Ribociclib in HR+/HER2− Advanced or Metastatic Breast Cancer Patients

Abstract

Objective: To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib (LEE011, Kisqali) in hormone receptor–positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) metastatic breast cancer. Data Sources: A PubMed search was performed using the terms ‘Ribociclib’, ‘Kisqali’, and ‘LEE011’ between May 2018 and November 2018. References of published articles and reviews were also assessed for additional information. Study Selection and Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib were evaluated. Data Synthesis: Ribociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is Food and Drug Administration (FDA) approved in combination with endocrine therapy for treatment of HR+/HER2− advanced or metastatic breast cancer in premenopausal/perimenopausal and postmenopausal women. Three phase III trials have evaluated ribociclib in combination with endocrine therapy, including letrozole, anastrozole, tamoxifen, and fulvestrant. These studies found that ribociclib 600 mg/d, 21 days on, 7 days off, leads to a significantly greater median progression-free survival (PFS), ranging from 8 to 13 months. Ribociclib is well tolerated in elderly patients, maintains health-related quality of life, and significantly reduces pain scores. The dose-limiting toxicities found in phase I studies were neutropenia, thrombocytopenia, and QTc prolongation. Common adverse effects seen in phase III trials include neutropenia, leukopenia, nausea, diarrhea, vomiting, and fatigue. Relevance to Patient Care and Clinical Practice: Literature on the safety and efficacy of ribociclib as well as its place in therapy in comparison to other FDA-approved CDK4/6 inhibitors for breast cancer is discussed. Conclusions: Ribociclib, when added to endocrine therapy, significantly improves PFS and has manageable toxicity in premenopausal/perimenopausal and postmenopausal women with HR+/HER2− advanced breast cancer.

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

“…Abemaciclib, palbociclib, and ribociclib were the first FDA approved CDKs inhibitors. They are mainly used for combined endocrine therapy for HR+/HER2 54 advanced or metastatic breast cancer in premenopausal/perimenopausal and postmenopausal women 100 . Alvocidib, as well as dinaciclib, seliciclib, SNS‐032, and RGB‐286638 are CDK9 targeted inhibitors, and are mainly used for the treatment of leukemia for reversing the progression of cytarabine resistance 101,102 (Figure 4).…”

Cyclin-Dependent Kinase 4 and 6 Inhibitors: A Quantum Leap in the Treatment of Advanced Breast Cancers

“…Moreover, independent of ET, individuals treated with ribociclib had a higher mean change in pain score and a substantially longer median time to deterioration than patients in the placebo group [48]. It is the only CDK4/6 inhibitor licensed with fulvestrant as a first-or second-line therapy for postmenopausal women with HR+/HER-positive advanced breast cancer [49]. Many ongoing trials explore ribociclib as the first line of treatment in patients with HR+ early and advanced disease.…”

Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

“…The ribociclib anti-tumor effects have been studied in different types of cancer as well, including breast cancer. Studies on xenograft models determined the efficacy of Ribociclib in many other types of Rb-positive cancers, such as ERα breast cancer [177] and neuroblastoma [172]. These studies showed that ribociclib induces pRB dephosphorylation that leads to G1 arrest in Rb-positive cells [172].…”