The US FDA has approved inavolisib in combination therapy for PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer. Key Approval Points: The US Food and Drug Administration (FDA) recently approved the PI3K inhibitor inavolisib (brand name: Itovebi) in combination with the CDK4/6 inhibitor palbociclib and fulvestrant for the treatment of adult patients with endocrine therapy-resistant, PIK3CA-mutated, HR-positive/HER2-negative locally advanced or metastatic breast cancer. This therapy is indicated for patients who have relapsed within 12 months of adjuvant endocrine therapy or its completion, and whose PIK3CA mutation must be confirmed by an FDA-approved test (such as FoundationOne Liquid CDx).
Key Efficacy and Safety Data
Efficacy Evidence (INAVO120 Clinical Trial)
Wors-Free Survival (PFS):
Median PFS in inavolisib triple therapy group: 15.0 months (95% CI: 11.3-20.5)
Control group (placebo + palbociclib/fulvestrant): 7.3 months (95% CI: 5.6-9.3)
57% reduction in disease progression risk (HR=0.43, P<0.0001)
Objective Response Rate (ORR):
Inavolisib group: 58% (95% CI: 50%-66%)
Control group: 25% (95% CI: 19%-32%)
Duration of Response (DoR):
Inavolisib group: 18.4 months vs Control group: 9.6 months
Overall survival (OS) (interim analysis):
Not statistically significant, but the trend is positive (HR=0.64, 95% CI: 0.43-0.97)
Safety overview
Common adverse reactions (≥20%):
Laboratory abnormalities: neutropenia, anemia, hyperglycemia, thrombocytopenia
Clinical symptoms: stomatitis, diarrhea, fatigue, rash, decreased appetite
Grade 3 or higher adverse events: mainly hematologic toxicities (e.g., neutropenia)
Management points:
Regular blood glucose monitoring is required (hyperglycemia incidence 58.6%)
Prophylactic use of steroid-containing mouthwash (stomatitis incidence 51.2%)
Clinical Application Guidelines
Applicable Patient Group
Molecular Characteristics: Confirmed PIK3CA mutation
Disease Status:
Locally advanced or metastatic HR+/HER2- breast cancer
Resistance to endocrine therapy (definition in table below)
Types of Endocrine Resistance
Definition
Primary Resistance
Relapse within 2 years of adjuvant endocrine therapy
Secondary Resistance
Relapse after 2 years of adjuvant therapy, or relapse within 12 months of completing treatment
Dosage Regimen
Inavolisib: 9 mg orally once daily (with food or on an empty stomach)
Palbociclib: 125 mg orally once daily (21 days on, 7 days off)
Fulvestrant: 500 mg intramuscularly (on days 1 and 15 of cycle 1, then every 28 days thereafter)
Expert Commentary and Clinical Significance
Dr. Nicholas Turner (Royal Marsden Hospital, Principal Investigator of INAVO120):
"This approval fills a significant treatment gap for patients with PIK3CA mutations. Inavolisib's unique dual mechanism (inhibiting PI3Kα and degrading mutant p110α) delivers significantly improved efficacy with manageable toxicity."
Practice Recommendations:
Testing First: All HR+/HER2- advanced breast cancer patients should be tested for PIK3CA mutations.
Adverse Reaction Management:
Hyperglycemia: Assess diabetes risk at baseline and intervene if necessary.
Stomatitis: Prophylactic care and early intervention.
Treatment Sequence: Can be considered as a first-line option after progression on CDK4/6 inhibitors.
Future Research Directions:
Further validate overall survival benefit (OS data is not yet mature)
Explore its use in adjuvant therapy or in combination with other targeted therapies (such as AKT inhibitors)
Complete prescribing information: Please refer to the FDA website (accessdata.fda.gov)
Note: This is the first approved combination of PI3K inhibitors specifically targeting PIK3CA-mutated HR+/HER2- breast cancer, marking a significant advancement in precision medicine. Clinical application requires a careful balance between efficacy and toxicity, and close monitoring of patient response.
Source: https://ascopost.com/news/october-2024/fda-approves-inavolisib-combination-in-pik3ca-mutated-hr-positive-her2-negative-advanced-breast-cancer/