Pharmacokinetic Drug Evaluation of Ribociclib for the Treatment of Metastatic, Hormone-Positive Breast Cancer

Introduction

Metastatic breast cancer (MBC) remains largely incurable. Treatment aims to enhance both lifespan and quality of life. Recent years have seen progress, particularly in luminal-like subtypes. A major advancement has been the emergence of CDK4/6 inhibitors, used in combination with endocrine therapy. Ribociclib, an orally bioavailable and highly selective small-molecule CDK4/6 inhibitor, induces G1 cell cycle arrest at sub-micromolar concentrations in pRb-positive cancer cells in vitro. It has shown efficacy when combined with other targeted therapies in preclinical studies and may be effective across various pRb-positive cancers with activated CDK4/6-pRb pathways.

In vivo studies confirm ribociclib’s antitumor activity in xenograft models of pRb-positive tumors, such as neuroblastoma, estrogen receptor-positive breast cancer, liposarcoma, melanoma, and malignant rhabdoid tumor. Ribociclib caused complete tumor regression in Jeko-1 MCL xenograft models at clinically achievable doses, highlighting its dependence on intact CDK4/6 activity due to CCND1 translocation. Nonclinical toxicity findings include QTc prolongation and effects on bone marrow, lymphoid system, testes, and liver, attributed to CDK4/6 inhibition of cellular replication.

Overview of the Market

In 2017, the United States anticipated 252,710 new breast cancer cases, representing 30% of female malignancies. Breast cancer is molecularly diverse, categorized into luminal A-like, luminal B-like, HER2-overexpressing, and triple-negative tumors, based on immunohistochemistry profiles of estrogen and progesterone receptors, HER2 status, and Ki-67 levels. These profiles guide treatment decisions.

The HR-positive metastatic disease has several biological treatment options, including CDK4/6 inhibitors like abemaciclib, palbociclib, and ribociclib. These ATP-binding CDK4/6 inhibitors are selective and structurally similar. Palbociclib is an oral, reversible CDK4/6 inhibitor, dosed at 125 mg/day for 21 days followed by 7 days off. Common toxicities include neutropenia, leukopenia, anemia, and thrombocytopenia. Grade 3 or 4 neutropenia occurs in 62% of patients. Non-hematologic adverse events include fatigue and nausea.

Palbociclib combined with fulvestrant improved progression-free survival in HR+ metastatic breast cancer. Fulvestrant was given at 500 mg intramuscularly, while palbociclib was administered at 125 mg orally for 3 weeks with a one-week break. This combination resulted in a median progression-free survival of 9.5 months versus 4.6 months with placebo. Abemaciclib, another CDK4/6 inhibitor, is dosed at 150 mg every 12 hours, with multiple clinical trials underway.

Introduction to the Compound

CDK4 and CDK6 regulate cell cycle progression by phosphorylating retinoblastoma protein (Rb). Dysregulation of the cyclin D-CDK4/6-INK4-Rb axis promotes unchecked cell proliferation. Ribociclib (LEE011) has demonstrated antiproliferative activity in Rb-positive tumors.

Chemistry

Ribociclib is chemically defined as 7-Cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate. Its solubility varies by pH, highest at pH 2.0 (>2.4 mg/mL) and lowest at pH 7.5 (0.3 mg/mL). It is orally administered as hard gelatin capsules (10 mg, 50 mg, 200 mg) or film-coated tablets (50 mg, 200 mg), with capsules containing only the active drug.

Pharmacodynamics

Preclinical Pharmacodynamics

Ribociclib demonstrated significant tumor regression in xenograft models at 75 or 150 mg/kg without weight loss. It reduced white blood cell counts and absolute neutrophil counts at effective doses. Ribociclib at 75 or 150 mg/kg nearly fully inhibited pRb phosphorylation over 24 hours. Inhibiting this phosphorylation correlates with tumor regression.

Combination therapy with ribociclib and agents like alpelisib or everolimus showed enhanced tumor regression in PIK3CA-mutant ER+ MCF-7 models. Ribociclib combined with letrozole and pan-PI3K inhibitor buparlisib in a letrozole-sensitive ER+ patient-derived model led to sustained tumor regression, indicating promise for triple combinations.

Clinical Pharmacodynamics

In a phase I trial, Ki67 and phosphorylated Rb levels were assessed in biopsies before and after ribociclib treatment. Skin biopsies showed consistent Ki67 reduction at doses ≥400 mg/day. Tumor biopsies also showed Ki67 and phosphorylated Rb reduction at higher doses. Gene expression of CDK4, CDK6, CCND2, CCND3, and CCNE1 decreased post-treatment. Pharmacokinetics of ribociclib and letrozole aligned with single-agent data.

Pharmacokinetics and Metabolism

In a phase I study, ribociclib was rapidly absorbed (Tmax 1–5 hours). Plasma levels increased 2–3 fold by day 18/21, with steady-state achieved around day 8. Its half-life was 32.6 hours. Exposure increased slightly more than proportionally with dose. Ribociclib’s main active metabolite, LEQ803, constituted about 10% of parent drug levels.

In plasma, ribociclib made up ~46% of drug-related content; Phase I metabolites ~50% and Phase II ~4%. LEQ803 contributed ~8% of the ribociclib AUC. Ribociclib and letrozole reached peak plasma levels within 2–4 hours. Ribociclib showed moderate inhibition of CYP3A4 and minimal effect on CYP1A2. Strong CYP3A4 inhibitors or inducers should be avoided due to significant pharmacokinetic interactions.

Clinical Efficacy

In a phase III randomized trial (MONALEESA-2), ribociclib combined with letrozole was evaluated in 668 postmenopausal women with HR+/HER2− advanced breast cancer. Patients received ribociclib (600 mg/day, 3 weeks on, 1 week off) plus letrozole (2.5 mg/day), or placebo plus letrozole. Ribociclib significantly extended progression-free survival (hazard ratio 0.56; P=3.29×10−6). At 18 months, the progression-free survival rate was 63.0% versus 42.2% for placebo. Overall response rates were 52.7% vs. 37.1% (P<0.001). Grade 3/4 adverse events included neutropenia (59.3%) and leukopenia (21.0%). Discontinuation rates due to adverse events were 7.5% for ribociclib versus 2.1% for placebo. Overall survival data were immature at interim analysis.

Safety and Tolerability

Phase I and III studies report hematologic toxicities as the most common adverse events, including neutropenia, leucopenia, thrombocytopenia, and anemia. Non-hematologic side effects included fatigue, nausea, vomiting, and diarrhea. Grade 3/4 events included neutropenia (59.3%), leukopenia (21.0%), and elevated liver enzymes. QTc prolongation occurred in 2.7% of ribociclib patients. Most were manageable without dose adjustment.

Regulatory Affairs

On November 1, 2016, the FDA granted Priority Review to ribociclib in combination with letrozole as a first-line treatment for HR+/HER2− metastatic breast cancer. This was supported by MONALEESA-2 trial data. The EMA also accepted a marketing authorization application for the same indication.

Conclusions

Ribociclib and palbociclib have established a new treatment standard for HR+ metastatic breast cancer. Nearly all patients with HR+ disease should receive CDK inhibitors with endocrine therapy. Identifying subgroups most likely to benefit remains essential, as no predictive biomarkers have yet emerged. Biomarker-driven trials are urgently needed.

Expert Opinion

CDK4/6 inhibitors have revolutionized breast cancer treatment. Exploring their combination with chemotherapy, radiotherapy, and immunotherapy is vital. Care must be taken with overlapping toxicities. Trials evaluating ribociclib in triplet regimens (e.g., with everolimus and exemestane) are underway. It is also important to evaluate if continued CDK4/6 inhibition beyond disease progression confers benefit. Clinical data from ongoing studies will help answer these JSH-150 crucial questions.