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Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial.

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Title: Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial.
Authors: Gómez Tejeda Zañudo J; Cancer Program, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Barroso-Sousa R; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Oncology Center, Hospital Sírio-Libanês, Brasília, Brazil., Jain E; Cancer Program, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Repare Therapeutics, Cambridge, MA, USA., Jin Q; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA., Li T; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA., Buendia-Buendia JE; Cancer Program, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Cellarity, Somerville, MA, USA., Pereslete A; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Abravanel DL; Cancer Program, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Ferreira AR; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Breast Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal., Wrabel E; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Helvie K; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Hughes ME; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Partridge AH; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Overmoyer B; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Lin NU; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Tayob N; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA., Tolaney SM; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Wagle N; Cancer Program, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Nikhil_Wagle@dfci.harvard.edu.; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Nikhil_Wagle@dfci.harvard.edu.; Department of Medicine, Harvard Medical School, Boston, MA, USA. Nikhil_Wagle@dfci.harvard.edu.; Genentech, South San Francisco, CA, USA. Nikhil_Wagle@dfci.harvard.edu.
Source: Nature communications [Nat Commun] 2024 Mar 19; Vol. 15 (1), pp. 2446. Date of Electronic Publication: 2024 Mar 19.
Publication Type: Clinical Trial, Phase II; Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language: English
Journal Info: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
MeSH Terms: Breast Neoplasms*/drug therapy , Breast Neoplasms*/genetics , Breast Neoplasms*/metabolism , Androstadienes* , Piperazines* , Pyridines*, Everolimus/therapeutic use ; Proto-Oncogene Proteins B-raf/genetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Erb-b2 Receptor Tyrosine Kinases/metabolism ; Cyclin-Dependent Kinase 4/metabolism ; Humans ; Female ; Transcriptome ; Gene Expression Profiling ; Genomics
Abstract: The landscape of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance is still being elucidated and the optimal subsequent therapy to overcome resistance remains uncertain. Here we present the final results of a phase Ib/IIa, open-label trial (NCT02871791) of exemestane plus everolimus and palbociclib for CDK4/6i-resistant metastatic breast cancer. The primary objective of phase Ib was to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase II dose (100 mg palbociclib, 5 mg everolimus, 25 mg exemestane). The primary objective of phase IIa was to determine the clinical benefit rate (18.8%, n = 6/32), which did not meet the predefined endpoint (65%). Secondary objectives included pharmacokinetic profiling (phase Ib), objective response rate, disease control rate, duration of response, and progression free survival (phase IIa), and correlative multi-omics analysis to investigate biomarkers of resistance to CDK4/6i. All participants were female. Multi-omics data from the phase IIa patients (n = 24 tumor/17 blood biopsy exomes; n = 27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAFV600E), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial's therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies.
(© 2024. The Author(s).)
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Grant Information: P50 CA168504 United States CA NCI NIH HHS; T32 CA009172 United States CA NCI NIH HHS
Molecular Sequence: ClinicalTrials.gov NCT02871791
dbGaP phs001285.v2.p1
Substance Nomenclature: 9HW64Q8G6G (Everolimus)
EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
EC 2.7.10.1 (Erb-b2 Receptor Tyrosine Kinases)
EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
0 (Androstadienes)
0 (Piperazines)
0 (Pyridines)
G9ZF61LE7G (palbociclib)
NY22HMQ4BX (exemestane)
Entry Date(s): Date Created: 20240320 Date Completed: 20240321 Latest Revision: 20261016
Update Code: 20261017
PubMed Central ID: PMC10951222
DOI: 10.1038/s41467-024-45835-6
PMID: 38503755
Database: MEDLINE
Description
ISSN:2041-1723
DOI:10.1038/s41467-024-45835-6