The use of targeted therapies for locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative breast cancer (BC) has greatly enhanced progression-free survival, objective response, and clinical benefit compared with endocrine monotherapy. Among the targeted therapies that are currently available are everolimus, an oral inhibitor of mammalian target of rapamycin, and oral selective inhibitors of cyclin-dependent kinases (CDK) 4 and 6, which include palbociclib, ribociclib, and abemacicib. However, these new therapies have more complex and potentially severe adverse events compared with hormonal therapy.
In an effort to address these concerns, a multidisciplinary panel was convened to review current evidence on drug interactions and drug toxicities associated with targeted therapies as well as to develop recommendations on the management of these drug-related issues. Special focus was placed on frail patients with metastatic disease, the elderly, and those with organ dysfunction.
Besides drug interactions, areas of safety concerns based on data from clinical trials include the risk of stomatitis and pneumonitis, gastrointestinal toxicity, neutropenia, liver-function test elevations, and QTc prolongation.
Both everolimus and the CDK 4/6 inhibitors are substrates for CYP3A4; everolimus is also a substrate for P-glycoprotein. Strong inhibitors or inducers of CYP3A should not be coadministered with either everolimus and CDK 4/6 inhibitors, if possible. If coprescribing is necessary, then the dose of the targeted agent should be adjusted as recommended. Liver-function tests should be monitored for abemaciclib and ribociclib. Drugs that prolong the QT interval should be avoided in patients receiving ribociclib, as it is a strong-to-moderate inhibitor of CYP3A4. Additionally, palbociclib is the only CDK 4/6 inhibitor that needs to be taken with food.
Stomatitis, pneumonitis, and hyperglycemia are associated with everolimus therapy and generally occur within the first 8 weeks of treatment. Stomatitis and hyperglycemia are mild to moderate in severity. Less than 10% of patients reported grade 3 to 4 stomatitis. Prophylactic use of glucocorticoid mouthwash is beneficial.
Everolimus has also been associated with gastrointestinal bleeding secondary to producing an erosive gastritis. Diarrhea, which is generally manageable with antidiarrheal medications and/or dose adjustments, is associated with CKD 4/6 inhibitor therapy, especially abemaciclib therapy.
Among the CKD 4/6 inhibitors, palbociclib is associated with the highest rate of neutropenia. Grade 3 and 4 neutropenia can occur in 55% and 10% of patients, respectively, with this drug. Of the CKD 4/6 inhibitors, abemaciclib has the least effect on blood parameters. Strategies to mitigate CKD 4/6 inhibitor–induced neutropenia include dose delay, interruption of therapy, or reduction of dose.
Among the CKD 4/6 inhibitors, ribociclib and abemaciclib are the most commonly associated with hepatobiliary toxicity. Fortunately, most cases of abnormal liver-function tests are asymptomatic and reverse with dosage adjustments.
Ribociclib has been associated with QTc prolongation, with a >60 ms prolongation in the QT interval compared to baseline occurring in 3% of patients. The authors concluded that electrocardiographic changes associated with the use of targeted therapies are generally asymptomatic and can be managed by dose adjustment and avoiding strong CYP inhibitors.
An algorithm for the management of CDK 4/6-related neutropenia and an algorithm to assess QT prolongation risk are provided. Recommendations are included for the management of targeted therapy-induced nausea, vomiting, and diarrhea.
There is a paucity of information regarding the management of metastatic BC in elderly and frail patients. After review of the literature, the authors strongly recommended initiating therapy with CKD 4/6 inhibitors at full therapeutic dose and to closely monitor for early signs and symptoms of toxicity. They were unable to make recommendations on the use of CKD 4/6 inhibitors in patients with organ dysfunction due to the lack of available information.
This paper is a useful resource for pharmacists managing patients with HR+ metastatic BC who are receiving targeted therapies.
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