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
Copyright © 2024 Elsevier Ltd. All rights reserved..
BACKGROUND: 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
The Lancet. Oncology - 25(2024), 4 vom: 26. Apr., Seite 474-487 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Layman, Rachel M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.04.2024 Date Revised 05.04.2024 published: Print ClinicalTrials.gov: NCT02684032 Citation Status MEDLINE |
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| doi: |
10.1016/S1470-2045(24)00034-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM37037424X |
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| 245 | 1 | 0 | |a Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer |b results from the dose expansion groups of an open-label, phase 1b study |
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| 500 | |a ClinicalTrials.gov: NCT02684032 | ||
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| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a FUNDING: Pfizer and Celcuity | ||
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