Outcomes of Women With HR+/HER2− Advanced Breast Cancer Receiving Gedatolisib Combined With Palbociclib and Endocrine Therapy
TAKE-HOME MESSAGE
- This phase Ib study evaluated the use of gedatolisib in combination with palbociclib and endocrine therapy (either fulvestrant or letrozole) in patients with advanced hormone receptor–positive, HER2-negative breast cancer. Gedatolisib resulted in significant objective response rates across patient subgroups, most notably in treatment-naïve patients, who experienced a response rate of 85.2% and a median progression-free survival of 48.4 months. Less robust responses (but still achieving the primary endpoint) were observed among second-line and beyond treatment groups, with response rates ranging from 25.0% to 61.5%. Overall, 78% of patients experienced grade 3 or higher adverse events, most commonly neutropenia and stomatitis.
- Early results support further research into the integration of gedatolisib in conjunction with established hormonal and cell cycle inhibition strategies.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
Pfizer and Celcuity.
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Additional Info
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Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study
Lancet Oncol 2024 Apr 01;25(4)474-487, RM Layman, HS Han, HS Rugo, EM Stringer-Reasor, JM Specht, EC Dees, P Kabos, S Suzuki, SC Mutka, BF Sullivan, I Gorbatchevsky, R WesolowskiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Such findings are promising and provide new hope for patients who have been receiving CDK4/6 inhibitor therapy in combination with hormonal therapy and are concerned about their future treatment options. Given that it is now 2024, it would be interesting to revisit the progression-free survival and overall survival outcomes of the participants in this clinical trial, as follow-up on these patients occurred some time ago.