The investigation of the PI3K inhibitor inavolisib (Itovebi) in patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative, advanced breast cancer is expanding into the frontline setting and may further establish the agent as a means of improving upon standard endocrine therapy plus CDK4/6 inhibitors.
Inavolisib plus palbociclib (Ibrance) and fulvestrant (Faslodex) was FDA approved in 2024 for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer who have disease recurrence on or after the completion of adjuvant endocrine therapy; this regulatory decision was based on data from the phase 3 INAVO120 trial (NCT04191499).1 Following positive data with the regimen in this population, the phase 3 INAVO123 trial (NCT06790693) is exploring the efficacy and safety of inavolisib plus a CDK4/6 inhibitor and letrozole the first-line setting in patients with endocrine-sensitive disease.2
“In the INAVO120 study, the triplet of fulvestrant plus inavolisib and palbociclib was superior to fulvestrant/palbociclib [alone],” Aditya Bardia, MD, MPH, FASCO, said in an interview with OncLive®. “There was improvement in progression-free survival [PFS] and overall survival [OS]. INAVO123 could increase or widen the use of inavolisib.”
Bardia is a professor in the Department of Medicine, Division of Hematology/Oncology, director of Translational Research Integration, and a member of Signal Transduction and Therapeutics at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California.
The INAVO123 Trial Design at a Glance
- Inavolisib is a highly potent and selective PI3Kα inhibitor that triggers the degradation of mutant p110α, a mechanism designed to achieve more sustained pathway inhibition and a broader therapeutic index than other inhibitors.
- The INAVO123 trial is a randomized, double-blind study evaluating whether adding inavolisib to a CDK4/6 inhibitor and letrozole improves outcomes vs placebo plus a CDK4/6 inhibitor and letrozole for patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative, endocrine-sensitive advanced breast cancer.
- The study aims to enroll approximately 450 patients and will primarily measure the regimen’s effect on PFS. Secondary end points include OS, safety, and patient-reported outcomes.
What data have been previously reported with inavolisib in PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer?
The pivotal INAVO120 trial demonstrated that frontline treatment with inavolisib plus palbociclib and fulvestrant generated a significant improvement in PFS compared with placebo plus palbociclib and fulvestrant among patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer.1 At a median follow-up of 34.2 months, the median PFS in the inavolisib arm (n = 161) was 15.0 months (95% CI, 11.3-20.5) vs 7.3 months (95% CI, 5.6-9.3) in the placebo arm (n = 164; stratified HR, 0.43; 95% CI, 0.32-0.59; P < .0001).1 Furthermore, data from the final OS analysis revealed that patients who received inavolisib achieved a median OS of 34.0 months (95% CI, 28.4-44.8) vs 27.0 months (95% CI, 22.8-38.7) for those in the placebo arm (stratified HR, 0.67; 95% CI, 0.48-0.94; P = .0190).3
What is the design of the INAVO123 trial?
Bardia noted that the INAVO123 trial design is largely complementary to that of INAVO120.
INAVO123 is enrolling women and men at least 18 years of age with histologically or cytologically confirmed breast carcinoma who have documented estrogen receptor– or progesterone receptor–positive and HER2-negative tumors.2,4 Patients will be included if they have HER2-negative advanced breast cancer that is de novo or has relapsed following 2 or more years of standard neoadjuvant or adjuvant endocrine therapy without disease progression during that treatment and a disease-free interval of at least 1 year since that treatment’s completion. Patients must also have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ and hematologic function within 14 days before initiating study treatment.
Patients will be excluded if they have metaplastic breast cancer; received any prior systemic therapy for locally advanced unresectable or metastatic breast cancer; type 2 diabetes that requires ongoing systemic treatment; any history of type 1 diabetes, carcinomatous meningitis, or leptomeningeal disease; active infectious or inflammatory conditions in either eye or a history of autoimmune-associated or idiopathic uveitis in either eye; symptomatic active lung disease; a history of or active inflammatory bowel disease; prior bone marrow or hematopoietic stem cell transplantation; or received treatment with strong CYP3A4 inducers or cytochrome P450 CYP3A4 inhibitors within 4 weeks or 5 drug-elimination half-lives before initiating study treatment.
Notably although patients with known and untreated or active central nervous system (CNS) metastases will be excluded, patients with a history of treated CNS metastases are permitted to enroll.2
Approximately 450 patients will be randomly assigned 1:1 to receive oral inavolisib at 9 mg daily plus an oral CDK4/6 inhibitor on days 1 to 21 and oral letrozole at 2.5 mg daily, or placebo plus a CDK4/6 inhibitor and letrozole at the same doses and schedules.4 Treatment will be administered in 28-day cycles. Pre- and perimenopausal women, as well as men, will receive a luteinizing hormone–releasing hormone agonist for the duration of study treatment. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or study termination.
PFS will serve as the primary end point.2,4 Secondary end points include OS; overall response rate; duration of response; clinical benefit rate; time to confirmed deterioration in pain, physical function, role function, and Global Health Status; adverse effects; and other patient-reported outcomes.
“More and more, [the breast oncology field is] going into precision medicine,” Bardia explained. “If INAVO123 is positive, we will be testing all patients for PIK3CA mutations at the time of metastatic disease diagnosis. We currently do this for a subset [of patients], but [it may soon be standard] for everyone, because that's an actionable finding. It further leads us down the precision medicine paradigm.”
The trial was initiated on April 9, 2025, and the estimated primary completion date is May 30, 2032.2 The trial is currently enrolling.
“Educational symposia, readouts, summaries, and journals are important, because it is important that a patient receives the latest treatment,” Bardia concluded. “It’s important that [we] remain up to date.”
References
- FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed January 21, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
- A study evaluating the efficacy and safety of inavolisib plus CDK4/6 inhibitor and letrozole vs placebo + CDK4/6i and letrozole in participants with endocrine-sensitive PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer (INAVO123). ClinicalTrials.gov. Updated January 7, 2026. Accessed January 21, 2026. https://www.clinicaltrials.gov/study/NCT06790693
- Turner N, Im SA, Saura C, et al. INAVO120 phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC).J Clin Oncol. 2025;43(suppl 16):1003. doi:10.1200/JCO.2025.43.16_suppl.1003
- Cortés J, Basho RK, Jhaveri K, et al. INAVO123: phase III study of first-line (1L) inavolisib/placebo + a CDK4/6 inhibitor + letrozole (INAVO/PBO + CDK4/6i + LET) in participants (pts) with PIK3CA-mutated (mut), hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-sensitive advanced breast cancer (aBC).Ann Oncol. 2025;10(suppl 4):104979. doi:10.1016/j.esmoop.2025.104979
