Dr Jhaveri on the Evolving Role of Inavolisib in PIK3CA-Mutated Metastatic Breast Cancer

“The INAVO120 [regimen] is an unprecedented way of treating first-line patients [with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer] whose tumors harbor PIK3CA mutations.”

Komal Jhaveri, MD, FACP, the section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center, discussed the rationale for, key findings from, and clinical implications of the phase 3 INAVO120 trial (NCT04191499) investigating first-line inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex) in select patients with advanced or metastatic breast cancer.

The INAVO120 trial represents a groundbreaking approach in the first-line treatment of patients with hormone receptor–positive, HER2-negative metastatic breast cancer harboring PIK3CA mutations who experience disease recurrence or progression during or within 12 months following adjuvant endocrine therapy, Jhaveri began. Historically, these patients were treated with a combination of fulvestrant and a CDK4/6 inhibitor, she said. In INAVO120, that combination served as the control arm, whereas the investigational arm incorporated inavolisib—a selective alpha-specific PI3K inhibitor with mutant-degrading capabilities—into the standard backbone of fulvestrant plus the CDK4/6 inhibitor palbociclib, she explained.

Preclinical models have demonstrated robust synergistic activity when combining PI3K inhibition with endocrine therapy and CDK4/6 blockade, Jhaveri noted. However, clinical implementation of such triplet regimens has historically been limited by toxicity concerns associated with agents like alpelisib (Piqray), she reported. Alpelisib is FDA approved for use in combination with fulvestrant for the treatment of patients with hormone receptor–positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer in the post-endocrine therapy setting based on findings from the phase 3 SOLAR-1 study (NCT02437318). However, this agent has limited applicability in earlier lines of therapy due to its safety profile, she emphasized. Notably, a small population of patients in SOLAR-1 had received prior CDK4/6 inhibition.

Capivasertib (Truqap), which was FDA approved for use in combination with fulvestrant for the treatment of patients with hormone receptor–positive, HER2-negative, advanced or metastatic breast cancer harboring alterations in PIK3CA, AKT1, or PTEN, has also been used post-CDK4/6 inhibition, she added. The INAVO120 study built upon phase 1 safety and efficacy signals observed with inavolisib-based triplet therapy, prompting its advancement into phase 3 development, according to Jhaveri.

In INAVO120, patients were stratified based on PIK3CA mutation status and randomly assigned 1:1 to receive either the standard doublet or the investigational triplet, Jhaveri stated. The primary end point was investigator-assessed progression-free survival (PFS), which was markedly improved with the inavolisib triplet vs doublet, Jhaveri reported. The median PFS was 7.3 months in the control arm vs 15.0 months in the inavolisib arm (HR, 0.43; 95% CI, 0.32-0.59; P < .0001), she highlighted. Although overall survival (OS) outcomes from the initial analysis of this trial did not meet the pre-specified threshold for significance, a press release published in January 2025 confirmed that the OS end point in INAVO120 has now been met with statistical significance and clinical relevance, she concluded.