by Institute of Cancer Research

Micrograph showing a lymph node invaded by ductal breast carcinoma, with extension of the tumor beyond the lymph node. Credit: Nephron/Wikipedia

A powerful, three-drug therapy for aggressive advanced breast cancer doubles the length of time before the cancer progresses, compared with a drug combination currently available on the NHS, new research has shown.

The INAVO120 study, led by Professor Nicholas Turner of The Institute of Cancer Research, 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.

The results of the international study, published in the New England Journal of Medicine, 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.

Patients in the control group of the phase III, randomized, 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.

The new therapy has been granted FDA approval

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 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 program of discoveries going back over a decade in the Breast Cancer Now Toby Robins Research Center 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.

Then in 2016, the ICR team published research that 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 tumor control compared with two-drug combinations.

An important proof of concept

Four years later, a study trialing a combination of the PI3K inhibitor taselisib with palbociclib, 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 inavolisib-based therapy and paved the way for the INAVO120 study.

About 55,000 women are diagnosed with breast cancer in the UK every year and 11,500 will die from the disease. About 70% of patients have HR+, HER2- breast cancer. PIK3CA mutations are found in 35%–40% of HR+ breast cancers, and are linked to tumor 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.

Breaking down the PIK3CA protein

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 United States Food and Drug Administration (FDA) to grant “breakthrough therapy” designation for inavolisib with full approval granted in October 2024.

A major focus for researchers

New treatments that prevent drug resistance and alter the evolutionary paths of cancer—including in combination and through targeted protein degradation—are a major focus for researchers at the ICR’s Center for Cancer Drug Discovery, which opened its doors in 2020.

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 that 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 program 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.”

‘Blocking off cancer’s escape routes’

Professor Kristian Helin, chief executive of The Institute of Cancer Research, London, said, “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.

“One challenge with combination therapies is finding the right dosages for drugs and untangling their individual effects. It is very encouraging to see that this study showed that the inavolisib-based therapy is not only very effective when taken together but the therapy generally was well-tolerated by patients.”

Dr. Simon Vincent, Breast Cancer Now’s director of research, support and influencing said, “Around 61,000 are thought to be living with secondary breast cancer in the UK which, although currently incurable, can be treated to slow the spread of the disease and improve quality of life.

“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.”

‘I wouldn’t be here if I hadn’t had the opportunity to join the trial’

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.

She said, “I first noticed a lump when I was out shopping and trying on bras. I’d had a benign non-cancerous lump removed when I was just 16, and initially I thought this lump 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 and when the cancer spread to other parts of my body 10 years later, 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.”

More information: Nicholas C. Turner et al, Inavolisib-Based Therapy in PIK3CA -Mutated Advanced Breast Cancer, New England Journal of Medicine (2024). DOI: 10.1056/NEJMoa2404625

Journal information:New England Journal of Medicine