Cohort-Specific Requirements:
Cohort A: Histologically confirmed locally advanced unresectable or metastatic Triple-Negative Breast Cancer \[TNBC\]; no prior systemic therapy for advanced disease; prior adjuvant/neoadjuvant taxane allowed if recurrence ≥6 months after last taxane dose; no prior Trop-2 Antibody-Drug Conjugate \[ADC\].
Cohort B: Histologically confirmed locally advanced unresectable or metastatic TNBC; no prior systemic therapy for advanced disease; prior adjuvant/neoadjuvant taxane allowed if recurrence ≥12 months after last taxane dose.
Cohort E: Histologically confirmed locally advanced unresectable or metastatic HR+/HER2- breast cancer; disease progression after ≥1 line of endocrine therapy (aromatase inhibitor and/or fulvestrant) and CDK4/6i in advanced setting; received ≥1 line of systemic chemotherapy in advanced setting; no prior Trop-2 ADC.
Cohort F: Histologically confirmed locally advanced unresectable or metastatic HR+/HER2- breast cancer; disease progression after ≥1 line of endocrine therapy and CDK4/6i with primary or secondary endocrine resistance; prior adjuvant/neoadjuvant taxane allowed if recurrence ≥12 months after last taxane dose.
Cohort G: Histologically confirmed locally advanced unresectable or metastatic HR+/HER2- breast cancer; prior CDK4/6i and endocrine therapy in any setting; received a TROP2 or HER2 ADC in advanced setting.
Inclusion Criteria:
1. Age ≥ 18 years, male or female.
2. Histologically confirmed locally advanced unresectable or metastatic breast cancer (Triple-Negative Breast Cancer \[TNBC\] or Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative \[HR+/HER2-\]).
3. At least one measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\].
4. No prior treatment with any immune checkpoint inhibitor (e.g., anti-Programmed Death-1 \[PD-1\], anti-Programmed Death-Ligand 1 \[PD-L1\], anti-Cytotoxic T-Lymphocyte-Associated Protein 4 \[CTLA-4\]) or Programmed Death-1/Vascular Endothelial Growth Factor \[PD-1/VEGF\] bispecific antibody, except for adjuvant therapy if relapse occurred ≥12 months after discontinuation.
5. Assessed by the investigator as suitable for the assigned combination therapy.
6. Eastern Cooperative Oncology Group \[ECOG\] performance status 0 or 1.
7. Life expectancy ≥ 3 months.
8. Adequate organ function (within 14 days before first dose, without transfusion or Granulocyte Colony-Stimulating Factor \[G-CSF\] support): Hemoglobin ≥ 9 g/dL, Absolute Neutrophil Count \[ANC\] ≥ 1.5×10\^9/L, Platelets ≥ 100×10\^9/L; Aspartate Aminotransferase \[AST\] and Alanine Aminotransferase \[ALT\] ≤ 3×Upper Limit of Normal \[ULN\] (≤5×ULN if liver metastases); Alkaline Phosphatase \[ALP\] ≤ 2.5×ULN (≤5×ULN if bone or liver metastases); Total Bilirubin ≤ 1.5×ULN (≤3×ULN for Gilbert's Syndrome); Serum Creatinine ≤ 1.5×ULN or Creatinine Clearance ≥ 50 mL/min (Cockcroft-Gault formula); Urine protein dipstick ≤ 1+ (if ≥2+, 24-hour urine protein quantification \< 1 g); Coagulation function: International Normalized Ratio \[INR\] or activated Partial Thromboplastin Time \[aPTT\] ≤ 1.5×ULN (for patients not on anticoagulation therapy).
9. Provide a Formalin-Fixed Paraffin-Embedded \[FFPE\] tumor tissue sample for biomarker testing.
10. Effective contraception for fertile participants.
Exclusion Criteria:
1. Prior anti-cancer therapy within specified washout periods.
2. Systemic immunosuppressive therapy within 2 weeks before first dose.
3. Major surgery or significant traumatic injury within 4 weeks before first dose.
4. Unresolved toxicity from prior therapy \> Grade 1 (except alopecia or Grade ≤2 hypothyroidism stable on hormone replacement).
5. Prior immune-related adverse events \[irAEs\] ≥ Grade 3 leading to treatment discontinuation.
6. Active Central Nervous System \[CNS\] metastases (except stable asymptomatic lesions).
7. History of other malignancies within 3 years (except cured non-melanoma skin cancer or carcinoma in situ).
8. Uncontrolled pleural effusion or ascites requiring repeated drainage.
9. Clinically significant cardiovascular disease (e.g., myocardial infarction, unstable angina, stroke within 6 months; QTcF prolongation; New York Heart Association \[NYHA\] Class II-IV heart failure; pericarditis/myocarditis).
10. History of Interstitial Lung Disease \[ILD\] or non-infectious pneumonitis requiring steroids.
11. Active or history of autoimmune disease requiring systemic treatment in the past 2 years.
12. History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea).
13. History of hypertensive crisis or hypertensive encephalopathy.
14. Severe coagulation disorders or significant bleeding risk (e.g., severe vascular disease, hemoptysis, intracranial/spinal hemorrhage, tumor invading major vessels).
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess.
16. Active infection requiring systemic anti-infective therapy within 2 weeks; severe infection within 4 weeks.
17. Uncontrolled intercurrent illness (e.g., poorly controlled hypertension or Type 2 diabetes mellitus).
18. Known active tuberculosis \[TB\].
19. Positive for Hepatitis B Virus \[HBV\] surface antigen \[HBsAg\] or core antibody \[HBcAb\] with HBV-Deoxyribonucleic Acid \[DNA\] \> 500 IU/mL; or positive Hepatitis C Virus \[HCV\] antibody with HCV-Ribonucleic Acid \[RNA\] above the lower limit of quantification.
20. Known primary immunodeficiency or positive Human Immunodeficiency Virus \[HIV\] antibody.
21. History of solid organ or hematopoietic stem cell transplantation (except corneal transplant).
22. Pregnant or breastfeeding women.
23. Known hypersensitivity to GB268 or its excipients; history of severe hypersensitivity to other monoclonal antibodies.
24. Any other condition that would make the participant unsuitable for the study.
25. History of severe hypersensitivity to other drugs in the combination regimen.
