Charles J. Sherr, MD, PhD
Many therapies for patients with breast cancer focus on targeting cancer cell proliferation, with a goal of diverting cells to a more senescent phenotype. In recent years, oncology drug developers have been able to leverage knowledge about a cause of proliferation— dysregulated activity of the cyclin-dependent kinases (CDKs)—to create a new class of therapy that has rapidly been integrated into the breast cancer treatment paradigm.
CDKs are serine/threonine kinases that affect the G1-S phase transition of the cell cycle, which is mediated by action on the retinoblastoma (Rb) protein (FIGURE).1,2
Aberrant activity of the CDK–Rb axis contributes to unrestricted cell growth. In the past 2 years, the FDA has approved 3 agents that disrupt oncogenic activity in this axis by inhibiting CDK4/6: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).
Figure. Role of CDK4 and 6 in the Cell Cycle1
Palbociclib, the first agent in this class to gain the FDA’s approval, is indicated for the treatment of women with hormone receptor (HR)– positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor (AI) as initial endocrine therapy in postmenopausal women as well as in combination with fulvestrant (Faslodex) following progression on endocrine therapy.
Ribociclib is approved for use in combination with an AI as initial endocrine-based therapy for postmenopausal women. Abemaciclib is indicated as monotherapy for patients who have previously received endocrine therapy and chemotherapy as well as in combination with fulvestrant in those with advanced disease following progression on endocrine therapy. Both agents also are designated for women with HR-positive, HER2-negative disease.
Although prospects for patients have improved with the use of these drugs, the effects of these inhibitors in many subsets of patients have not been investigated. The potential synergy of CDK4/6 inhibitors with other treatment strategies, including immunotherapeutic and targeted approaches, is currently being investigated in various clinical trials with the hope of identifying combinations of these agents that increase responses and improve duration of response.
Charles J. Sherr, MD, PhD, of St. Jude Children’s Research Hospital, Memphis, Tennessee, and colleagues noted in a review article published in Cancer Discovery
, “In the next few years, we are likely to see combinations of targeted therapies—some obvious combinations being RAF/ MEK/ERK and PI3K inhibitors used in conjunction with those targeting CDK4/6—for which trials are now underway.”3
Ongoing Research in Breast Cancer Subtypes
Brain metastases are a common incidence in patients with breast cancer, specifically those with HER2-positive disease. A phase II trial has been designed to evaluate potential antitumor activity of the CDK4/6 inhibitor palbociclib in patients with metastatic HER2- positive breast cancer with brain metastasis (NCT02774681). The primary endpoint is the radiographic response rate in the central nervous system (CNS) as measured by the modified Response Assessment in Neuro-Oncology Brain Metastasis criteria. Additional outcomes include the incidence of adverse events (AEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR), time to CNS progression, change in cognitive function, change in genomic landscape of CNS and non-CNS tumors, change in quality of life, and cyclin D1 aberrations. This study is currently recruiting, with an estimated enrollment of 33 patients and a primary completion date of November 2019.
Additionally, a phase II trial has been created to determine the safety and efficacy of abemaciclib in approximately 247 patients with HR-positive breast cancer, non–small cell lung cancer, or melanoma that has spread to the brain (NCT02308020). Investigators are focusing on the percentage of patients who achieve a complete or partial response as the primary endpoint. Moreover, secondary outcome measures will include best overall intracranial response, duration of intracranial response, intracranial disease control rate (DCR), intracranial clinical benefit rate (CBR), OS, ORR, overall DCR, PFS, and change from baseline in neurologic symptoms on the MD Anderson Symptom Inventory– Brain Tumor Scale. The ongoing trial is set to be completed in October 2018.