Taselisib

Image: metastatic breast cancer cells in pleural fluid 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, funded by Roche and 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, 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 per cent of patients in the inavolisib therapy group were still showing no signs of disease progression, compared with 21.1 per cent 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 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. 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 comination 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. 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 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 per cent of patients in the inavolisib therapy group compared to 25 per cent 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. 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 Centre 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, 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.” 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 precious more time with their loved ones.” 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.”

Novartis announced that its BYL719 (alpelisib) met the primary endpoint of progression-free survival (PFS) in its Phase III SOLAR-1 trial. The drug is an alpha-specific PI3K inhibitor, a category of cancer drugs that has a troubling history of adverse events. Novartis announced that its BYL719 (alpelisib) met the primary endpoint of progression-free survival (PFS) in its Phase III SOLAR-1 trial. The drug is an alpha-specific PI3K inhibitor, a category of cancer drugs that has a troubling history of adverse events. The SOLAR-1 trial studied BYL719 in combination with fulvestrant compared to fulvestrant alone in postmenopausal women and men with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) PIK3CA-mutant advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor. There are currently no approved PI3K inhibitors for HR+ advanced breast cancer. The PI3K pathway plays a significant role in regulating cells and is, according to Novartis, “the most frequently altered pathway promoting tumor growth, disease progression and treatment resistance in HR+ advanced breast cancer.” Specific data was not released at this time other than it showed improvement in PFS. “BYL719 is the only alpha-specific PI3K inhibitor and the first one to show potential increased benefit and acceptable tolerability for patients,” said Samit Hirawat, Head, Novartis Oncology Global Drug Development, in a statement. “We are encouraged by the results observed in the SOLAR-1 study and look forward to submitting the data to an upcoming medical congress and starting discussions with health authorities worldwide.” Some analysts seemed to think the drug could become a blockbuster. Bruno Bulic , an analyst at Baader Helvea, said in a note to clients, “We estimate alpelisib peak sales potential at $1.9 billion, and lift our probability of success to 80 percent.” Given the history of this class of drugs, one has to wonder if the positive analysts are being premature without seeing the actual data. In July, Novartis, according to Reuters, “unloaded rights to a similar molecule, called buparlisib, to China’s Adlai Nortye Biopharma Co. Ltd. , after doctors concluded it was too dangerous to continue developing in the advanced breast cancer setting, when combined with hormone therapy.” A month earlier, in June, Roche gave up on its own PI3K inhibitor, taselisib, after data showed that the side effects didn’t outweigh the modest PFS benefit. In their trials, almost 20 percent of breast cancer patients receiving the drug abandoned treatment early. Novartis’ statement indicates that adverse events were “consistent” with other studies of BYL719, which is worrying. Gilead has Zydelig, which is marketed with a black box warning concerning serious and sometimes fatal toxicities. In February, Gilead withdrew its European marketing application for Zydelig in combination with Roche’s Rituxan (rituximab) and the chemotherapy drug bendamustine for chronic lymphocytic leukemia (CLL) patients who had already had at least one line of therapy. This came after the European Medicines Agency ’s Committee for Medicinal Products for Human Use (CHMP) indicated it was unlikely to give a positive recommendation. CHMP suggested that it would need longer-term data to evaluate the drug’s benefit/risk profile. Zydelig is otherwise approved in Europe for second-line CLL in combination with Rituxan or Novartis’ Arzerra (ofatumumab) and third-line follicular lymphoma.