A Study on the Efficacy and Safety of Sintilimab Combined With Ramucirumab and Paclitaxel in the Treatment of Gastric Cancer Patients With Short-term Recurrence After Adjuvant Therapy

A Study on the Efficacy and Safety of Sintilimab Combined With Ramucirumab and Paclitaxel in the Treatment of Gastric Cancer Patients With Short-Term Recurrence After Adjuvant Therapy

To explore the efficacy and safety of sintilimab combined with ramucirumab and paclitaxel in the treatment of advanced gastric cancer patients with short-term recurrence after postoperative adjuvant therapy, and to identify efficacy-related biomarkers to guide subsequent individualized treatment.

The treatment of gastric cancer relies first on surgical resection. Especially for patients with early-stage and locally advanced gastric cancer, surgical resection of the tumor and regional lymph nodes constitutes the most effective therapeutic approach. The goal of surgery is to maximize survival rates and prolong patients' disease-free survival (DFS) by completely eradicating cancer cells . However, due to the high metastatic potential of gastric cancer-particularly lymph node metastasis and peritoneal metastasis-the postoperative recurrence rate remains considerable . Therefore, postoperative adjuvant therapy has become crucial for reducing recurence and improving survival outcomes.

According to the clinical guidelines of the Chinese Society of Clinical Oncology (CSCO) and the European Society for Medical Oncology (ESMO), postoperative adjuvant therapy typically adopts chemotherapy regimens, such as oxaliplatin plus S-1 (SOX), oxaliplatin plus capecitabine (CAPOX), and oxaliplatin plus 5-fluorouracil plus leucovorin (FOLFOX) . These chemotherapy regimens have achieved remarkable results by inhibiting residual micrometastatic tumor cells and reducing the risk of postoperative recurrence.

Nonetheless, despite the certain success of postoperative adjuvant therapy, some patients still experience recurrence either during adjuvant treatment or within 6 months after its completion. Once recurrence occurs, tumor treatment becomes more challenging. Such recurrence usually indicates resistance of the gastric cancer to initial therapy, and the treatment strategy post-recurrence is more complex. For patients with short-term recurrence after postoperative adjuvant therapy, the adjuvant therapy is defined as first-line treatment, and recurrence signifies progression to the second-line treatment phase.The choice of second-line treatment for this specific patient population is generally based on the patients' HER2 expression status. For HER2-positive gastric cancer patients, the trastuzumab plus chemotherapy regimen is usually administered . Multiple clinical trial results have demonstrated that trastuzumab combined with chemotherapy can significantly enhance the efficacy and survival rates of HER2-positive gastric cancer patients . For HER2-negative patients, the RAINBOW study has provided a novel therapeutic regimen of paclitaxel combined with ramucirumab for gastric cancer. The study indicated that the combination of paclitaxel and ramucirumab can significantly prolong patients' median overall survival (OS) and improve their progression-free survival (PFS). This treatment regimen has been recommended by guidelines as the standard second-line treatment option .

In recent years, the emergence of immune checkpoint inhibitors (ICIs)-especially those targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1)-has brought revolutionary changes to cancer treatment. Immunotherapy activates the patients' own immune system to recognize and eliminate tumor cells, and it has exhibited significant clinical efficacy in various malignancies, including non-small cell lung cancer, melanoma, and hepatocellular carcinoma . Clinical trials such as ORIENT-16, CheckMate-649, and ATTRACTION-4 have shown that immunotherapy combined with chemotherapy can significantly improve the OS and PFS of patients with PD-L1-positive tumors.The choice of second-line treatment for this specific patient population is generally based on the patients' HER2 expression status. For HER2-positive gastric cancer patients, the trastuzumab plus chemotherapy regimen is usually administered . Multiple clinical trial results have demonstrated that trastuzumab combined with chemotherapy can significantly enhance the efficacy and survival rates of HER2-positive gastric cancer patients . For HER2-negative patients, the RAINBOW study has provided a novel therapeutic regimen of paclitaxel combined with ramucirumab for gastric cancer. The study indicated that the combination of paclitaxel and ramucirumab can significantly prolong patients' median overall survival (OS) and improve their progression-free survival (PFS). This treatment regimen has been recommended by guidelines as the standard second-line treatment option .

In recent years, the emergence of immune checkpoint inhibitors (ICIs)-especially those targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1)-has brought revolutionary changes to cancer treatment. Immunotherapy activates the patients' own immune system to recognize and eliminate tumor cells, and it has exhibited significant clinical efficacy in various malignancies, including non-small cell lung cancer, melanoma, and hepatocellular carcinoma . Clinical trials such as ORIENT-16, CheckMate-649, and ATTRACTION-4 have shown that immunotherapy combined with chemotherapy can significantly improve the OS and PFS of patients with PD-L1-positive tumors

Inclusion Criteria:

• Age ≥18 years at the time of informed consent.
• Histologically confirmed gastric or gastroesophageal junction (GEJ)adenocarcinoma.
• HER2-negative disease, as determined by standard testing methods.
• Prior D2 radical gastrectomy with R0 resection.
• Disease recurrence during adjuvant chemotherapy or within 6 months after completion of adjuvant chemotherapy.
• At least one measurable lesion according to RECIST version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Adequate organ and bone marrow function.
• Life expectancy of at least 3 months.
• Ability to understand and willingness to sign written informed consent.

Exclusion Criteria:

• Active malignancy within the past 5 years, except for adequately treated in situ carcinoma or other cancers with a negligible risk of recurrence.
• Prior participation in another investigational drug study within 4 weeks prior to enrollment.
• Symptomatic central nervous system (CNS) metastases.
• Active autoimmune disease requiring systemic treatment.
• Uncontrolled cardiovascular disease or uncontrolled hypertension.
• History of thromboembolic events or clinically significant bleeding disorders within 6 months prior to enrollment.
• Active tuberculosis or interstitial lung disease.
• Known hypersensitivity to monoclonal antibodies or any excipients of the study drug.