A novel three-drug therapy combining inavolisib, palbociclib, and fulvestrant has demonstrated a significant improvement in progression-free survival for patients with advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer harboring PIK3CA mutations. The international INAVO120 study, led by Professor Nicholas Turner, highlights the potential of this new combination to address a common and aggressive form of breast cancer.
The results, published in the New England Journal of Medicine, revealed that the triplet therapy delayed disease progression by an average of 15 months, compared to 7.3 months in the control group receiving palbociclib and fulvestrant, a combination already approved for use on the NHS since September 2022. This represents a clinically meaningful improvement for patients with this challenging disease.
INAVO120 Trial Results
The Phase III, randomized, double-blind trial involved 325 patients across 28 countries. The study population included patients with metastatic disease, many of whom had already experienced disease spread to three or more organs and had prior chemotherapy (82.8%). Notably, at the 18-month mark, 46.2% of patients in the inavolisib therapy group showed no signs of disease progression, compared to only 21.1% in the control group.
This significant improvement in progression-free survival, coupled with substantial tumor shrinkage observed in 58.4% of patients in the inavolisib arm versus 25% in the control arm, led to FDA approval of the new therapy combination. It is anticipated that this regimen will become a standard of care for women with this specific subtype of breast cancer.
Targeting PIK3CA Mutations
PIK3CA mutations are present in 35-40% of HR+ breast cancers and are associated with tumor growth, disease progression, and treatment resistance. Inavolisib functions by blocking the activity of the PIK3CA protein and also triggers the breakdown of the mutated PI3K alpha protein through targeted protein degradation. Palbociclib, a CDK4/6 inhibitor, prevents cancer cell growth by blocking CDK4 and CDK6 proteins.
The inavolisib-based therapy was generally well-tolerated, with few patients discontinuing treatment due to side effects. This favorable safety profile, combined with the efficacy data, supports its potential as a valuable treatment option.
A Decade of Research
This breakthrough is the culmination of over a decade of research at the Breast Cancer Now Toby Robins Research Center at the ICR. Earlier studies, including the PALOMA3 trial in 2015, demonstrated the benefit of palbociclib with hormone therapy. Subsequent research in 2016 identified the mechanisms of resistance to CDK4/6 inhibitors, paving the way for the development of triplet therapies.
Professor Nick Turner stated, "This is the first study to demonstrate the potential of a therapy combination that targets the three key aspects of the biology of PIK3CA mutant HR-positive breast cancer...This new combination helps prevent the cancer becoming resistant to therapy, and results in more frequent long-term responses."
Impact on Patient Care
Dr. Simon Vincent, Breast Cancer Now's director of research, support and influencing, noted, "These findings show that this new treatment approach, using a combination of three drugs, could provide people living with secondary breast cancer an additional eight months without their disease getting worse, giving them more precious time with their loved ones."
