Advanced gastroesophageal cancer (AGOC)

This study aims to determine: i. Whether regorafenib in combination with nivolumab helps prolong survival in patients with advanced gastroesophageal cancer (AGOC); ii. The effect of the treatment on progression-free survival; iii. The number of participants who respond to the treatment; iv. The impact of the treatment on quality of life; v. The side effects and tolerability of the treatment; vi. The molecular differences (e.g., genetic or protein variations) that may influence the effects of regorafenib plus nivolumab.

Regorafenib (BAY 73-4506)

Regorafenib

tablet

40 mg

To determine the effect of regorafenib on the following endpoint:

Overall survival (OS) in the overall study population, defined as time from randomization to death from any cause.

Inclusion Criteria

Adults (aged ≥20 years) with metastatic or locally recurrent gastroesophageal cancer (AGOC):
a. The primary site is located in the gastroesophageal junction (GEJ) or stomach, and
b. The histologic subtype is adenocarcinoma or undifferentiated carcinoma, and
c. Measurable disease according to RECIST version 1.1, as assessed by CT scan within 21 days before randomization.

For previously irradiated lesions, objective evidence of disease progression prior to study entry is required for the lesion to be considered measurable.
d. Prior failure or intolerance to at least two lines of systemic anticancer therapy for recurrent/metastatic disease.

Prior therapy must have included at least one platinum compound and one fluoropyrimidine analog.

Note: Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy is considered first-line therapy if recurrence or progression occurred within six months after completion.

Chemoradiation given for purely palliative purposes (e.g., radiosensitization) does not count as a line of therapy.

Ramucirumab monotherapy or immunotherapy with immune checkpoint inhibitors may be considered a line of therapy.
e. HER2-positive participants must have previously received trastuzumab.

ECOG performance status 0 or 1.

Ability to swallow oral medication.

Adequate bone marrow function:

Platelet count ≥ 100 × 10⁹/L

Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L

Hemoglobin ≥ 9.0 g/dL

Adequate renal function, as determined by creatinine clearance > 50 mL/min (Cockcroft–Gault formula, 24-hour urine collection, or GFR scan), and serum creatinine ≤ 1.5 × ULN.

Adequate hepatic function:

Total bilirubin ≤ 1.5 × ULN

INR ≤ 1.5 × ULN

ALT, AST, and ALP ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present)

Participants receiving anticoagulants such as warfarin or heparin may be included if no prior evidence of abnormal coagulation exists.

Willing and able to comply with all study requirements, including treatment, timing, and assessments.

Planned and able to initiate study treatment within 7 days after randomization.

Note: Participants randomized on Friday should not begin treatment before the following Monday.

Written informed consent obtained.

Exclusion Criteria

Known hypersensitivity to regorafenib, similar compounds, or any excipients in the formulation.

Uncontrolled hypertension (systolic > 140 mmHg or diastolic > 90 mmHg despite treatment).

Known uncontrolled malabsorption syndrome.

Prior treatment with small-molecule anti-VEGF tyrosine kinase inhibitors (TKIs) (e.g., apatinib).

Prior anti-VEGF monoclonal antibody therapy (e.g., bevacizumab or ramucirumab) is allowed.

Prior treatment with more than one immune checkpoint inhibitor.

Use of any investigational therapy within 2 weeks prior to the first study treatment.

Use of biological response modifiers (e.g., G-CSF) within 3 weeks before randomization.

Concurrent treatment with strong CYP3A4 inhibitors or inducers.

Palliative radiotherapy within 14 days before enrollment, unless all radiation-related adverse events have resolved to ≤ Grade 1 (per CTCAE v5.0).

Major surgery, biopsy, or traumatic injury within 28 days prior to randomization.

Arterial thrombotic or ischemic events (e.g., stroke) within 6 months prior to randomization.

Venous thromboembolism or pulmonary embolism within 3 months prior to randomization.

Bleeding events of ≥ Grade 3 (CTCAE v5.0) within 4 weeks prior to randomization.

Unhealed wounds, ulcers, or fractures.

Symptomatic interstitial lung disease.

Clinically significant thyroid dysfunction (hyper- or hypothyroidism).

Laboratory abnormalities of thyroid hormones without clinical significance (e.g., euthyroid sick syndrome) are allowed.

Persistent Grade ≥ 3 proteinuria (≥ 3.5 g/24 h).

Uncontrolled CNS metastases.

CNS lesions must have been treated (surgery/radiation) and stable for ≥ 2 weeks prior to randomization, with no new neurologic symptoms and stable corticosteroid dose.

History of other malignancy within 2 years prior to randomization, except for:
a. Carcinoma in situ of the cervix,
b. Non-melanoma skin cancer,
c. Superficial bladder tumor (T1a or Tis), or
d. Cured papillary thyroid carcinoma.

Any major active infection, including chronic active HBV, HCV, or HIV infection.

Testing is not mandatory unless clinically indicated.

Participants with controlled HBV/HCV on stable antiviral therapy with documented viral suppression may be eligible.

Acute coronary syndrome or cardiac catheterization/interventional procedure within 6 months.

Ongoing Grade ≥ 3 infection per CTCAE v5.0.

Autoimmune disease.

Requirement for corticosteroid therapy.

Seizure disorders requiring anticonvulsant medication.

Any severe medical or psychiatric condition that could interfere with protocol compliance.

Pregnancy, breastfeeding, or inadequate contraception.

Women must be postmenopausal, surgically sterile, or using reliable contraception with a negative pregnancy test within 7 days before randomization.

Men must be surgically sterile or use barrier contraception.