Efficacy and Safety of Inavolisib, CDK4/6 Inhibitor, and Letrozole in Endocrine-Sensitive PIK3CA-Mutated HR+ HER2- Advanced Breast Cancer

The primary objective of this study is to evaluate the **efficacy** of inavolisib combined with a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) and letrozole, compared to placebo combined with a CDK4/6i and letrozole, in terms of the time from randomization to the first occurrence of disease progression in patients with endocrine-sensitive phosphatidylinositol 3-kinase (PIK3CA)-mutated, hormone receptor-positive, HER2-negative advanced breast cancer. This is clinically relevant as it aims to determine the potential of inavolisib in delaying disease progression, which is crucial for improving patient outcomes in this specific cancer subtype.

Secondary objectives include: - Evaluating the efficacy of inavolisib plus a CDK4/6i and letrozole compared with placebo plus a CDK4/6i and letrozole with respect to time from randomization to death from any cause. - Assessing the efficacy based on investigator-assessed confirmed objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). - Evaluating patient-reported pain severity, functioning, and health-related quality of life (HRQoL). - Assessing the safety of inavolisib plus a CDK4/6i and letrozole compared with placebo. - Evaluating the tolerability of inavolisib plus a CDK4/6i and letrozole from the participant's perspective.

The clinical trial involves a total of **274 participants** diagnosed with **endocrine-sensitive phosphatidylinositol 3-kinase (PIK3CA)-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer**. The study population includes both men and women, encompassing individuals of postmenopausal, premenopausal, or perimenopausal status. Participants are required to have adequate hematologic and organ function within 14 days prior to the initiation of study treatment. The age range of participants spans from adults to the elderly, specifically categorized as ages 18 to 64 and 65 and older. The trial population was selected based on specific inclusion criteria, including the confirmation of biomarker eligibility through valid results from central or local testing documenting the presence of a study-eligible PIK3CA mutation. Additionally, participants must have measurable disease per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). The trial also considers lifestyle factors, requiring men and women of pre- or perimenopausal status to undergo and maintain treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy for the duration of the study treatment. The selection process ensures a diverse and representative sample of the target population, including vulnerable groups, to evaluate the efficacy of the investigational treatment regimen.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **inavolisib** in combination with a **CDK4/6 inhibitor** and **letrozole** compared to a placebo with the same combination in patients with **endocrine-sensitive PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer**. The trial aims to assess the time from randomization to the first occurrence of disease progression or death from any cause. The study is expected to commence recruitment on April 1, 2025, and conclude by January 31, 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as measurable disease per RECIST v1.1, postmenopausal or premenopausal/perimenopausal status, and adequate hematologic and organ function. Following randomization, participants will receive either the investigational treatment or placebo for a maximum treatment period of 30 days, with the possibility of continuation based on the absence of disease progression. Follow-up visits will be conducted to monitor efficacy and safety endpoints, including objective response rate, duration of response, and adverse events. The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed.

Participant involvement is expected to last until the occurrence of disease progression or unacceptable toxicity, with the possibility of early termination if any exclusion criteria are met during the study. Conditions leading to early termination include progression of the disease during or within one year of prior CDK4/6 inhibitor treatment, or failure to maintain treatment with luteinizing hormone-releasing hormone agonist therapy for premenopausal or perimenopausal participants. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding and treatment of advanced breast cancer.

The clinical trial involves the administration of several treatments, including **Palbociclib**, **Inavolisib**, and **Letrozole**, as well as a placebo. **Palbociclib** is provided in the form of a film-coated tablet, with a maximum daily dose of 125 mg. The total maximum dose over the treatment period is 84 grams. The administration route is oral, and the treatment period is set for 30 days. The product has been relabeled specifically for clinical trial use. **Palbociclib** is a small molecule with a chemical origin, and it is not a pediatric formulation.

**Inavolisib**, also known by its sponsor product code RO 711-3755/F14-02 or GDC-0077, is another experimental medication used in this trial. It is also administered as a film-coated tablet with a maximum daily dose of 9 mg and a total maximum dose of 0.29 grams over the treatment period. The administration is oral, and the treatment duration is 30 days. **Inavolisib** is a small molecule of chemical origin, and it is not formulated for pediatric use.

**Letrozole** is included in the study as a standard-of-care therapy. It is administered in tablet form with a maximum daily dose of 2.5 mg and a total maximum dose of 2.28 grams over the 30-day treatment period. The administration route is oral, and the product has been relabeled for clinical trial use. **Letrozole** is a small molecule with a chemical origin and is not a pediatric formulation.

The trial also includes a placebo for **Inavolisib**, which is used to maintain the double-blind nature of the study. The placebo is not associated with any active substance and is not formulated for pediatric use. The administration details for the placebo are not specified beyond its role in the trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy and safety of the combination of **Inavolisib** with a CDK4/6 inhibitor and **Letrozole** compared to a placebo combination in patients with endocrine-sensitive PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer.

The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the time from randomization to the first occurrence of disease progression, as determined by the investigator according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first. This endpoint will provide a measure of the treatment's impact on delaying disease progression in patients with endocrine-sensitive PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer.

Secondary endpoints include a variety of measures to further evaluate the treatment's efficacy and impact on patient quality of life. These include:

• Time from randomization to death from any cause.
• Investigator-assessed confirmed objective response rate (ORR), defined as the proportion of participants with a complete response (CR) and/or partial response (PR) on at least two consecutive assessments ≥ 4 weeks apart, according to RECIST v1.1.
• Investigator-assessed duration of response (DOR), defined as the time from the first occurrence of a confirmed objective response to the first occurrence of disease progression or death from any cause.
• Investigator-assessed clinical benefit rate (CBR), defined as the proportion of participants with a CR, PR, and/or stable disease (SD) for at least 24 weeks.
• Time to confirmed deterioration (TTCD) in pain, physical function, role function, and health-related quality of life (HRQoL), using validated scales such as the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30).
• Incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
• Changes from baseline in targeted vital signs and clinical laboratory test results.
• Assessment of symptomatic treatment toxicities and treatment side-effect bother using the National Cancer Institute Patient Reported Outcomes Common Terminology Criteria for Adverse Events (NCI PRO-CTCAE) and the Functional Assessment of Cancer Therapy-General Questionnaire (FACT-G).

The efficacy assessments will be conducted at specified intervals throughout the trial, with data collection and analysis performed according to the trial protocol. The use of validated instruments and criteria ensures the reliability and accuracy of the efficacy evaluations.