A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Patients with PIK3CA -Mutant, Hormone Receptor-Positive, HER2 -Negative Locally Advanced or Metastatic Breast Cancer

The primary objective of this study is to evaluate the efficacy of inavolisib plus palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis of progression-free survival in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer. This endpoint is clinically relevant as it directly measures the ability of the combination therapy to delay disease progression in this molecularly defined patient population.

The secondary objectives include:

• Evaluation of efficacy based on overall survival, objective response rate, best overall response rate, duration of response, clinical benefit rate, and time to confirmed deterioration in pain, physical function, role function, and global health status/health-related quality of life.

• Assessment of safety through monitoring the incidence and severity of adverse events, and changes from baseline in targeted vital signs, clinical laboratory test results, and electrocardiogram parameters.

• Characterization of the pharmacokinetics of inavolisib, palbociclib, and fulvestrant when administered in combination, based on their plasma concentrations.

• Characterization of the pharmacokinetics of inavolisib at additional timepoints in patients enrolled in China.

The clinical trial enrolled a total of **233 participants** diagnosed with **HR+/HER2-negative locally advanced or metastatic breast cancer** harboring a **PIK3CA mutation**. The study population included both **male and female subjects** across **adult and elderly age groups**. Participants were selected based on confirmed diagnosis of HR+/HER2-negative breast cancer with metastatic or locally advanced disease not amenable to curative therapy. Eligibility required confirmation of **PIK3CA mutation** detection via a specified biomarker test. Participants demonstrated **disease progression** during adjuvant endocrine treatment or within 12 months of completing adjuvant endocrine therapy with an **aromatase inhibitor** or **tamoxifen**. All enrolled subjects had **measurable disease** according to **Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)**. The trial population included individuals classified as a **vulnerable population**.

This is a **Phase III**, **randomized**, **double-blind**, **placebo-controlled** clinical trial designed to evaluate the efficacy and safety of **inavolisib** in combination with **palbociclib** and **fulvestrant** compared to placebo plus palbociclib and fulvestrant in patients with **PIK3CA-mutant**, **hormone receptor-positive**, **HER2-negative** locally advanced or **metastatic breast cancer**. The trial is classified as a confirmatory study with an ongoing development program for the investigational molecule. The estimated recruitment start date was September 30, 2020, and the estimated completion date is September 30, 2030, indicating an overall trial duration of approximately 10 years.

The primary objective of the trial is to evaluate the efficacy of the investigational treatment regimen based on **progression-free survival**. Secondary endpoints include **overall survival**, **objective response rate**, best overall response rate, **clinical benefit rate**, **duration of response**, time to confirmed deterioration in pain, time to confirmed deterioration in physical function, time to confirmed deterioration in role function, and time to confirmed deterioration in global health status and health-related quality of life. Safety assessments include monitoring the incidence and severity of **adverse events** according to **National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)**, changes from baseline in vital signs, clinical laboratory test results, and **electrocardiogram (ECG)** parameters. Pharmacokinetic evaluations will measure plasma concentrations of inavolisib, palbociclib, and fulvestrant at specified timepoints, with additional sampling for patients enrolled in China.

The investigational medicinal products include inavolisib administered as **film-coated tablets** via the **oral route** at a maximum daily dose of 9 mg, palbociclib administered as **hard capsules** via the oral route at a maximum daily dose of 125 mg, and fulvestrant administered as a **solution for injection** via **intramuscular injection** at a maximum daily dose of 500 mg. The maximum treatment period for all investigational products is **96 weeks**, with total cumulative doses of 26.3 g for inavolisib, 273 g for palbociclib, and 52.5 g for fulvestrant. All investigational products are classified as **small molecules** with chemical active substances.

Participants must meet principal inclusion criteria including confirmed diagnosis of hormone receptor-positive, HER2-negative breast cancer, metastatic or locally advanced disease not amenable to curative therapy, confirmation of **PIK3CA mutation** via specified testing, disease progression during or within 12 months of completing adjuvant endocrine therapy with an **aromatase inhibitor** or **tamoxifen**, and **measurable disease** per **Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)**. The expected length of participant involvement extends up to the maximum treatment period of 96 weeks, with ongoing follow-up for survival and disease progression assessments. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on participant safety considerations.

The experimental medication inavolisib (also known as GDC-0077) is administered as a film-coated tablet via the oral route. The active substance is inavolisib, a small molecule of chemical origin. Multiple formulations are utilized in this trial, identified by sponsor product codes RO 711-3755/F15-02, RO 711-3755/F14-02, RO 711-3755/F08-02, and RO 711-3755/F09-02, all manufactured by F. Hoffmann-La Roche Ltd. The maximum daily dose is 9 mg, with a maximum total dose of 26.3 g administered over a maximum treatment period of 96 weeks.

Palbociclib is administered as a hard capsule via the oral route. The active substance is palbociclib, a small molecule of chemical origin. The product has been relabeled for clinical trial use and is sourced from Pfizer US. The maximum daily dose is 125 mg, with a maximum total dose of 273 g administered over a maximum treatment period of 96 weeks.

Fulvestrant is administered as Faslodex 250 mg solution for injection via intramuscular injection. The active substance is fulvestrant, a small molecule of chemical origin, with ATC code L02BA03. The product holds marketing authorization number EU/1/03/269/002 under the centralized procedure (EMEA/H/C/000540) and is manufactured by AstraZeneca AB. The product has been relabeled for clinical trial use. The maximum daily dose is 500 mg, with a maximum total dose of 52.5 g administered over a maximum treatment period of 96 weeks.

Efficacy will be assessed through multiple parameters to evaluate the therapeutic benefit of inavolisib in combination with palbociclib and fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer. The primary efficacy endpoint is progression-free survival, which will be evaluated according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Secondary efficacy endpoints include overall survival, objective response rate, best overall response rate, clinical benefit rate, and duration of response. Additional patient-reported outcomes will be assessed through time to confirmed deterioration in pain, physical function, role function, and global health status/health-related quality of life. Tumor response will be measured using RECIST v1.1 criteria to determine disease progression and treatment response. Pharmacokinetic parameters will also be evaluated through measurement of plasma concentrations of inavolisib, palbociclib, and fulvestrant at specified timepoints during the study, with additional timepoints for patients enrolled in China.