Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR+, HER2- Advanced Breast Cancer.

Abstract

PURPOSE:

Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).

PATIENTS AND METHODS:

Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.

RESULTS:

Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug-drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.

CONCLUSIONS:

Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2- ABC.

• Authors: Aditya Bardia, Shanu Modi, Mafalda Oliveira, Javier Cortes, Mario Campone, Brigette Ma, Luc Dirix, Amy Weise, Becker Hewes, Ivan Diaz-Padilla, Yu Han, Priya Deshpande, Tanay S Samant, Karen Rodriguez Lorenc, Wei He, Fei Su, Mariana Chavez-MacGregor
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 24 Pg. 6417-6428 (12 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32998962 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Aminopyridines
• Androstadienes
• Biomarkers, Tumor
• Purines
• Receptors, Estrogen
• Receptors, Progesterone
• Everolimus
• Receptor, ErbB-2
• exemestane
• ribociclib

Topics

• Aminopyridines (administration & dosage)
• Androstadienes (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Dose-Response Relationship, Drug
• Everolimus (administration & dosage)
• Female
• Follow-Up Studies
• Humans
• Middle Aged
• Postmenopause
• Prognosis
• Purines (administration & dosage)
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)