Elsevier

The Breast

Volume 28, August 2016, Pages 191-198
The Breast

Original article
Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study

https://doi.org/10.1016/j.breast.2016.06.008Get rights and content

Highlights

  • This trial provides analysis of the biological activity of ribociclib + letrozole.

  • Ribociclib + letrozole was well tolerated over a 2-week treatment period.

  • Pharmacokinetic data suggest no ribociclib–letrozole drug interaction.

  • Reduced Ki67 expression is reported in patients with HR+, HER2– breast cancer.

  • Pharmacodynamic data provide evidence for on-target inhibition by ribociclib.

Abstract

Objectives

Cyclin D–cyclin-dependent kinase (CDK) 4/6–inhibitor of CDK4/6–retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting.

Materials and methods

Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2–) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling.

Results

Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38–100%; n = 2), Arm 2 96% (range 78–100%; n = 6), Arm 3 92% (range 75–100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment.

Conclusion

The results suggest absence of a drug–drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2– BC (NCT01919229).

Introduction

Endocrine therapy is a key treatment strategy for hormone receptor-positive (HR+) breast cancer due to the dependency of these tumors on estrogen signaling [1]. Combining endocrine therapy with targeted therapies may enhance the effect of treatment by targeting compensatory pathways that act downstream of estrogen signaling. Short-term, window-of-opportunity studies of drug combinations can inform the optimal biological dose [2], enable the investigation of pharmacodynamic (PD) markers, identify biomarkers for patient selection, and may expedite drug development [3]. Moreover, short-term endpoints in window-of-opportunity studies, such as cell proliferation as measured by Ki67, can act as surrogate markers of longer-term patient outcomes [4], and several short-term studies have contributed to treatment decisions for endocrine therapy, including the potential of combination therapies [5] and the preferred patient biomarker profile [6].

The cyclin D–cyclin-dependent kinase (CDK) 4/6–inhibitor of CDK4/6 (INK4)–retinoblastoma (Rb) pathway acts downstream of estrogen receptor (ER) activation to promote cell cycle progression and cell division in response to estrogen signaling [7]. As such, endocrine therapy inhibits activation of this pathway, downregulating cell proliferation [8]. Recent data demonstrate that endocrine therapy-resistant tumor cells are able to maintain cyclin D–CDK4/6–INK4–Rb pathway activity [1]. Additionally, the cyclin D–CDK4/6–INK4–Rb pathway is frequently disrupted in favor of cell cycle progression in HR+ breast cancer [9], [10], [11] and has been associated with poor clinical outcome [1]. Therefore, targeting the cyclin D–CDK4/6–INK4–Rb pathway may present an effective strategy to enhance the efficacy of endocrine therapies.

Ribociclib (LEE011) is an orally bioavailable, selective inhibitor of CDK4/6 that prevents Rb phosphorylation, resulting in G1 cell cycle arrest in vitro [12], [13]. Ribociclib has exhibited synergistic activity with letrozole in preclinical xenograft models of ER-positive (ER+) breast cancer [14]. In clinical trials, ribociclib has demonstrated clinical activity both as a single agent in patients with advanced solid tumors, and when administered in combination with letrozole to patients with advanced ER+, human epidermal growth factor receptor 2-negative (HER2–) breast cancer [15], [16].

We report results of a Phase II, window-of-opportunity, presurgical treatment study evaluating the safety, pharmacokinetics (PK), and PD of two clinical doses of ribociclib (400 mg and 600 mg) in combination with letrozole versus single-agent letrozole in HR+ early breast cancer (ClinicalTrials.gov study number: NCT01919229).

Section snippets

Study design

The primary objective of this multicenter, randomized study (Fig. 1) was to assess the difference in antiproliferative activity of ribociclib in combination with letrozole versus single-agent letrozole, as measured by changes in expression level of the proliferative marker Ki67 from baseline to time of surgery. Secondary objectives included the assessment of safety, tolerability, and PK of ribociclib and letrozole in combination, and the evaluation of PD markers related to ribociclib activity

Patient characteristics and disposition

Table 1 summarizes the characteristics of all patients enrolled in the study. From October 10, 2013 to July 17, 2014, 14 patients with a median age of 65 years (range 51–78 years) were randomized to one of three treatment arms: letrozole 2.5 mg/day (Arm 1, n = 4), letrozole 2.5 mg/day plus ribociclib 400 mg/day (Arm 2, n = 6) or 600 mg/day (Arm 3, n = 4). Thirteen patients (93%) completed treatment; one patient in Arm 3 discontinued due to patient decision. This study was prematurely terminated

Discussion

In this window-of-opportunity study, patients with HR+, HER2– early breast cancer received letrozole with or without ribociclib prior to surgery. There were few enrolled patients in each treatment group with evaluable samples, precluding definitive conclusions regarding PK, PD, and biomarker evaluations. Accrual may have been affected by the short duration of therapy, which may have a limited clinical benefit, coupled with the clinical complexity of this window-of-opportunity study (multiple

Conclusions

Collectively, the findings from this study indicated that the combination of ribociclib and letrozole was associated with an acceptable safety profile over a 2-week treatment period. The comparison of letrozole PK parameters across all treatment arms suggests the absence of a drug–drug interaction between ribociclib and letrozole. The ability of ribociclib in combination with letrozole to improve progression-free survival compared with letrozole single-agent has recently been confirmed in the

Conflict of interest statement

This study was initiated, funded, and sponsored by Novartis Pharmaceuticals Corporation, who also provided financial support for medical editorial assistance. S. Dhuria, Z. Tang, N. Solovieff, M. Miller, and E. Di Tomaso are Novartis employees; Z. Tang holds Novartis stock and options. F. Meric-Bernstam served as a consultant to, and received research funding from, Novartis. Outside the submitted work, F. Meric-Bernstam served as a consultant to Celgene, Genentech, Inflection Biosciences, and

Acknowledgments

The authors would like to thank the patients who took part in the trial and their families, as well as the staff who assisted with the study at each site. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex. We thank Jenny Winstanley PhD for medical editorial assistance with this manuscript.

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