Genentech's Itovebi (inavolisib), in combination with palbociclib (Ibrance) and fulvestrant (Faslodex), has demonstrated a statistically significant and clinically meaningful benefit in overall survival (OS) for patients with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. The Phase III INAVO120 trial results, recently published in the New England Journal of Medicine, underscore the potential of this regimen to become a new standard of care for this patient population.
The INAVO120 trial (NCT04191499) was a randomized, double-blind, placebo-controlled study involving 325 patients with PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who had not received prior systemic therapy for metastatic disease. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival, objective response rate, and clinical benefit rate.
The study revealed that the Itovebi-based regimen reduced the risk of disease worsening or death by 57% compared to 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). At the time of the primary analysis, overall survival data were immature, but a clear positive trend has since been observed (stratified HR=0.64, 95% CI: 0.43-0.97, p=0.0338).
Clinical Significance
The PIK3CA mutation is present in approximately 40% of HR-positive metastatic breast cancers and is often associated with a poor prognosis. The FDA has approved Itovebi in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.
"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."
Ongoing Research
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 dual HER2 blockade versus dual HER2 blockade and optional physician's choice of endocrine therapy as a maintenance treatment in HER2-positive disease (INAVO122; NCT05894239).
Genentech is also 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.
