Roche’s Itovebi Regimen Shows Significant Survival Benefits for HR-Positive Breast Cancer in Phase III Trial Results

(IN BRIEF) Roche announced the publication of pivotal phase III results for its Itovebi™ (inavolisib)-based regimen at the Clinical Trials in Alzheimer’s Disease congress, demonstrating a 57% reduction in the risk of disease progression or death in patients with HR-positive, HER2-negative breast cancer with a PIK3CA mutation. The findings, published in the New England Journal of Medicine, indicate a doubling of progression-free survival compared to the standard treatment of palbociclib and fulvestrant. The U.S. FDA has approved this regimen as a first-line treatment for adults with endocrine-resistant disease. The study, which included 492 participants, highlighted the importance of early biomarker testing to identify patients who may benefit from targeted therapies like Itovebi.

(PRESS RELEASE) BASEL, 31-Oct-2024 — /EuropaWire/ — On October 31, 2024, Roche (SIX: RO, ROG; OTCQX: RHHBY) announced the publication of groundbreaking phase III data from the INAVO120 study in the New England Journal of Medicine, highlighting the effectiveness of its Itovebi™ (inavolisib)-based treatment regimen. This innovative combination therapy demonstrated a remarkable 57% reduction in the risk of disease progression or death compared to the standard treatment of palbociclib and fulvestrant, indicating a doubling of progression-free survival (PFS) in patients with HR-positive, HER2-negative breast cancer harboring a PIK3CA mutation.

The recently approved regimen by the U.S. FDA is indicated for adults suffering from endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative breast cancer, particularly after recurrence post-adjuvant endocrine therapy. This notable advancement aims to address a critical need in the treatment landscape, especially for patients facing metastatic disease, which often presents in challenging locations such as the liver and lungs.

Dr. Komal Jhaveri, section head for endocrine therapy research at Memorial Sloan Kettering Cancer Center and a principal investigator of the study, commented on the findings: “The significant improvement in progression-free survival and consistent benefits for patients with widespread disease are pivotal. I am optimistic that this Itovebi-based regimen could establish a new first-line standard of care for those with one of the most prevalent mutations in metastatic breast cancer.”

The trial’s results showed a PFS of 15.0 months for the Itovebi regimen versus 7.3 months for the standard treatment, with a hazard ratio of 0.43 (95% CI: 0.32-0.59, p<0.001). While overall survival (OS) data are still maturing, a promising trend has emerged, warranting continued follow-up.

Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer, expressed enthusiasm regarding the implications of these findings: “The publication of the phase III results underscores the transformative potential of the Itovebi-based regimen. This therapy exemplifies our commitment to effectively target specific disease pathways and enhance outcomes for breast cancer patients while emphasizing the necessity of comprehensive testing for mutations such as PIK3CA.”

The PIK3CA mutation is prevalent in approximately 40% of HR-positive metastatic breast cancers and is often associated with a poor prognosis. Historically, the utilization of PI3K-targeted therapy in advanced stages has been limited, making early biomarker testing essential to identify candidates for targeted treatments like Itovebi. Roche is currently advancing multiple phase III clinical trials (INAVO120, INAVO121, INAVO122) for PIK3CA-mutated locally advanced or metastatic breast cancer and is exploring additional studies in other tumor types, aiming to address the unmet needs of patients affected by these mutations.

About the INAVO120 study
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.6

The study included 325 patients, who were randomly assigned to either the investigational or control treatment arm.6 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.6 Secondary endpoints include overall survival, objective response rate, and clinical benefit rate.6

Beyond INAVO120, Itovebi is currently being investigated in two additional company-sponsored phase III clinical studies in PIK3CA-mutated locally advanced or metastatic breast cancer in various combinations:7,8

in combination with fulvestrant versus alpelisib plus fulvestrant in HR-positive/HER2-negative breast cancer post cyclin-dependent kinase 4/6 inhibitor and endocrine combination therapy (INAVO121; NCT05646862), and
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).

About hormone receptor (HR)-positive breast cancer
HR-positive breast cancer is the most prevalent type of all breast cancers, accounting for approximately 70% of cases.9,10 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.10-12 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

About Roche in breast cancer
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.9,10

About Roche
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.

For more information, please visit www.roche.com.

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References
[1] Turner NC, et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. NEJM. 2024;391(17).
[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] Princic N, et al. Abstract P1-18-18: PIK3CA mutation testing prevalence among post-menopausal (PM) women with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC) using real world data. Cancer Res. 2020;80(4):P1-18-18.
[5] Wales Cancer Network. PIK3CA-mutated breast cancer clinical guidance document [Internet; cited 2024 October]. Available from: https://executive.nhs.wales/functions/networks-and-planning/cancer/wcn-documents/mutated-breast-cancer-clinical-guidance-document//.
[6] 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 2024 October]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04191499.
[7] 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 2024 October]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05646862.
[8] 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 [Internet; cited 2024 October]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05894239.
[9] National Cancer Institute: Surveillance, Epidemiology and Ends Result Program. Cancer Stat Facts: Female Breast Cancer Subtypes [Internet; cited 2024 October]. Available from: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
[10] Lim E, et al. The natural history of hormone receptor-positive breast cancer. Oncology (Williston Park). 2012;26(8):688-94,696.
[11] 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.
[12] 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.