A new therapy could double progression-free survival in advanced breast cancer.
The powerful three-drug combination for aggressive advanced breast cancer doubles the length of time before the cancer progresses, compared with a drug combination currently available on the NHS.
The results of the international study, funded by Roche, showed that the new three-drug combination which is made up of two targeted drugs – inavolisib and palbociclib – along with the hormone therapy fulvestrant, delayed the disease progression by an average of 15 months.
The INAVO120 study, led by Professor Nicholas Turner of The Institute of Cancer Research (ICR), London, and The Royal Marsden NHS Foundation Trust, demonstrates the potential of the new therapy combination for targeting PIK3CA-mutated hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer – a common form of the disease.
Patients in the control group of the phase III, randomised, double blind trial who were given palbociclib and fulvestrant, a combination which has been approved for use on the NHS since September 2022, saw the progression of their disease halted for an average of 7.3 months.
At the 18-month mark, 46.2% of patients in the inavolisib therapy group were still showing no signs of disease progression, compared with 21.1% in the control group.
As a result, the new therapy combination has been granted Food and Drug Administration (FDA) approval and it is hoped that it will become the standard of care in women with this form of the disease.
This breakthrough follows a pioneering programme of discoveries going back over a decade in the Breast Cancer Now Toby Robins Research Centre at the ICR. The results of the PALOMA3 trial in 2015 showed that women treated with a combination of palbociclib and standard hormone therapy saw their disease progress after an average of nine months, compared with fewer than four months with hormone therapy alone.
Around 55,000 women are diagnosed with breast cancer in the UK every year and 11,500 will die from the disease. Around 70% of patients have HR+, HER2- breast cancer.
PIK3CA mutations are found in 35-40% of HR+ breast cancers, and are linked to tumour growth, disease progression, and treatment resistance.
The INAVO120 study recruited 325 patients from 28 countries. More than half had metastatic disease that had already spread to three or more organs and most (82.8%) had prior chemotherapy.
The researchers used ctDNA ‘liquid biopsy’ tests to determine whether patients had a PIK3CA mutation. Participants were then allocated to receive either the inavolisib therapy or a combination of palbociclib, fulvestrant and a dummy pill.
The new drug, inavolisib works by blocking the activity of the PIK3CA protein. However, it also has a second mode of action which triggers the breakdown of the mutated PI3K alpha protein, destroying it altogether – a process known as targeted protein degradation.
Palbociclib is a type of drug called a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. It works by simultaneously blocking two proteins called CDK4 and CDK6 in cancer cells and preventing them from growing.
The inavolisib-based therapy was generally well tolerated with only a few patients experiencing side effects that led them to discontinue the treatment.
The study results, which also showed substantial shrinking in cancer growth in around 58.4% of patients in the inavolisib therapy group compared to 25% in the control group, led the FDA to grant ‘breakthrough therapy’ designation for inavolisib with full approval granted in October 2024.
Lead author Professor Nick Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said: “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. The results show that inavolisib in combination with palbociclib and fulvestrant significantly improves progression-free survival when given as a first treatment for the disease. It is a huge breakthrough that builds on a long programme of research at the ICR which could represent a transformative advance for people with this type of breast cancer. 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.”
