physical examinations, electrocardiograms, laboratory tests, etc. were evaluated.

[0125] Statistical analysis methods:

[0126] Data processing and statistical methods SPSS17.0 or above statistical analysis software will be used for data analysis. Descriptive statistics (such as number of cases, mean, median, standard deviation [SD], minimum and maximum values) will be used for continuous variables. Categorical variables will be statistically described using frequency tables (frequency and percentage). The time-to-event indicators will be statistically analyzed using the Kaplan-Meier method, and the median, 25% and 75% quantiles and their 95% confidence intervals of the time-to-event indicators of each cohort will be calculated, and the Kaplan-Meier curve will be drawn.

[0127] Efficacy analysis:

[0128] The Kaplan-Meier method was used to perform statistical analysis on PFS and OS. The median, 25% quantile, 75% quantile and 95% confidence interval of PFS and OS were calculated, and the Kaplan-Meier survival curve was drawn.

[0129] Security Analysis:

[0130] All AEs will be statistically analyzed for treatment-emergent adverse events (TEAEs) in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. The number of occurrences and incidence rates of all AEs, AEs related to the study treatment, SAEs, and AEs leading to dropout will be calculated separately. Descriptive statistics will be performed on the changes in vital signs relative to baseline, and the abnormal test items after treatment will be listed in a checklist.

[0131] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of an immune checkpoint inhibitor in combination with a VEGFR inhibitor in the preparation of a medicament for maintenance therapy of cancer patients, wherein the cancer patients are patients with HER2-negative advanced gastric cancer or gastroesophageal junction adenocarcinoma who achieve disease control after 3 months of first-line induction therapy.

2. The application according to claim 1, characterized in that, The immune checkpoint inhibitor is selected from at least one of the following: (1) Anti-PD-1 antibodies, such as nivolumab, pembrolizumab, cemiplimab, sintilimab, tislelizumab or their biosimilars; (2) Anti-PD-L1 antibodies, such as avelumab, atezolizumab, durvalumab, CX-072 or their biosimilars; (3) Anti-PD-L2 antibodies; (4) Anti-CTLA-4 antibodies, such as ipilimumab, QL1706 or their biosimilars.

3. The application according to claim 2, wherein The anti-PD-1 antibody is selected from nivolumab, pembrolizumab, sintilimab or tislelizumab.

4. The application according to claim 3, wherein The dose of the anti-PD-1 antibody is 200-600 mg, such as 200 mg, 300 mg, 360 mg, 400 mg or 600 mg; the dosing frequency is selected from once a week, once every two weeks, once every three weeks or once every four weeks.

5. The application according to claim 1, characterized in that, The VEGFR inhibitor further includes a VEGF inhibitor, and the VEGFR inhibitor or VEGF inhibitor is selected from at least one of the following or its pharmaceutically acceptable salts: fruquintinib, apatinib, tafatinib, canertinib, anlotinib, deritinib, cediranib, sotorasib, dovitinib, donafenib, famitinib, teratinib, axitinib, sorafenib, metatinib, regorafenib, pazopanib, ningetinib or sunitinib.

6. The application according to claim 5, wherein The pharmaceutically acceptable salts are selected from mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate or phosphate.

7. The application according to claim 5, wherein The VEGFR inhibitor or VEGF inhibitor is fruquintinib, and the dose of fruquintinib is 1-10 mg, such as 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg; the dosing frequency is selected from once a day, once every two days or once every three days.

8. The application according to any one of claims 1-7, characterized in that, The maintenance therapy regimen is: fruquintinib 3 mg, orally, once a day, stop for 1 week after oral administration for 3 weeks; the PD-1 monoclonal antibody is selected from nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1, and the treatment cycle is 21 days / 3 weeks.

9. The application according to claim 1, wherein The first-line induction therapy includes administering: (1) A chemotherapeutic agent; and (2) An immune checkpoint inhibitor; The chemotherapeutic agent is a combination of oxaliplatin and capecitabine, or a combination of oxaliplatin and tegafur, or a combination of oxaliplatin, fluorouracil and calcium folinate; The immune checkpoint inhibitor is an anti-PD-1 antibody, such as nivolumab, pembrolizumab, cemiplimab, sintilimab, tislelizumab or their biosimilars.

10. The application according to claim 9, wherein The first-line induction therapy method is selected from any one of the following regimens: (1) Oxaliplatin 130 mg / m 2 , intravenous injection, D1; Capecitabine 1000 mg / m 2 , twice daily, stop for 1 week after 2 weeks of treatment, or Tegafur, 40 mg morning and evening for body surface area < 1.25, 50 mg morning and evening for body surface area ≥ 1.25 and < 1.5, 60 mg morning and evening for body surface area ≥ 1.5, stop for 1 week after 2 weeks of treatment; The PD-1 monoclonal antibody is selected from nivolumab 360 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1, and the treatment cycle is 21 days / 3 weeks; (2) Oxaliplatin 85 mg / m 2 , intravenous injection, D1; Fluorouracil 2400 mg / m 2 , maintained by microinfusion pump for 46 h; Fluorouracil 400 mg / m 2 , intravenous bolus injection, D1; Calcium folinate 400 mg / m 2 , intravenous injection, D1; The PD-1 monoclonal antibody is selected from nivolumab 240 mg, or sintilimab 200 mg, or tislelizumab 200 mg, or pembrolizumab 200 mg, intravenous injection, D1, and the treatment cycle is 14 days / 2 weeks.