Ivonescimab (AK112) Plus Paclitaxel as Second-line Therapy in Patients With Advanced G/GEJ Cancer

This is a randomized, controlled, multi-center Phase II trial (N ≈ 110) conducted in China to assess the safety and antitumor activity of AK112 combined with paclitaxel versus paclitaxel with or without ramucirumab in subjects with advanced gastric/gastroesophageal junction adenocarcinoma who failed immunochemotherapy. The study objective was to assess the progression-free survival (PFS) of AK112 combined with paclitaxel versus paclitaxel with or without ramucirumab in subjects with advanced gastric/gastroesophageal junction adenocarcinoma who failed immunochemotherapy. The primary endpoint was PFS assessed by RECIST v1.1, and the secondary endpoints were ORR, OS, DoR, time to response (TTR), DCR, and incidence/severity of adverse events (AEs) graded by NCI CTCAE v5.0. Eligible patients with progression after PD-1/L1 inhibitor plus platinum chemotherapy will be stratified by peritoneal metastasis (present vs. absent) and randomized 1:1 to: Group A (n=55): AK112 (20 mg/kg IV, D1/D15) + paclitaxel (80 mg/m² IV, D1/D8/D15), Q4W; Group B (n=55): Paclitaxel (80 mg/m² IV, D1/D8/D15) ± ramucirumab (8 mg/kg IV, D1/D15), Q4W. Treatment continues until disease progression, intolerable toxicity, or investigator-determined clinical futility.Tumor assessments occur every 8 weeks (±7 days) via RECIST v1.1.

Inclusion criteria

• Voluntary written informed consent provided
• Age ≥18 and ≤75 years, regardless of gender
• Histologically or cytologically confirmed advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma
• Prior treatment failure with PD-1/L1 inhibitor combined with platinum-based chemotherapy; no other systemic antitumor therapy allowed (only first-line therapy permitted, with initial immunotherapy duration ≥12 weeks).Note: Patients who previously received adjuvant/neoadjuvant PD-1 inhibitor plus platinum-based chemotherapy for non-metastatic disease or curative-intent platinum chemoradiotherapy + PD-1 inhibitor for locally advanced or recurrent/metastatic disease are eligible if disease progression occurred within <6 months after the last treatment and no subsequent systemic therapy was administered.
• ECOG performance status of 0-1
• Life expectancy ≥3 months
• At least one measurable lesion per RECIST v1.1. Previously irradiated lesions may qualify as target lesions if evidence of post-radiotherapy progression exists and no alternative target lesions are available.
• Adequate organ function:

Hematology (without transfusions/growth factors for 7 days): ANC ≥1.5×10⁹/L; platelets ≥100×10⁹/L; hemoglobin ≥90 g/L.

Liver: Total bilirubin ≤1.5×ULN; AST/ALT ≤2.5×ULN (≤5×ULN for hepatic metastases); albumin ≥28 g/L.

Kidney: Serum creatinine ≤1.5×ULN and CrCl ≥50 mL/min; urine protein <2+ or 24-hour urinary protein <1.0 g.

Coagulation: INR/PT ≤1.5×ULN (unless on anticoagulants with therapeutic ranges maintained).

Cardiac: LVEF ≥50%.

• For females of childbearing potential: Negative pregnancy test within 3 days prior to treatment; highly effective contraception required during screening and for 120 days post-treatment. Postmenopausal women (amenorrhea ≥1 year) or surgically sterilized females are exempt.
• For non-sterilized males with childbearing partners: Effective contraception during screening and for 120 days post-treatment.
• Willingness and ability to comply with protocol-specified visits, treatments, and laboratory tests.

Exclusion criteria

• Histologically or cytologically confirmed as other pathological types (e.g., squamous cell carcinoma, undifferentiated carcinoma, neuroendocrine carcinoma). Mixed pathological types will be categorized based on the predominant component; only subjects with >70% adenocarcinoma component confirmed by a pathologist may enroll.
• History of other malignancies within 3 years prior to enrollment. Exceptions include malignancies cured by local therapy (e.g., basal or squamous cell skin cancer, superficial bladder cancer, in situ cervical or breast cancer).
• Systemic anti-cancer therapy (e.g., chemotherapy, radiotherapy, immunotherapy, targeted therapy [<2 weeks for small-molecule agents], biologics) within 3 weeks prior to first dose; palliative local therapy for non-target lesions within 2 weeks.
• Prior immunotherapy other than PD-1/PD-L1 inhibitors, including checkpoint inhibitors (anti-CTLA-4, anti-CD47, anti-SIRPα, anti-LAG-3), checkpoint agonists (ICOS, CD40, CD137, GITR, OX40), cell therapies, or biologics targeting tumor immunity.
• Prior treatment with ramucirumab, VEGFR2 antagonists, or other VEGFR2-targeting antibodies/proteins.
• Prior use of taxane-based agents (e.g., paclitaxel, docetaxel) in first-line systemic therapy.
• Prior PD-1/PD-L1 inhibitor treatment with any of the following:

• Grade ≥3 irAEs (excluding endocrine irAEs), irAEs leading to permanent discontinuation, Grade 2 immune-related cardiotoxicity, or any-grade neurological/ocular irAEs.
• Unresolved toxicities from prior PD-1/PD-L1 therapy (not resolved to ≤Grade 1). Grade ≥2 endocrine toxicities are allowed if stable and asymptomatic under replacement therapy.
• IrAEs requiring non-corticosteroid immunosuppressants or recurrent irAEs necessitating systemic corticosteroids.
• Hypersensitivity to any study drug component or history of severe allergic reactions to monoclonal antibodies.
• Bleeding diathesis or coagulation disorders.
• Imaging showing tumor invasion of adjacent organs/vessels, necrosis, or cavitation posing risk of perforation/hemorrhage.
• Major surgery/trauma within 30 days prior to first dose or planned surgery within 30 days post-dose; minor surgery within 3 days prior to first dose (excluding PICC/port placement).
• Gastrointestinal risks:Esophagogastric varices, severe ulcers, unhealed wounds, perforation, fistula, abscess, or acute bleeding within 6 months; Arterial thromboembolism or Grade ≥3 venous thromboembolism (per NCI CTCAE v5.0), TIA, stroke, hypertensive crisis, or COPD exacerbation within 6 months; Uncontrolled hypertension (≥160/100 mmHg on oral therapy).
• Cardiac history:Myocarditis, cardiomyopathy, malignant arrhythmia; Unstable angina, MI, NYHA Class ≥2 heart failure, or aortic aneurysm within 12 months; Poorly controlled arrhythmias or ischemia.
• Active autoimmune disease requiring systemic treatment within 2 years (excluding hormone replacement).
• Symptomatic effusions requiring diuretics or drainage (pleural, pericardial, or ascites).
• Severe infection (hospitalization-required/sepsis) within 4 weeks; active infection requiring systemic antibiotics within 2 weeks (excluding antiviral therapy for HBV/HCV).
• Active tuberculosis (must be ruled out if suspected) or active syphilis.
• Organ or stem cell transplant history (excluding corneal transplants).
• Immunodeficiency:HIV-positive; Chronic systemic corticosteroids/immunosuppressants.
• Chronic viral hepatitis:Active HBV (HBsAg-positive with HBV DNA >500 IU/mL or >2500 copies/mL); Active HCV (allowed if cured or HCV RNA-negative).
• Live/attenuated vaccines administered within 30 days prior to first dose or planned during the study (inactivated vaccines permitted).
• Pregnancy, lactation.
• History of psychiatric disorders, substance abuse, or alcoholism.
• Other conditions deemed ineligible by the investigator.