For patients with a specific type of breast cancer—hormone receptor-positive, HER2-negative—that also carries a PIK3CA mutation, a new combination treatment shows promising results. The treatment combines inavolisib, a targeted therapy, with palbociclib and fulvestrant, helping to significantly slow disease progression compared to standard treatment. This combination not only targets multiple cancer growth pathways but also has been shown to help patients stay progression-free longer. If you’re looking for more on how this treatment works and its potential benefits, keep reading for details.
Hormone receptor-positive, HER2-negative breast cancer is the most common subtype of breast cancer, and while treatments have improved significantly, challenges persist, especially in patients with advanced disease and mutations in the PIK3CA gene. Around 35-40% of hormone receptor-positive breast cancers have PIK3CA mutations, which lead to activation of the PI3K/AKT pathway, driving cancer progression and resistance to traditional therapies. This blog explores the latest findings from a phase 3 trial on the combination of inavolisib, palbociclib, and fulvestrant, offering new hope for patients with this aggressive subtype.
Understanding the Mechanisms of Inavolisib, Palbociclib, and Fulvestrant
- PI3K Pathway and PIK3CA Mutation:
- The PI3K/AKT/mTOR pathway plays a crucial role in cell growth and survival, and its overactivation through PIK3CA mutations contributes to cancer cell proliferation.
- Inavolisib is a highly selective PI3Kα inhibitor targeting the p110α subunit of the PI3K enzyme, especially effective in tumors with PIK3CA mutations. It not only inhibits PI3K signaling but also promotes degradation of mutated p110α, potentially offering a better safety and efficacy profile than earlier PI3K inhibitors.
- Role of CDK4/6 Inhibition:
- Palbociclib, a CDK4/6 inhibitor, blocks the cell cycle progression, which works synergistically with PI3K inhibition, making cancer cells more susceptible to treatment and delaying resistance.
- Hormone Receptor Blockade with Fulvestrant:
- Fulvestrant, a selective estrogen receptor degrader (SERD), inhibits the estrogen receptor, which is a major growth driver in hormone receptor-positive breast cancer.
This triplet therapy aims to provide a comprehensive blockade of estrogen receptor, CDK4/6, and PI3K pathways, which are critical drivers of this breast cancer subtype, potentially delaying the onset of resistance.
The INAVO120 Trial: Design and Key Findings
Study Design
The INAVO120 trial was a phase 3, double-blind, randomized study conducted across multiple countries, designed to evaluate inavolisib in combination with palbociclib and fulvestrant against a placebo. The trial included 325 patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer. Patients had previously relapsed within 12 months of completing adjuvant endocrine therapy, indicating a more aggressive and treatment-resistant form of cancer.
Efficacy Outcomes
- Progression-Free Survival (PFS): The inavolisib combination achieved a median PFS of 15 months, compared to 7.3 months in the control group, nearly doubling the time without disease progression. The hazard ratio for disease progression or death was 0.43 (P<0.001), suggesting a substantial improvement.
- Objective Response Rate (ORR): The ORR was notably higher in the inavolisib group, with 58.4% of patients experiencing tumor shrinkage compared to 25% in the placebo group.
Subgroup Analysis
The benefits of the inavolisib combination were observed across various subgroups, including those with or without visceral metastases, though efficacy appeared slightly reduced in patients older than 65 and those previously treated with both tamoxifen and an aromatase inhibitor.
Safety Profile and Side Effects
The addition of inavolisib to standard therapy led to manageable side effects, although some adverse events were more common in the inavolisib group:
- Common Side Effects: Neutropenia, hyperglycemia, and stomatitis were among the most frequent side effects. Hyperglycemia, a known side effect of PI3K inhibitors, was managed with supportive care.
- Serious Adverse Events: A small percentage (6.8%) of patients discontinued inavolisib due to adverse events, while in the placebo group, discontinuation due to side effects was minimal.
Implications for Clinical Practice
This study suggests that inavolisib, combined with palbociclib and fulvestrant, could become a new standard of care for patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative breast cancer. The triplet therapy significantly delays progression, offering new hope to patients with limited treatment options. However, careful monitoring for hyperglycemia and neutropenia is essential.
Inavolisib’s selective targeting of PI3Kα, combined with CDK4/6 inhibition and estrogen receptor degradation, addresses the complexities of PIK3CA-mutated breast cancer, delivering a more robust response. This promising approach underscores the importance of genetic profiling in breast cancer, as identifying PIK3CA mutations can guide treatment and improve outcomes. As ongoing studies further explore PI3K inhibition, inavolisib is positioned to play a crucial role in the evolving landscape of breast cancer therapy.
About the author
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. Currently practicing at the renowned Orlando Health Cancer Institute, he brings a wealth of expertise to the complex and challenging world of oncology.