A Phase ll, Interventional, Single-arm Study Evaluating the Efficacy and Safety of Inavolisib Plus Ribociclib and Fulvestrant in Chinese Patients With PIK3CA-mutant, HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer.

Inclusion criteria

• Patients must meet all of the following criteria:

• Signed informed consent form (ICF).
• Female, aged ≥18 years at the time of signing the ICF.
• Must meet one of the following definitions of postmenopausal status:

• Age ≥60 years; OR
• Age <60 years with amenorrhea for ≥12 consecutive months in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone (GnRH) agonists/antagonists, and with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range per local laboratory assessment; OR
• Documented bilateral oophorectomy performed ≥14 days before Cycle 1 Day 1 (first treatment), with recovery to baseline status.

For premenopausal or perimenopausal women (i.e., those not meeting postmenopausal criteria), the following is also required:

• Ongoing treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin or leuprorelin) initiated at least 2 weeks before Cycle 1 Day 1 and continued throughout study treatment.
• Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and not amenable to curative surgery or radiotherapy.
• Estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive tumor per ASCO/CAP guidelines, defined as ≥1% of tumor cells showing positive staining on the most recent tumor biopsy.
• HER2-negative per ASCO/CAP guidelines, defined as: HER2 IHC score 0 or 1+, or IHC 2+ with negative ISH (FISH/CISH/SISH), or HER2/CEP17 ratio <2.0 on the most recent biopsy, based on local laboratory assessment.
• Biomarker eligibility: PIK3CA mutation status must be determined by PCR or NGS testing of blood or tumor tissue at a local or regional laboratory. Blood samples should represent metastatic disease and be collected after the most recent anticancer therapy; tumor tissue should preferably be from metastatic lesions.
• Disease progression during or within 12 months after completion of adjuvant endocrine therapy (aromatase inhibitor or tamoxifen). If CDK4/6 inhibitor was used in neoadjuvant/adjuvant setting, time from completion of CDK4/6 inhibitor to progression must be >12 months.
• At least one measurable lesion per RECIST v1.1. Patients with only bone metastases are not eligible, even if lesions are measurable.
• Women of childbearing potential must agree to abstinence or use effective non-hormonal contraception (failure rate <1% per year) during treatment and for specified post-treatment periods (depending on study drug), and must not donate oocytes.
• ECOG performance status 0-1.
• Life expectancy >6 months.
• Adequate hematologic and organ function within 14 days prior to treatment initiation, including:

ANC ≥1500/μL Hemoglobin ≥9 g/dL Platelets ≥100,000/μL Fasting glucose <126 mg/dL and HbA1c <6.0% Total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert syndrome) Albumin ≥2.5 g/dL AST/ALT ≤2.5×ULN (≤5×ULN with liver metastases) ALP ≤2.5×ULN (≤5×ULN with liver/bone metastases) Creatinine clearance ≥60 mL/min (Cockcroft-Gault) INR <1.5×ULN and aPTT <1.5×ULN (with specified exceptions for anticoagulation)

• Ability and willingness to comply with study procedures as judged by the investigator.

Exclusion criteria

• Metaplastic breast carcinoma.
• Any history of leptomeningeal disease or carcinomatous meningitis.
• Prior systemic therapy for metastatic breast cancer (mBC).
• Prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), except neoadjuvant use ≤6 months.
• Prior exposure to PI3K, AKT, or mTOR inhibitors, or any drugs targeting the PI3K-AKT-mTOR pathway.
• Requirement for cytotoxic chemotherapy at study entry (e.g., visceral crisis as per local guidelines).
• Type 2 diabetes requiring ongoing systemic treatment at enrollment, or history of type 1 diabetes.
• Inability or unwillingness to take oral medication or receive intramuscular injections.
• Malabsorption syndrome or any condition affecting gastrointestinal absorption.
• Untreated or active CNS metastases (progressive disease or requiring anticonvulsants or corticosteroids for symptom control).
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage more frequently than every 2 weeks.
• Severe infection requiring intravenous antibiotics within 7 days prior to enrollment.
• Any concurrent ocular or intraocular disease requiring intervention during the study to prevent or treat potential vision loss.
• Active inflammatory or infectious ocular disease, or history of autoimmune/idiopathic uveitis.
• Requirement for daily supplemental oxygen therapy.
• Symptomatic active pulmonary disease, including pneumonia.
• Active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or current immunosuppressive treatment for such disease.
• Any active intestinal inflammation, including diverticulitis.
• Symptomatic hypercalcemia requiring ongoing bisphosphonate or denosmab therapy.
• Clinically significant active liver disease, including severe hepatic impairment (Child-Pugh B/C), viral hepatitis, cirrhosis, or current alcohol abuse.
• Known HIV infection.
• Any severe, uncontrolled systemic disease (e.g., significant cardiopulmonary, metabolic, or infectious disease) that may affect study safety or interpretation.
• Anticancer therapy within 2 weeks prior to first dose.
• Investigational drug use within 4 weeks prior to first dose.
• Prior irradiation of ≥25% of bone marrow, or prior stem cell/bone marrow transplantation.
• Unresolved toxicities from prior therapy (except alopecia, hot flashes, or peripheral neuropathy ≤Grade 2).
• Other malignancy within 5 years prior to screening, except low-risk cancers (e.g., treated cervical carcinoma in situ, non-melanoma skin cancer, or stage I uterine cancer).
• Significant cardiovascular disease, including:

• Stroke or TIA within 6 months
• Myocardial infarction within 6 months
• NYHA class III-IV heart failure or clinically significant CHF
• Uncontrolled arrhythmias or ventricular arrhythmias requiring treatment
• Clinically significant coronary artery disease or unstable angina
• QTc prolongation (>470 ms using Fridericia formula) or history of long/short QT syndrome, Brugada syndrome, or torsades de pointes
• Clinically significant ECG abnormalities (e.g., complete LBBB, high-grade AV block)
• Evidence of prior myocardial infarction on ECG
• Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia).
• Chronic use of ≥10 mg/day prednisone equivalent or other systemic corticosteroids/immunosuppressants.
• Known hypersensitivity to inavolisib, ribociclib, or fulvestrant components.
• Use of strong CYP3A4 inhibitors or inducers within 1 week or 5 half-lives (whichever is longer) prior to treatment initiation.
• Pregnancy, breastfeeding, or planning pregnancy during study or within defined post-treatment periods (inavolisib 7 days, ribociclib 21 days, fulvestrant up to 2 years).
• Major surgery or significant trauma within 28 days prior to Cycle 1 Day 1, or expected need for major surgery during the study.
• Minor surgery within 7 days prior to first dose without adequate recovery (including proper wound healing).