As reported in The Lancet Oncology by Layman et al, findings in dose-expansion groups of a phase Ib trial indicated activity of the pan-PI3K–mTOR inhibitor gedatolisib in combination with palbociclib and endocrine therapy in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer.
Study Details
The U.S. multicenter study included four dose-expansion groups with a total of 103 patients enrolled between December 2017 and June 2019:
- Group A: patients who were treatment-naive in the advanced setting (n = 31)
- Group B: patients with disease progression on one to two lines of endocrine therapy who were CDK4/6 inhibitor–naive (n = 13)
- Groups C and D: patients with at least one previous line of therapy (second-line and higher), including a CDK4/6 inhibitor (n = 32 in group C, n = 27 in group D).
Patients could have wild-type or mutant PIK3CA. Gedatolisib was given at 180 mg intravenously weekly in 28-day cycles in groups A, B, and C, and on days 1, 8, and 15 in group D. Letrozole (group A), fulvestrant (groups B, C, and D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint of the study was investigator-assessed objective response rate.
Key Findings
Weekly gedatolisib plus palbociclib and letrozole produced objective responses in 23 (85.2%, 90% confidence interval [CI] = 69.2%–94.8%) of 27 evaluable patients receiving first-line treatment (group A). Median response duration was 46.7 months (95% CI = 22.2 months to not reached).
Weekly gedatolisib plus palbociclib and fulvestrant produced objective responses in 8 (61.5%, 90% CI = 35.5%–83.4%) of 13 evaluable patients with disease progression on one or two lines of prior endocrine therapy who were CDK4/6 inhibitor–naive (group B). Median response duration was 12.2 months (95% CI = 3.7–40.6 months).
Weekly gedatolisib plus palbociclib and fulvestrant produced objective responses in 7 (25.0%, 90% CI = 12.4%–41.9%) of 28 evaluable patients in the one or more previous line(s) of therapy (second-line and higher) including a CDK4/6 inhibitor (group C). Median response duration was 16.6 months (95% CI = 3.7 months to not reached).
Gedatolisib on days 1, 8, and 15 (3 weeks on/1 week off) plus palbociclib and fulvestrant produced objective responses in 15 (55.6%, 90% CI = 38.2%–72.0%) of 27 evaluable patients with at least one previous line of therapy (second-line and higher) including a CDK4/6 inhibitor (group D). Median response duration was 12.6 months (95% CI = 7.3–21.2 months).
Among 103 patients in the safety population, the most common grade 3 or 4 treatment-related adverse events were neutropenia (63%), stomatitis (27%), and rash (20%); grade 3 or 4 hyperglycemia occurred in 6% of patients. Treatment-related serious adverse events occurred in 22% of patients. Adverse events led to treatment discontinuation in 9%. No treatment-related deaths were reported.
The investigators concluded, “Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile.”
Rachel M. Layman, MD, of the Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Pfizer and Celcuity. For full disclosures of the study authors, visit thelancet.com.
