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

Jorge Gómez Tejeda Zañudo, Romualdo Barroso-Sousa, Esha Jain, Qingchun Jin, Tianyu Li, Jorge E. Buendia-Buendia, Alyssa Pereslete, Daniel L. Abravanel, Arlindo R. Ferreira, Eileen Wrabel, Karla Helvie, Melissa E. Hughes, Ann H. Partridge, Beth Overmoyer, Nancy U. Lin, Nabihah Tayob, Sara M. Tolaney and Nikhil Wagle ()
Additional contact information
Jorge Gómez Tejeda Zañudo: Eli and Edythe L. Broad Institute of MIT and Harvard
Romualdo Barroso-Sousa: Dana-Farber Cancer Institute
Esha Jain: Eli and Edythe L. Broad Institute of MIT and Harvard
Qingchun Jin: Dana-Farber Cancer Institute, Boston
Tianyu Li: Dana-Farber Cancer Institute, Boston
Jorge E. Buendia-Buendia: Eli and Edythe L. Broad Institute of MIT and Harvard
Alyssa Pereslete: Dana-Farber Cancer Institute
Daniel L. Abravanel: Eli and Edythe L. Broad Institute of MIT and Harvard
Arlindo R. Ferreira: Dana-Farber Cancer Institute
Eileen Wrabel: Dana-Farber Cancer Institute
Karla Helvie: Dana-Farber Cancer Institute
Melissa E. Hughes: Dana-Farber Cancer Institute
Ann H. Partridge: Dana-Farber Cancer Institute
Beth Overmoyer: Dana-Farber Cancer Institute
Nancy U. Lin: Dana-Farber Cancer Institute
Nabihah Tayob: Dana-Farber Cancer Institute
Sara M. Tolaney: Dana-Farber Cancer Institute
Nikhil Wagle: Eli and Edythe L. Broad Institute of MIT and Harvard

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45835-6

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