Roche's Itovebi (inavolisib) in combination with palbociclib and fulvestrant has demonstrated a significant improvement in progression-free survival (PFS) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer harboring PIK3CA mutations. The results of the phase III INAVO120 study, published in the New England Journal of Medicine, highlight a 57% reduction in the risk of disease worsening or death compared to palbociclib and fulvestrant alone.
Landmark INAVO120 Study Results
The INAVO120 study (NCT04191499) is a phase III, randomized, double-blind, placebo-controlled trial involving 325 patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer. These patients had experienced disease progression during or within 12 months of completing adjuvant endocrine therapy and had not received prior systemic therapy for metastatic disease. The study compared Itovebi in combination with palbociclib and fulvestrant against placebo plus palbociclib and fulvestrant.
The primary endpoint, progression-free survival (PFS), showed a median PFS of 15.0 months in the Itovebi arm compared to 7.3 months in the control arm (HR=0.43, 95% CI: 0.32-0.59, p<0.001). This clinically meaningful benefit was consistent across all pre-specified subgroups, including patients with disease spread to three or more locations. While overall survival (OS) data were immature at the time of analysis, a positive trend was observed (stratified HR=0.64, 95% CI: 0.43-0.97, p=0.03), with ongoing follow-up for further analysis.
Clinical Significance and Expert Commentary
"With a doubling of progression-free survival and consistent benefits in people whose disease had spread to multiple challenging-to-treat locations, including the liver and lungs, these INAVO120 data are significant for patients," 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. "I’m confident this Itovebi-based regimen could become a new first-line standard of care for this patient population with one of the most commonly mutated genes in metastatic breast cancer, associated with a poor prognosis."
Regulatory Approval and Future Directions
The U.S. FDA recently approved the Itovebi-based regimen as a first-line treatment for 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. Data from INAVO120 are also being used for filing submissions to other global health authorities, including the European Medicines Agency.
The Role of PIK3CA Mutations in Breast Cancer
The PIK3CA mutation is found in approximately 40% of HR-positive metastatic breast cancers and is associated with a poor prognosis. Early biomarker testing with an FDA-approved test, such as Foundation Medicine’s FoundationOne®Liquid CDx, before first-line treatment is crucial to help identify people who may benefit from targeted therapy, such as Itovebi.
Ongoing Research
Itovebi is currently being investigated in three company-sponsored phase III clinical studies (INAVO120, INAVO121, INAVO122) in PIK3CA-mutated locally advanced or metastatic breast cancer in various combinations. Roche is exploring additional studies in breast cancer and other tumor types with the hope of bringing the benefit of this targeted therapy to more people with PIK3CA mutations and addressing patient unmet needs.
