A novel therapy combining inavolisib with 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, funded by Roche, revealed that this three-drug combination doubled the time before cancer progression compared to the currently available treatment of palbociclib and fulvestrant. This breakthrough, which has already received FDA approval, offers a promising new standard of care for a common and aggressive form of breast cancer.
INAVO120 Trial Results
The Phase III, randomized, double-blind INAVO120 trial involved 325 patients across 28 countries. The study focused on patients with PIK3CA-mutated HR+, HER2- breast cancer, a subtype that accounts for approximately 70% of all breast cancer cases. PIK3CA mutations are present in 35-40% of HR+ breast cancers and are known to drive tumor growth, disease progression, and treatment resistance.
Patients in the control group, treated with palbociclib and fulvestrant (a combination approved for use since September 2022), experienced disease progression after an average of 7.3 months. In contrast, patients receiving the inavolisib-based therapy saw their disease progression delayed by an average of 15 months. 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.
Mechanism of Action
Inavolisib functions by blocking the activity of the PIK3CA protein and triggering the breakdown of the mutated PI3K alpha protein through targeted protein degradation. Palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, prevents cancer cell growth by simultaneously blocking CDK4 and CDK6 proteins.
Clinical Implications and Future Directions
Professor Nick Turner from The Institute of Cancer Research (ICR), London, and The Royal Marsden NHS Foundation Trust, the lead author of the study, emphasized the potential of this therapy combination to target the key biological aspects of PIK3CA mutant HR-positive breast cancer. He stated, "This new combination helps prevent the cancer becoming resistant to therapy, and results in more frequent long-term responses. We look forward to seeing this treatment option being licensed and becoming the standard of care as quickly as possible."
The inavolisib-based therapy was generally well-tolerated, with few patients discontinuing treatment due to side effects. Furthermore, the study showed substantial cancer shrinkage in approximately 58.4% of patients in the inavolisib therapy group, compared to 25% in the control group. These results led the FDA to grant breakthrough therapy designation for inavolisib, with full approval granted in October 2024, paving the way for its integration into standard clinical practice.
