Dr Kaklamani on the Efficacy of Inavolisib in HR+, PIK3CA-Mutated Breast Cancer

“Once we find that a patient had developed metastatic disease, the first thing we do is…next-generation sequencing [to] test for PI3K [pathway] mutations or other potential biomarkers that might help us in tailoring our treatment for the patients.”

Virginia Kaklamani, MD, DSc, a professor of medicine in the Division of Hematology-Medical Oncology at The University of Texas Health Science Center San Antonio, as well as the leader of the breast cancer program at the Mays Cancer Center, home to the UT Health San Antonio MD Anderson Cancer Center, discussed the efficacy and safety profiles of inavolisib in patients with hormone receptor (HR)–positive, HER2-negative, PIK3CA-mutated metastatic breast cancer.

The FDA approval of inavolisib was based on on findings from the phase 3 INAVO120 trial, which evaluated this agent as part of a first-line treatment regimen in patients with HR-positive, HER2-negative metastatic breast cancer harboring PIK3CA mutations. Notably, the trial enrolled patients with tumors exhibiting endocrine resistance, which was defined as disease progression either during or shortly after adjuvant endocrine therapy, Kaklamani began. Historically, this subset of tumors has demonstrated suboptimal responses to standard endocrine therapy in combination with CDK4/6 inhibitors, necessitating novel therapeutic strategies, she emphasized.

The INAVO120 study assessed the efficacy of a triplet regimen comprising inavolisib, palbociclib, and fulvestrant. The results demonstrated a significant improvement in progression-free survival with the triplet, which had a median PFS of 15.0 months vs 7.3 months with standard fulvestrant plus palbociclib (HR, 0.43; 95% CI, 0.32-0.59; P < .0001). More recently, a January 2025 press release indicated a statistically significant and clinically meaningful improvement in overall survival with the triplet vs the doublet, underscoring the potential paradigm-shifting role of inavolisib in the first-line setting, Kaklamani reported.

From a safety perspective, PI3K pathway inhibitors—including inavolisib—are associated with class-related toxicities, such as diarrhea, dermatologic reactions, and metabolic disturbances like hyperglycemia. Among these, hyperglycemia was the predominant concern for patients treated with inavolisib in INAVO120. In the trial, strict eligibility criteria excluded patients with hemoglobin A1c levels greater than 6.5%, emphasizing the importance of initiating this treatment only in patients with controlled hemoglobin A1c levels and maintaining close glucose monitoring during therapy, Kaklamani noted.

The role of biomarker-driven treatment selection is critical in this context, according to Kaklamani. Routine genomic profiling, particularly next-generation sequencing, is essential at the time of metastatic diagnosis to identify actionable mutations, such as PIK3CA, which may render patients eligible for targeted therapies like inavolisib, she explained. Although tissue biopsy remains a standard method for genomic testing, liquid biopsy is another testing approach. However, practical challenges like insurance coverage may influence test selection, she added. Previously, PIK3CA testing was primarily conducted in the second-line setting, Kaklamani stated. However, with inavolisib’s availability for frontline use, early biomarker testing is now imperative, she concluded.