Efficacy and Safety of Inavolisib plus Combination Therapy in Patients with Endocrine-Resistant HR+/HER2- Advanced Breast Cancer with Chromosome 8p Loss

The primary objective of this study is to evaluate the efficacy of inavolisib, ribociclib, and fulvestrant compared to placebo, ribociclib, and fulvestrant in patients with endocrine-resistant hormone-receptor-positive, HER2-negative advanced breast cancer characterized by chromosome 8p loss and the absence of PIK3CA mutation. This evaluation is measured by the investigator-assessed confirmed objective response rate (5).

The secondary objectives include:

• Assessment of efficacy through progression-free survival, overall survival, investigator-assessed duration of response, and investigator-assessed clinical benefit rate.
• Evaluation of safety (4).
• Assessment of tolerability (13) from the participant's perspective.

This clinical trial involves 36 participants diagnosed with endocrine-resistant hormone-receptor-positive, HER2-negative advanced breast cancer. The study population includes both men and women within specific age ranges. Participants must present with locally advanced or metastatic carcinoma that is not amenable to curative surgical or radiation therapy. Eligible individuals have documented estrogen receptor-positive and/or progesterone receptor-positive tumors. A required biomarker profile includes the presence of heterozygous loss of chromosome 8p and the absence of a PIK3CA mutation. Selected subjects have not received prior systemic therapy for their advanced disease but have progressed during or within 12 months of completing adjuvant endocrine-based therapy. All participants must possess measurable disease as defined by RECIST v1.1.

This Phase II, multicenter, randomized, double-blind, placebo-controlled study evaluates the efficacy and safety of inavolisib combined with ribociclib and fulvestrant compared to a placebo plus ribociclib and fulvestrant. The study focuses on patients with endocrine-resistant hormone-receptor-positive, HER2-negative advanced breast cancer characterized by chromosome 8p loss and the absence of a PIK3CA mutation. The primary endpoint is the investigator-assessed confirmed objective response rate. Secondary endpoints include progression-free survival, overall survival, duration of response, and clinical benefit rate, alongside assessments of adverse events and patient-reported outcomes. Participants must meet specific criteria, including histologically confirmed carcinoma, measurable disease per RECIST v1.1, and documented biomarker eligibility through central laboratory testing. The trial is estimated to occur between April 2026 and December 2030.

Inavolisib is administered as a 9 mg film-coated tablet via an oral route.

Ribociclib is administered at a dosage of 600 mg via an oral route.

Fulvestrant is administered as a 500 mg intramuscular injection.

The control group receives an inavolisib placebo in place of the experimental medication.

The primary efficacy endpoint is the investigator-assessed confirmed objective response rate (ORR). Secondary efficacy parameters include progression-free survival (PFS), overall survival (OS), investigator-assessed duration of response (DOR), and investigator-assessed clinical benefit rate (CBR).

Additional assessments involve the following:

• The change from baseline in vital signs and clinical laboratory test results.
• The presence, frequency, severity, and degree of interference with daily activities regarding symptomatic treatment toxicities, evaluated using the National Cancer Institute Patient-Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument.
• The proportion of participants reporting response options for treatment side-effect bother via the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, specifically the General Population, Question 5 (GP5) item.
• Changes from baseline or worsening in symptomatic treatment toxicities and treatment side-effect bother as assessed through the PRO-CTCAE and FACT-G GP5.