Patients with hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer who carry PIK3CA mutations showed a clear survival benefit when treated with the combination of inavolisib (Itovebi), palbociclib (Ibrance), and fulvestrant (Faslodex). This was demonstrated in the final overall survival (OS) analysis of the phase 3 INAVO120 trial (NCT04191499). The results were presented at a press conference ahead of the 2025 American Society of Clinical Oncology (ASCO) meeting.
With a median follow-up of 34.2 months, patients receiving inavolisib had a median OS of 34.0 months, compared to 27.0 months for those on placebo. The hazard ratio (HR) was 0.67 (95% CI, 0.48-0.94; P = 0.019), indicating a 33% reduction in risk of death. Survival rates at 6, 12, 18, 24, and 30 months were consistently higher in the inavolisib group, confirming the treatment’s lasting benefit.
“This is the first time a PI3K pathway-targeted drug has significantly improved overall survival,” said Dr. Nicholas C. Turner, lead author and director of the National Institute for Health and Care Research Biomedical Research Center at the Royal Marsden Hospital, London.
Understanding the INAVO120 Trial and Its Significance
PIK3CA gene mutations occur in about 40% of patients with advanced hormone receptor-positive, HER2-negative breast cancer. These mutations typically signal poor prognosis and resistance to existing PI3K inhibitors. Tumor growth in this cancer type depends on three key pathways: estrogen receptors, CDK4/6, and PI3K signaling. Blocking all three pathways simultaneously can enhance treatment response and delay resistance.
However, earlier efforts to combine PI3K inhibitors with CDK4/6 inhibitors failed due to unacceptable toxicity. Inavolisib is a potent, selective oral PI3K inhibitor that degrades mutant PI3Kα (p110α) protein. Importantly, it can be safely combined at full doses with palbociclib and fulvestrant.
Based on promising early results from INAVO120, which showed more than double the progression-free survival (PFS) and improved response rates compared to palbociclib and fulvestrant alone, the FDA approved this triplet therapy in October 2024.
Trial Design and Patient Eligibility
The double-blind INAVO120 trial enrolled 325 patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer. Mutations were confirmed via circulating tumor DNA (ctDNA) or tissue testing. Eligible patients had measurable disease progression during or within 12 months after completing adjuvant endocrine therapy. They also had prior treatment for advanced disease and met specific glucose control criteria.
Patients were randomized 1:1 to receive either 9 mg daily oral inavolisib plus palbociclib and fulvestrant, or placebo plus palbociclib and fulvestrant. Treatment continued until disease progression or unacceptable toxicity.
The study stratified patients based on presence of visceral disease, type of endocrine resistance, and geographic region.
Efficacy Results: Prolonged Progression-Free Survival and Delayed Chemotherapy
Earlier analysis with 12.8 months median follow-up confirmed that inavolisib significantly improved PFS. Median PFS was 17.2 months in the inavolisib group versus 7.3 months in the placebo group (HR 0.42). PFS rates at 6, 12, 18, and 24 months were substantially higher with inavolisib.
Moreover, the combination delayed the need for chemotherapy. Median time to first subsequent chemotherapy was 35.6 months in the inavolisib group, compared to 12.6 months with placebo. This nearly two-year delay is considered a major benefit for patients with metastatic disease.
Dr. Julie Gralow, ASCO’s Chief Medical Officer, emphasized the importance of this finding: “Delaying chemotherapy by nearly two years is a significant result that can greatly improve patients’ quality of life.”
Safety Profile of Inavolisib Combination
Adverse events (AEs) occurred in all patients. Grade 3 or 4 AEs were reported in 90.7% of the inavolisib group and 84.7% of the placebo group. Grade 5 (fatal) events were rare and not linked to treatment. Serious AEs were more frequent in the inavolisib group (27.3%) than placebo (13.5%).
Treatment discontinuations due to AEs occurred in 6.8% of patients taking inavolisib versus 0.6% in the placebo group. Dose reductions were also higher with inavolisib. Despite this, Dr. Turner noted the safety profile was consistent with prior studies, and treatment-related discontinuations remained low.
A New Standard for PIK3CA-Mutated Advanced Breast Cancer
Dr. Turner concluded, “Inavolisib plus palbociclib and fulvestrant significantly improved overall survival compared to placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer.”
This study marks a major step forward in targeted therapy, offering new hope to patients with limited treatment options. The INAVO120 trial establishes this triple combination as a new standard of care for this challenging breast cancer subtype.
Related topics:
- Bills Rookie Jackson Turns Hair Loss Into Mental Health Advocacy
- Ashley Iaconetti Reveals She’S Had Two Breast Biopsies
- Alexis Bellino’s Warning: Silicone Leaking After Fourth Implant Surgery
