CDK Inhibitors in Breast Cancer: Manageable Toxicity Profile

Roxanne Nelson, BSN, RN

July 18, 2017

Cyclin-dependent kinase (CDK) 4/6 inhibitors have recently emerged as a new treatment option in hormone receptor–positive breast cancer, and overall, they appear to be well tolerated, with a manageable toxicity profile, say the authors of a new review article.

This new class of drugs includes palbociclib (Ibrance, Pfizer) and ribociclib (Kisqali, Novartis) ― both of which have been approved for the treatment of hormone receptor–positive metastatic breast cancer in combination with endocrine therapies ― and abemaciclib, which is under development by Lilly Oncology.

"Given the excitement with these drugs, there has been considerable uptake in clinical practice for management of patients with metastatic breast cancer," commented senior author Aditya Bardia, MBBS, MPH, a breast cancer specialist from the Massachusetts General Hospital Cancer Center in Boston.

"However, these agents are different from endocrine therapies and have a unique set of side effects," said Dr Bardia in a statement. "Therefore, we felt it was important to have a dedicated review article on clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors and summarize practical management strategies for a medical oncologist."

The review was published online July 18 in the Oncologist.

Toxicity and Management

Dr Bardia and colleagues analyzed the data from clinical trials that had been conducted on palbociclib, ribociclib, and abemaciclib, including studies used by the US Food and Drug Administration in approving these drugs.

For palbociclib and ribociclib, the most common adverse event is neutropenia, although febrile neutropenia is rare, they note. Unlike the neutropenia that occurs with cytotoxic drugs, the neutropenia associated with CDK4/6 inhibitors is rapidly reversible.

Other side effects associated with palbociclib included leukopenia, fatigue, and nausea. Use of ribociclib was associated with hepatobiliary toxicity and cardiac signs (QT prolongation).

Abemaciclib is structurally distinct from the other two agents and has a greater selectivity for CDK4, the authors note. Gastrointestinal–related toxicity and fatigue are more common with abemaciclib than with the other two drugs, whereas hematologic adverse events, including neutropenia, are not as prominent.

Management Strategies

The authors recommend that patients receiving CDK4/6 inhibitors be carefully monitored for hematologic events. Complete blood counts with differentials should be conducted at baseline and every 2 weeks for the first two cycles of treatment.

For palbociclib, the recommendation is to perform blood counts before each 28-day cycle and then as clinically indicated. The recommendation differs slightly for ribociclib, in that blood counts should be conducted at the start of each of the subsequent four cycles and then as clinically indicated.

Both palbociclib and ribociclib should be held at an absolute neutrophil count less of than 1000/mm3 (grade 3) on the first day of each cycle, the authors write.

In general, most hematologic abnormalities that occur with CDK4/6 inhibitors can be adequately managed with standard supportive care and dose reduction, they comment.

The rates of grade 3 or 4 gastrointestinal toxicities are low with palbociclib and ribociclib, although nausea and diarrhea can occur. Because the risk for nausea is low, prophylactic antiemetics are not routinely indicated.

Conventional antidiarrheal agents or dose reduction has been used to treat diarrhea associated with abemaciclib, and for all three drugs, standard nonpharmacologic care, such as hydration and dietary modification, as well as pharmacologic therapies are recommended.

For nausea and vomiting, routine antiemetics, including metoclopramide, prochlorperazine, haloperidol, or serotonin 5-HT3 antagonists, can be used as needed. However, the authors note that caution is needed when prescribing antiemetics with ribociclib because of the risk for QT prolongation.

Patients and treating physicians should be aware of certain drug-drug interactions with CDK4/6 inhibitors, the authors warn, particularly interactions with drugs that inhibit the cyclooxygenase CYP3A enzyme in the hepatic metabolism of drugs. Concomitant use of strong CYP3A inhibitors should be avoided if possible; if they must be used, then the dose of the CDK4/6 inhibitors must be reduced.

Dr Bardia and coauthor Dr Spring are supported by grants from the National Cancer Institute grants.

Oncologist. Published online July 18, 2017. Abstract

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