Phase 1b Dose Escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women With HR+, HER2- Advanced Breast Cancer.

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). Methods Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), pre-treated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose escalation phase was to estimate the maximum tolerated dose 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 naive 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 2- to 4-fold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily (QD), 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg QD, plus exemestane 25 mg QD 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. Conclusion 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.