Inavolisib Plus Palbociclib and Fulvestrant Approved for Endocrine-Resistant, PIK3CA-Mutated, HR-Positive, HER2-Negative, Advanced Breast Cancer
Expert Perspectives · Lyn Brook · 2024-10-11
The FDA has granted approval to inavolisib (Itovebi™, Genentech, Inc.) plus palbociclib and fulvestrant 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.
Why it matters: “The FDA’s approval of inavolisib in combination with palbociclib and fulvestrant for patients with PIK3CA-mutated, HR-positive, endocrine-resistant breast cancer represents a pivotal advance in targeted therapy,” wrote Jason Mouabbi, MD, an Assistant Professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, and Oncology Data Advisor Editorial Board member. “PIK3CA mutations drive resistance to endocrine therapy, limiting treatment options for these patients. Inavolisib directly targets this mutation, offering a new strategy to overcome resistance and extend the benefits of endocrine therapy in a population with limited options. This approval marks a significant step toward personalized medicine for breast cancer, enhancing outcomes in this specific subset of patients.”
What they studied: Efficacy was measured in the phase 3, double-blind, placebo-controlled INAVO120 trial (NCT04191499), on which approval was based. The trial enrolled 325 patients with endocrine-resistant, 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 locally advanced or metastatic disease. Patients were randomized 1:1 to receive either 9 mg of inavolisib or placebo orally, once daily, plus 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment to maintain a 28-day cycle, plus 500 mg of fulvestrant given intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle. Patients were treated until disease progression or unacceptable toxicity.
Key stratification criteria included presence of visceral disease, endocrine resistance, and geographic region. Primary endocrine resistance was defined as relapse while on the first two years of adjuvant endocrine therapy (ET). Secondary endocrine resistance was defined as relapse while on adjuvant ET after at least two years or relapse within 12 months of completing adjuvant ET.
The primary efficacy outcome measured was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key secondary efficacy measures included overall survival, investigator-assessed objective response rate, and duration of response.
What they found: Statistically significant outcomes were observed in the inavolisib arm compared to the placebo arm. The median progression-free survival was 15 months in the inavolisib arm compared with 7.3 months in the placebo arm. The objective response rate was 58% in the inavolisib arm compared with 25% in the placebo arm. The median duration of response was 18.4 months in the inavolisib arm compared with 9.6 months in the placebo arm. At the overall survival interim analysis, based on 63% information fraction, a statistically significant benefit was not reached but supported the overall benefit risk assessment with a hazard ratio (HR) of 0.64.
Adverse events: The most common adverse events experienced in ≥20% of patients receiving inavolisib, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased alanine aminotransferase (ALT), nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.
Conclusion: “When integrating inavolisib into clinical practice, it’s crucial to conduct PIK3CA mutation testing early to identify eligible patients,” concluded Dr. Mouabbi. “Monitoring for common side effects like hyperglycemia and gastrointestinal disturbances (such as nausea and diarrhea) is essential, given the PI3K pathway’s role in metabolism. While the efficacy of inavolisib is promising, its use should be carefully balanced with these potential toxicities, requiring a tailored approach for each patient.”
Instructions: The recommended dosage of inavolisib is 9 mg taken orally, once daily, with or without food, until disease progression or unacceptable toxicity. Refer to the prescribing information for palbociclib and fulvestrant dosing information.