The PI3K–mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)–mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K–mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein.

This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0–1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1–2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A–C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B–D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032.

Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7–48·4) for group A, 11·0 months (7·6–16·9) for group B, 3·6 months (1·8–7·5) for group C, and 9·4 months (5·3–16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2–94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5–83·4) of 13 evaluable group B participants, seven (25·0%; 12·4–41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2–72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3–4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3–4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event.

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.

Pfizer and Celcuity.