Inavolisib

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. The new combination therapy which is made up of two targeted drugs – inavolisib and palbociclib – along with hormone therapy fulvestrant, was shown to haveimproved 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. 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. 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. 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. 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." 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.”

Positive recommendation based on phase III INAVO120 data showing ItovebiTM (inavolisib) in combination with palbociclib and fulvestrant more than doubled progression-free survival in the first-line setting1 The Itovebi-based regimen also demonstrated a statistically significant and clinically meaningful benefit in overall survival (OS) in the final OS analysis Final OS data will be presented in an oral session at the 2025 American Society of Clinical Oncology Annual Meeting 23 May 2025 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for Itovebi™ (inavolisib), in combination with palbociclib (Ibrance®) and fulvestrant, for the treatment of adult patients with PIK3CA-mutated, oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, following recurrence on or within 12 months of completing adjuvant endocrine treatment. If approved, the Itovebi-based regimen has the potential to transform the standard of care in this first-line setting, where treatments are currently limited.1 A final decision regarding the approval is expected from the European Commission in the near future. “The positive CHMP recommendation for the Itovebi-based regimen represents a significant step towards providing people in the EU with PIK3CA-mutated, ER-positive advanced breast cancer with a targeted therapy in the first-line setting,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “This recommendation is further enforced by the recent final overall survival results from the INAVO120 study, showing the regimen can meaningfully extend survival.” The presence of a PIK3CA mutation, found in approximately 40% of hormone receptor (HR)-positive breast cancers, can make the disease more aggressive and worsen survival outcomes.2,3 This underscores the importance of testing for PIK3CA mutations prior to first-line treatment so that people with a poor prognosis can benefit from an effective, PI3K-targeted therapy as soon as possible. The CHMP’s positive opinion is based on the phase III INAVO120 results, published in the New England Journal of Medicine in October 2024, which showed a 57% reduction in the risk of disease worsening or death (progression-free survival [PFS]) with the Itovebi-based regimen compared with palbociclib and fulvestrant alone (15.0 months vs. 7.3 months; hazard ratio [HR]=0.43, 95% CI: 0.32-0.59, p1 The PFS benefit was consistent across all pre-specified subgroups, including people whose disease had spread to three or more locations, characterised as difficult-to-treat disease.1 The Itovebi-based regimen was well tolerated, with no new safety signals observed.1 Positive topline results from the final overall survival (OS) analysis, announced in January 2025, showed a statistically significant and clinically meaningful OS benefit with the Itovebi-based regimen. OS data were immature at the time of primary analysis, but a clear positive trend was observed (stratified HR=0.64, 95% CI: 0.43-0.97, p=0.0338 (boundary of 0.0098)).1 The full results from the OS analysis will be presented in an oral session at the 2025 American Society of Clinical Oncology Annual Meeting. The Itovebi-based regimen is approved for the treatment of adults with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer in the United States, Switzerland, Canada, Australia, United Arab Emirates and China, with data from INAVO120 under review with other global health authorities. Beyond INAVO120, Itovebi is currently being investigated in three company-sponsored phase III studies (INAVO121, INAVO122, INAVO123), all in PIK3CA-mutated, locally advanced or metastatic breast cancer in various combinations.4-7 We are exploring additional studies in breast cancer and other tumour types with the hope of providing the benefit of this targeted therapy to more people with PIK3CA mutations. Itovebi is an oral, targeted treatment that has been shown to provide well-tolerated and durable disease control in people with advanced PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, who often have a poor prognosis and are in urgent need of new treatment options.1-3 Itovebi has been designed to help minimise the overall burden and toxicity of treatment and is differentiated from other PI3K inhibitors due to its high potency and specificity for the PI3K alpha isoform versus other isoforms, and unique mechanism of action that facilitates the degradation of mutated PI3K alpha.8,9 The INAVO120 study [NCT04191499] is a phase III, randomised, double-blind, placebo-controlled study evaluating the efficacy and safety of Itovebi™ (inavolisib) in combination with palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in people with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer whose disease progressed during treatment or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for metastatic disease.4 The study included 325 patients, who were randomly assigned to either the investigational or control treatment arm.4 The primary endpoint is progression-free survival, as assessed by investigators, defined as the time from randomisation in the clinical trial to the time when the disease progresses, or a patient dies from any cause.4 Secondary endpoints include overall survival, objective response rate, and clinical benefit rate.4 Beyond INAVO120, Itovebi is currently being investigated in three additional company-sponsored phase III clinical studies in PIK3CA-mutated, locally advanced or metastatic breast cancer in various combinations:5-7 in combination with fulvestrant versus alpelisib plus fulvestrant in HR-positive/HER2-negative breast cancer post cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and endocrine combination therapy (INAVO121; NCT05646862). in combination with pertuzumab plus trastuzumab for subcutaneous injection (SC) versus pertuzumab plus trastuzumab for SC and optional physician's choice of endocrine therapy as a maintenance treatment in HER2-positive disease (INAVO122; NCT05894239). in combination with a CDK4/6 inhibitor and letrozole versus placebo plus a CDK4/6 inhibitor and letrozole in the first-line setting in PIK3CA-mutated HR-positive/HER2-negative, endocrine-sensitive breast cancer (INAVO123; NCT06790693). HR-positive breast cancer is the most prevalent type of all breast cancers, accounting for approximately 70% of cases.10,11 A defining feature of HR-positive breast cancer is that its tumour cells have receptors that attach to one or both hormones – oestrogen or progesterone – which can contribute to tumour growth. People diagnosed with HR-positive metastatic breast cancer often face the risk of disease progression and treatment side effects, creating a need for additional treatment options.11-13 The PI3K signalling pathway is commonly dysregulated in HR-positive breast cancer, often due to activating PIK3CA mutations, which have been identified as a potential mechanism of intrinsic resistance to standard of care endocrine therapy in combination with cyclin-dependent kinase 4/6 inhibitors.3 Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough outcomes in human epidermal growth factor 2-positive and triple-negative breast cancers. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for other subtypes of the disease, including oestrogen receptor-positive breast cancer, which is a form of hormone receptor-positive breast cancer, the most prevalent type of all breast cancers.10,11 Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. For over 125 years, sustainability has been an integral part of Roche’s business. As a science-driven company, our greatest contribution to society is developing innovative medicines and diagnostics that help people live healthier lives. Roche is committed to the Science Based Targets initiative and the Sustainable Markets Initiative to achieve net zero by 2045. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. References [1] Turner NC, et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. NEJM. 2024;391(17):1584-96. [2] Fillbrunn M, et al. PIK3CA mutation status, progression and survival in advanced HR+/HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22:1002. [3] Anderson E, et al. A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2– Metastatic Breast Cancer. Int J Breast Cancer. 2020;2020:3759179. [4] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120) [Internet; cited 2025 May]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04191499. [5] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination Therapy (INAVO121) [Internet; cited 2025 May]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05646862. [6] ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer (INAVO122) [Internet; cited 2025 May]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05894239. [7] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Inavolisib Plus CDK4/​6 Inhibitor and Letrozole vs Placebo + CDK4/​6i and Letrozole in Participants With Endocrine-Sensitive PIK3CA-Mutated, Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (INAVO123) [Internet; cited 2025 April]. Available from: https://clinicaltrials.gov/study/NCT06790693. [8] Juric D, et al. A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer. Presented at San Antonio Breast Cancer Symposium, 2020 December 7-10; San Antonio, USA. Abstract #P5-17-05. [9] Hong R, et al. GDC-0077 is a selective PI3K alpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies. Cancer Res. 2018;78(4):4-14. [10] National Cancer Institute: Surveillance, Epidemiology and Ends Result Program. Cancer Stat Facts: Female Breast Cancer Subtypes [Internet; cited 2025 April]. Available from: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. [11] Lim E, et al. The natural history of hormone receptor-positive breast cancer. Oncology (Williston Park). 2012;26(8):688-94,696. [12] Tomas R and Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304-20. [13] Galipeau N, et al. Understanding key symptoms, side effects, and impacts of HR+/HER- advanced breast cancer: qualitative study findings. J Patient-Rep Outcomes. 2019;3(1):10. The content above comes from the network. if any infringement, please contact us to modify.