CDK4/6 Inhibitors in Breast Cancer Treatment: Recent Research, Safety Profiles, Acquired Resistance, Next Steps

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Breast tumors can become resistant to CDK 4/6 inhibitors, but improved understanding of the mechanisms of acquired resistance might point to additional treatment strategies.
Breast tumors can become resistant to CDK 4/6 inhibitors, but improved understanding of the mechanisms of acquired resistance might point to additional treatment strategies.

Selective cyclin-dependent kinase (CDK) 4/6 inhibitors are a new breast cancer treatment option with manageable side effects. Like other drugs that target intracellular signaling pathways, breast tumors can become resistant to these agents, but improved understanding of the mechanisms of acquired resistance might point to additional treatment strategies. A newly reported animal study suggests that in addition to tumor cell cycle inhibition, CDK4/6 inhibitors also facilitate antitumor immune response — raising the intriguing possibility of combination therapy with immune checkpoint inhibitors.

CDKs are key cell cycle regulators; they regulate progression between the G1 and S phases, when cells synthesize new DNA strands in preparation for mitosis. Altered CDK proteins in the cyclin D1/CDK4/6/RB pathway occur in breast cancers and other solid tumors.1-5

Estrogen receptor̶positive breast cancer appears to be particularly dependent on CDK4 in cell proliferation, and therefore, CDK4/6 inhibitors.

“Taken together, there is very strong data to support the use of these drugs in front-line in combination with a non-steroidal aromatase inhibitor [AI] if patients are considered AI-sensitive and with fulvestrant if they have progressed on an [non-steroidal] AI,” said Richard S. Finn, MD, of the division of hematology/oncology at the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

Palbociclib (Ibrance®, Pfizer) and ribociclib (Kisqali®, Novartis) are US Food and Drug Administration (FDA)-approved for first-line therapy with letrozole endocrine therapy among women with advanced hormone-receptor-positive (HR+), HER2-negative breast cancer. The FDA approvals for palbociclib and ribociclib were based on similar progression-free survival (PFS) outcomes from pivotal phase 3 trials (PALOMA-2 for palbociclib [ClinicalTrials.gov Identifier: NCT01740427]) and MONALEESA-2 for ribociclib [ClinicalTrials.gov Identifier: NCT01958021]). Adding palbociclib or ribociclib to endocrine therapy yielded a PFS of 24.8 months and 25.3 months, respectively, compared with 14.5 to 16 months without a CDK4/6 inhibitor.6-9 Overall survival (OS) data are not yet mature.

“The efficacy data is very similar between all of the compounds — a very consistent improvement with the addition of CDK 4/6 inhibition to endocrine therapy,” noted Dr Finn. “Based on the published clinical data, it is hard to say there is any real difference in efficacy.” 

It is too soon to know whether or not these agents increase OS among patients with advanced breast cancer, cautioned Conleth G. Murphy, MB, BCh, BAO, MRCPI, a medical oncologist at Bons Secours Hospital in Cork, Ireland. “The hope is that the significant improvements in progression free survival in advanced breast cancer will translate into an increased cure rate in early breast cancer,” he said.

“While these therapies provide exciting new options for extending the duration of control with endocrine therapy in women with advanced breast cancer, they do increase the complexity of treatment,” Dr Murphy said.

More CDK inhibitors are in development.

Eli Lilly's investigational CDK4/6 inhibitor abemaciclib is “coming down pike,” noted Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston, Massachusetts. It was granted FDA Priority Review on July 10, 2017, based on PFS outcomes from MONARCH-2 (ClinicalTrials.gov Identifier: NCT02107703).10,11

“It will probably be approved very shortly,” Dr Shapiro said. “It's a little bit different; it can be given chronically and does not have as much neutropenia.”

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