Background: Immunotherapy has revolutionized landscape of cancer treatment. Anti-PD-1 therapy provides significant clinical benefit and durable response in various types of cancers. However, clinical response rate to anti-PD-1 therapy has been reported to vary from 10%-40% in different cancers. And, a substantial number of patients who initially responded to anti-PD-1 therapy developed acquired resistance over time. Few effective treatment options are available for such patients. Previous studies indicated that prior anti-PD-1 exposure might increase tumor response to anti-VEGFR2 (ramucirumab) plus chemotherapy in patients with advanced/metastatic GA/GEA. Apatinib, a highly selective VEGFR2 inhibitor, has been demonstrated to be efficacious and well-tolerated for the treatment of chemotherapy-refractory advanced GA/GEA. The PIONEER study is designed to evaluate the efficacy and safety of second-line apatinib plus chemotherapy in GA/GEA patients after prior anti-PD-1 therapy. Methods: PIONEER (NCT05029453) is a multicenter, open label, randomized phase II trial of second-line apatinib plus chemotherapy versus chemotherapy alone in patients with histologically confirmed advanced GA/GEA refractory to or intolerant of prior anti-PD-1 therapy for no less than 2 months. Patients must be ≥18 years of age, with ECOG PS of 0 or 1, and have measurable disease per RECIST v1.1, adequate organ function, and expected survival time of ≥12 weeks. Patients who previously received antiangiogenic agents (such as apatinib or ramucirumab), had concurrent or previous tumor history within past 3 years, or underwent anti-tumor therapy within 4-week of recruitment will be excluded. Approximately 60 patients will be randomized (1:1) to receive apatinib (500 mg orally qd) plus chemotherapy (docetaxel 60/75 mg/m², d1 q3w, and nab-paclitaxel 125 mg/m² d1 & d8 q3w or 260 mg/m² d1 q3w) or chemotherapy alone until disease progression, unacceptable toxicity, or death. The primary endpoint is progression-free survival (PFS). The secondary endpoints are overall response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and adverse events (AEs) per NCI CTCAE v5.0. Patient enrollment has just started and is expected to be completed in June 2022. Clinical trial information: NCT05029453.