Roche’s Itovebi in Combo with Palbociclib & Fulvestrant Gets FDA Approval

US FDA approves Roche’s Itovebi in combo with palbociclib & fulvestrant to treat advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation

Overview

Roche announced that the United States Food and Drug Administration (FDA) approved Itovebi (inavolisib), in combination with palbociclib (Ibrance) and fulvestrant, for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. The PIK3CA mutation is found in approximately 40% of HR-positive metastatic breast cancers.

From principal investigators of the INAVO120 study

• The PI3K pathway plays a pivotal role in disease progression and has been challenging to target,” said Komal Jhaveri, M.D., section head for the endocrine therapy research portfolio and clinical director of the early drug development service at Memorial Sloan Kettering Cancer Center, and one of the principal investigators of the INAVO120 study. 
• The Itovebi-based regimen more than doubled progression-free survival and maintained a manageable safety and tolerability profile, adding a new standard in how PIK3CA-mutated breast cancers are treated.

Statement from the CMO: Roche

• With the approval of this Itovebi-based regimen, we continue our long-standing track record of cancer therapeutic discovery by offering an important new first-line option for people living with HR-positive breast cancer with a PIK3CA mutation,” said Levi Garraway, M.D., Ph.D., Roche’s chief medical officer and head of global product development. 
• Despite the high prevalence of PIK3CA mutations in this setting, treatment options have thus far remained limited, which makes today’s approval all the more significant.

Behind the approval: phase III INAVO120 study

• This approval is based on results of the pivotal phase III INAVO120 study, which showed that the Itovebi-based regimen reduced the risk of disease worsening or death by 57% compared with palbociclib and fulvestrant alone (15.0 months vs. 7.3 months; hazard ratio [HR]=0.43, 95% CI: 0.32-0.59, p<0.0001) in the first-line setting, demonstrating a statistically significant and clinically meaningful benefit. 
• Overall survival (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]). Follow-up for OS is continuing to the next analysis.

From the Living Beyond Breast Cancer

• We are thrilled by the approval of the Itovebi-based regimen, which is a huge step forward for advanced breast cancer patients with a PIK3CA mutation,” said Jean Sachs, CEO of Living Beyond Breast Cancer. 
• It remains critical that all patients have access to early, comprehensive biomarker testing so they can better understand what treatment options may be most beneficial for them and their tumour type.

FDA Priority Review & BTA: Itovebi

• The Itovebi-based regimen was granted FDA Priority Review and Breakthrough Therapy Designation in May 2024 based on the INAVO120 study results. 
• Data from INAVO120 are also being used for filing submissions to other global health authorities, including the European Medicines Agency. 
• Itovebi will be available in the US in the coming weeks. 
• Early, comprehensive biomarker testing with an FDA-approved test, such as Foundation Medicine’s FoundationOne Liquid CDx, can help identify people with HR-positive, HER2-negative breast cancer with a PIK3CA mutation.

Current investigation on Itovebi

• Itovebi is currently being investigated in various combinations across three company-sponsored phase III clinical studies (INAVO120, INAVO121, INAVO122) in PIK3CA-mutated locally advanced or metastatic breast cancer. 
• We continue to evaluate opportunities to expand our clinical development programme to address patient unmet needs in various tumour types across oncology.

The trial: 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.

Trial details 

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

Another study for phase III

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: 

• 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 HR-positive breast cancer

• HR-positive breast cancer is the most prevalent type of all breast cancers, accounting for approximately 70% of cases. 
• 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. 
• 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.

Roche: research on 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. 
• Its medicines, along with companion diagnostic tests, have contributed to bringing breakthrough outcomes in human epidermal growth factor 2-positive and triple-negative breast cancers.

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