fulvestrant + inavolisib + palbociclib

The combination of fulvestrant + inavolisib + palbociclib is a triplet therapy approved for treating certain types of breast cancer. This combination was approved by the FDA on October 10, 2024, 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[1]. ## Mechanism of Action This triplet therapy combines three distinct mechanisms: 1. **Inavolisib (Itovebi)** is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA). It not only inhibits but also promotes the degradation of mutated p110α[5]. 2. **Palbociclib (Ibrance)** is a CDK4/6 inhibitor that blocks cell cycle progression by inhibiting the activity of CDK4/6 enzymes[4][7]. 3. **Fulvestrant (Faslodex)** is a hormone therapy drug that acts as an estrogen receptor antagonist[4][7]. The combination has shown synergistic activity in preclinical models, with the INAVO120 clinical trial demonstrating significant improvements in progression-free survival and overall survival compared to palbociclib and fulvestrant alone[2][4]. ## Clinical Efficacy In the phase 3 INAVO120 trial involving 325 patients: - Progression-free survival was 15 months in the inavolisib combination arm versus 7.3 months in the control arm[6]. - Objective response rate was 58.4% with the triplet therapy compared to 25% with palbociclib and fulvestrant alone[6]. - Final analysis showed that patients survived an average of 7 months longer with the triplet therapy[7]. - Patients receiving the triplet therapy were able to delay subsequent chemotherapy treatment by almost two years longer than those in the control group[7]. ## Administration The regimen consists of: - Inavolisib 9 mg orally once daily - Palbociclib 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment (28-day cycle) - Fulvestrant 500 mg administered intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle[1] ## Side Effects The most common adverse reactions (≥20%) include decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache[1]. The triplet therapy was generally well tolerated, with only a few people experiencing side effects that caused them to stop treatment[7].

Brand names

Itovebi

Other names

inavolisib + palbociclib + fulvestrant