A promising new therapy can help patients with aggressive advanced breast cancer live longer and delay the need for further chemotherapy, new research has shown.
Final results of the INAVO120 study, led by an international team of researchers including scientists at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, have demonstrated 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.
The international study, funded by Roche, was presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago on 31 May 2025 and simultaneously published in The New England Journal of Medicine.
A new combination therapy
The new combination therapy which is made up of two targeted drugs – inavolisib and palbociclib – along with hormone therapy fulvestrant, was shown to have improved overall survival by an average of seven months, compared with the patients in the control group, who were given palbociclib and fulvestrant, a combination which has been approved for use on the NHS since September 2022. The median overall survival in the inavolisib group was 34 months, compared with 27 months in the control group.
Updated results of the phase III, randomised, double blind trial also showed that the new combination delayed the progression of the disease by 17.2 months, on average, compared with 7.3 months in the control group.
Patients taking inavolisib were able to delay subsequent chemotherapy treatment by almost two years longer than the patients in the control group.
The team, led by Professor Nicholas Turner, Professor of Medical Oncology in the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research (ICR), now hopes the combination will become the standard of care in women with this form of the disease.
Tackling PIK3CA mutations
Around 55,000 women are diagnosed with breast cancer in the UK every year and 11,500 will die from the disease. Around 70 per cent of patients have HR+, HER2- breast cancer. PIK3CA mutations are found in 35-40 per cent 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 per cent) had prior adjuvant chemotherapy.
The researchers used circulating tumour DNA (ctDNA) ‘liquid biopsy’ blood tests to determine whether patients had a PIK3CA mutation. Participants were then allocated to receive either the inavolisib-based regimen or a combination of palbociclib, fulvestrant and a dummy pill.
Combating treatment resistance
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. At the ICR, researchers are working to discover new protein degrading drugs like this, which could help people with advanced cancers live well for longer.
Palbociclib is a type of drug called cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. It works by simultaneously blocking two proteins called CDK4 and CDK6 in cancer cells and preventing them from growing.
The inavolisib combination was generally well tolerated with only a few patients experiencing side effects that led them to discontinue the treatment.
A decade of discoveries
The results also showed substantial shrinking, or response, in cancer growth in around 62.7 per cent of patients in the triplet therapy group compared to 28 per cent in the control group.
Earlier results led the United States Food and Drug Administration (FDA) to grant ‘breakthrough therapy’ designation for inavolisib in May 2024.
The breakthrough follows a pioneering programme of discoveries in the lab at the ICR, going back over a decade. 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.
Then in 2016, the ICR team published research which showed how breast cancer cells become resistant to CDK4/6 inhibitors such as palbociclib and identified that a combination of three drugs — a CDK4/6 inhibitor, a hormone therapy and a PI3K inhibitor — would provide the best tumour control compared with two-drug combinations.
Four years later, a study trialling a combination of palbociclib, taselisib and hormone therapy showed some success, although the researchers determined that taselisib was not the right PI3K inhibitor. However, these results demonstrated an important proof of concept for the combination therapy and paved the way for the INAVO120 study.
'This could become the new option for patients with a PIK3CA mutation'
Lead author Professor Nicholas Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“The key findings from this study showed that the inavolisib-based therapy not only helped patients live longer but it more than doubled the time before their cancer progressed or worsened. It also gave them more time before needing subsequent chemotherapy which we know is something that patients really fear and want to delay for as long as possible.
“These results give us confidence that this treatment could become the new go-to option for patients who have HR+, HER2- breast cancer with a PIK3CA mutation, as it has shown significant improvements in both survival and quality of life.
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:
"If we are to continue improving cancer survival rates, we need to tackle treatment resistance head-on. This research demonstrates how this triple combination approach, effectively shuts down cancer’s escape routes, giving people with metastatic breast cancer the opportunity to live well for longer.
“One of the challenges with combination therapies is ensuring the right drug dosages and understanding their individual effects. It is extremely encouraging that this study not only demonstrates the effectiveness of this approach but also shows that the therapy was generally well-tolerated by patients.
“This research reinforces our commitment to developing innovative treatments that transform lives and set new standards in cancer care. It is a powerful reminder of how scientific innovation can reshape the future of cancer care and give hope to countless patients worldwide."
CASE STUDY
Anne Lury, 53, was diagnosed with stage two breast cancer in 2007 and 10 years later she was given the news that her cancer had spread to other parts of her body. Anne received the new PI3K inhibitor drug, inavolisib, after joining a clinical trial at The Royal Marsden.
“I’d had a benign noncancerous lump removed when I was just 16, so when I first noticed a new lump, I initially thought it might also be benign, but unfortunately further tests revealed that I had breast cancer.
“Following my diagnosis, I was treated with surgery, chemotherapy and radiotherapy over a period of 10 years. I was always on some kind of treatment but despite this the cancer eventually spread to other parts of my body, which is when I received the targeted therapy drug palbociclib. After three years the treatment stopped working for me, but thankfully I was able to receive inavolisib as part of a clinical trial.
“Aside from fatigue, I had minimal side effects, and although I’m now on other treatment I wouldn’t be here if I hadn’t had the opportunity to join the trial at The Royal Marsden.”