A novel three-drug combination has shown promising results in extending progression-free survival for patients with advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The international INAVO120 study, published in the New England Journal of Medicine, found that the combination of inavolisib, palbociclib, and fulvestrant doubled the time before cancer progression compared to the palbociclib and fulvestrant regimen currently available. This breakthrough, stemming from research at The Institute of Cancer Research (ICR), London, and The Royal Marsden NHS Foundation Trust, has led to FDA approval and hopes for a new standard of care.
INAVO120 Trial: A Detailed Look
The Phase III, randomized, double-blind INAVO120 trial enrolled 325 patients across 28 countries. Participants had PIK3CA-mutated HR+, HER2- advanced breast cancer. The study compared a combination of inavolisib, palbociclib, and fulvestrant against palbociclib and fulvestrant alone. The primary endpoint was progression-free survival.
The results indicated a significant improvement in progression-free survival with the inavolisib combination. The median progression-free survival was 15 months in the inavolisib group compared to 7.3 months in the control group. At 18 months, 46.2% of patients on the inavolisib therapy showed no signs of disease progression, compared to only 21.1% in the control group.
Mechanism of Action and Targeted Therapy
Inavolisib functions as a PI3K inhibitor, blocking the activity of the PIK3CA protein. Uniquely, it 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.
Professor Nick Turner, lead author and Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, stated, "This is the first study to demonstrate the potential of a therapy combination, which targets the three key aspects of the biology of PIK3CA mutant HR-positive breast cancer... It is a huge breakthrough... which could represent a transformative advance for people with this type of breast cancer."
Impact and Future Directions
Approximately 70% of breast cancer patients have HR+, HER2- breast cancer, with PIK3CA mutations present in 35-40% of these cases. These mutations are associated with tumor growth, disease progression, and treatment resistance. The INAVO120 study's findings offer a significant advancement in addressing this unmet need.
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, emphasized the importance of overcoming drug resistance: "To drive further improvements in cancer survival, we must find new ways of overcoming resistance to drug treatments. By developing medicines with different mechanisms of action, we can block off cancer’s escape routes and give people living with metastatic breast cancer the chance to live well for longer."
While the inavolisib-based therapy was generally well-tolerated, researchers continue to focus on optimizing dosages and understanding the individual effects of combination therapies. The ICR's Centre for Cancer Drug Discovery remains dedicated to developing new treatments that prevent drug resistance and alter the evolutionary paths of cancer.
