Genentech, a member of the Roche Group, announced that the U.S. Food and Drug Administration (FDA) has 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. This approval marks a significant advancement in the treatment landscape for this patient population.
Clinical Efficacy of Itovebi
The FDA's decision was primarily based on the results of the pivotal Phase III INAVO120 study (NCT04191499). The study demonstrated that the Itovebi-based regimen significantly improved progression-free survival (PFS) compared to palbociclib and fulvestrant alone. Specifically, the Itovebi regimen reduced the risk of disease worsening or death by 57% (HR=0.43, 95% CI: 0.32-0.59, p<0.0001), with a median PFS of 15.0 months versus 7.3 months in the control arm.
Overall survival (OS) data, while immature at the time of the primary analysis, showed a positive trend (stratified HR=0.64, 95% CI: 0.43-0.97, p=0.0338). Follow-up for OS is ongoing to the next analysis.
Expert Commentary
"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."
Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development, stated, "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. 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."
Trial Design and Patient Population
The INAVO120 study is a Phase III, randomized, double-blind, placebo-controlled trial evaluating Itovebi in combination with palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, HR-positive, 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. The study included 325 patients randomized to either the investigational or control treatment arm. The primary endpoint was progression-free survival, as assessed by investigators.
Addressing Unmet Needs in HR-positive Breast Cancer
Hormone receptor (HR)-positive breast cancer is the most prevalent type of all breast cancers, accounting for approximately 70% of cases. The PI3K signaling 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. Itovebi offers a targeted approach to address this resistance mechanism.
Ongoing Clinical Development
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. These studies aim to further explore the potential of Itovebi in different treatment settings and combinations.
