San Antonio, Texas—Preliminary data being presented at the 2019 San Antonio Breast Cancer Symposium demonstrate the promising anti-tumor activity of the p110α-selective and mutant-degrading inhibitor GDC-0077 in patients with PIK3CA-mutant breast cancer.

“Activating mutations in PIK3CA, encoding the p110α subunit of…(PI3K), are highly prevalent in breast cancer and solid tumor malignancies. GDC-0077 is a potent p110α-selective inhibitor with a novel mechanism of action that degrades mutant p110α and anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with anti-estrogens with or without a CDK4/6 inhibitor,” explained Dejan Juric, MD, Massachusetts General Hospital, Boston, and colleagues.

Currently, an open-label, phase 1, dose-escalation trial is underway examining the use of GDC-0077 alone or in combination with endocrine therapies and palbociclib in patients with locally advanced or metastatic PIK3CA-mutant solid tumors.

Here, Dr Juric et al present data from a completed portion of the study that focuses on the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of GDC-0077 administered daily at 6 mg, 9 mg, or 12 mg in 28-day cycles until intolerable toxicity or disease progression occurred. In addition, the investigators profiled tumor and ctDNA samples for related signaling and pharmacodynamic (PD) biomarkers.

As of March 2019 (clinical cut-off date), there were 20 patients enrolled in the single-agent arm of the study, including 19 with hormone receptor–positive breast cancer and 1 with colorectal cancer.

There were dose-limiting toxicities reported in 2 patients receiving 12-mg doses, including 1 case of grade 4 hyperglycemia and 1 case of grade 3 fatigue. A total of 6 (30%) patients required dose reductions because of adverse events (AEs).

The most common treatment-related AEs occurring in ≥3 (15%) patients included hyperglycemia (70%), diarrhea (40%), decreased appetite (20%), vomiting (20%), alopecia (15%), fatigue (15%), nausea (15%), and decreased weight (15%).

The median duration of treatment with GDC-0077 was 5.3 months (cumulative dose intensity, 97%), and all patients in the study ultimately discontinued therapy because of disease progression.

Findings demonstrated that 5 (25%) patients had partial responses and 4 (20%) had confirmed partial responses. In addition, the clinical benefit rate was 45%.

In most specimens, results showed decreased PI3K pathway effector expression in paired tumor biopsies and decreased PIK3CA mutant allele frequency over time. Furthermore, metabolic responses were observed at all dose levels assessed according to ¹⁸F-fluorodeoxyglucose-positron emission tomography scans conducted at baseline and after 2 weeks of therapy.

“The single agent dose escalation study of the p110α-selective and mutant-degrading inhibitor GDC-0077 demonstrated linear PK, a manageable safety profile, PD modulation of the PI3K pathway, and promising preliminary anti-tumor activity,” Dr Juric and colleagues concluded.—Hina Porcelli

Juric D, Kalinsky K, Oliveira M, et al. A first-in-human phase Ia dose escalation study of GDC-0077, a p110a-selective and mutant-degrading PI3K inhibitor, in patients with PIK3CA-mutant solid tumors. Presented at: the 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract OT1-08-04.