A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY EVALUATING THE EFFICACY AND SAFETY OF INAVOLISIB PLUS FULVESTRANT VERSUS ALPELISIB PLUS FULVESTRANT IN PATIENTS WITH HORMONE RECEPTOR- POSITIVE, HER2-NEGATIVE, PIK3CA MUTATED, LOCALLY ADVANCED OR METASTATIC BREAST CANCER WHO PROGRESSED DURING OR AFTER CDK4/6 INHIBITOR AND ENDOCRINE COMBINATION THERAPY

The primary objective of this study is to evaluate the efficacy of **inavolisib** plus **fulvestrant** compared with **alpelisib** plus fulvestrant, based on blinded independent central review (BICR)-assessed progression-free survival (PFS) in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer who have progressed during or after CDK4/6 inhibitor and endocrine combination therapy. This is clinically relevant as it aims to determine the potential of inavolisib in improving PFS, a critical endpoint in the management of metastatic breast cancer, which could lead to better therapeutic strategies for this patient population.

Secondary objectives include:

• Evaluating the efficacy of inavolisib plus fulvestrant compared with alpelisib plus fulvestrant based on overall survival (OS), BICR-assessed objective response rate (ORR), best overall response (BOR), clinical benefit rate (CBR), duration of response (DOR), and times to deterioration in pain, physical function, role function, and global health status/health-related quality of life (HRQoL).
• Assessing the safety and tolerability of inavolisib plus fulvestrant compared with alpelisib plus fulvestrant.
• Characterizing the pharmacokinetics of inavolisib in the inavolisib plus fulvestrant arm.

The clinical trial involves a total of **308 participants** diagnosed with **metastatic breast cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic, and not amenable to surgical or radiation therapy with curative intent. The trial also requires documented HR-positive/HER2-negative tumors according to ASCO/CAP guidelines and confirmation of biomarker eligibility through detection of specified mutations in the PIK3CA gene. Participants must have experienced disease progression after or during treatment with a combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy, with up to two prior lines of systemic therapy in the metastatic breast cancer setting. Additionally, an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 is required. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of **inavolisib** plus **fulvestrant** compared to **alpelisib** plus fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA mutated, locally advanced or metastatic breast cancer. The primary objective is to assess progression-free survival as determined by blinded independent central review. Secondary endpoints include overall survival, overall response rate, clinical benefit rate, and incidence of adverse events, among others. The trial is expected to conclude by March 2029, with recruitment having commenced in June 2023.

Participants will be randomly assigned to receive either inavolisib plus fulvestrant or alpelisib plus fulvestrant. The trial will involve several study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the breast, documented HR+/HER2- status, and disease progression after specific prior therapies. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 85 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure adherence to the protocol and to address any safety concerns promptly. The trial's design and procedures are structured to provide robust data on the comparative efficacy and safety of the investigational treatments in the specified patient population.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Metformin** is utilized in the form of film-coated tablets, with a maximum daily dose of 3 grams. It is administered orally, and the treatment period extends up to 85 days. Metformin is classified as a biguanide and is not a pediatric formulation.

**Dexamethasone Sodium Phosphate** is provided as a mouthwash, with a maximum daily dose of 4 grams. This corticosteroid is applied topically, and the treatment duration is also 85 days. It is not formulated for pediatric use.

**Fulvestrant** is administered as a solution for injection in a pre-filled syringe. The maximum daily dose is 500 milligrams, delivered via intramuscular injection. The treatment period is 85 days, and it is categorized as a steroidal antiestrogen.

**Alpelisib** is available in various formulations, including Piqray 150 mg, 50 mg, and 200 mg film-coated tablets. The maximum daily dose is 300 milligrams, administered orally. The treatment period is 85 days, and it is classified as a kinase inhibitor. Alpelisib is not a pediatric formulation.

**Inavolisib** is provided in film-coated tablet form, with a maximum daily dose of 9 milligrams. It is administered orally, with a treatment period of 85 days. Inavolisib is also classified as a kinase inhibitor and is not formulated for pediatric use.

The trial also includes a non-experimental treatment involving a **Luteinizing Hormone-Releasing Hormone Agonist**, administered via injection. The maximum daily dose is 0.13 milligrams, with a total dose of 306 milligrams over the 85-day treatment period.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**, as evaluated by a blinded independent central review (BICR). This primary endpoint will provide a robust measure of the time during which patients experience no progression of their disease. Secondary endpoints include overall survival (OS), BICR-assessed overall response rate, best overall response, clinical benefit rate, and duration of response. Additionally, time to confirmed deterioration (TTCD) in pain, physical functioning, role functioning, and global health status/quality of life (QOL) will be evaluated. The incidence and severity of adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) grading scale, along with treatment discontinuations due to adverse events. Changes from baseline in targeted clinical laboratory test results and plasma concentration of inavolisib at specified timepoints will also be monitored.