Originally published by our sister publication Specialty Pharmacy Continuum
Although typically associated with advanced breast cancer (BC), cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors may be life changing for patients with early-stage disease who face a high risk for recurrence, according to a session at the HOPA Annual Conference 2024, in Tampa, Fla.
But the agents are not without risk. “Because of the known quantity and potential severity of toxicities, oncology pharmacists should be at the forefront of managing CDK4/6 inhibitors,” explained presenter Danielle Roman, PharmD, BCOP, the manager of oncology pharmacy services at Allegheny Health Network, in Pittsburgh. “Through our knowledge of primary literature, guidance recommendations and patient-specific factors, we are well positioned to advise on drug monitoring and management, including dose holding, dose reductions and supportive care strategies.”
Benefits for Early-Stage Disease
The American Cancer Society estimates that 310,720 new BC cases will be diagnosed in 2024 in the United States alone. When early-stage BC is localized to a malignant tumor, survival odds are 98.9% five years later. When the cancer has spread to nearby lymph nodes, tissues or organs, survival odds are 86.3%. Nonetheless, BC can recur within 10 years for up to 20% of these patients. To reduce this risk, adjuvant treatment is prescribed after surgery, radiation therapy and/or chemotherapy to eliminate lingering micrometastatic disease. Endocrine therapy (ET; typically nonsteroidal aromatase inhibitors and/or anti-estrogens with/without ovarian suppression) is the first-line adjuvant treatment prescribed for up to 10 years for patients with hormone receptor (HR)-positive, HER2-negative cancer. This BC subtype accounts for 70% of all cases.
CDK4/6 plus aromatase inhibitors are standard of care for advanced BC because they extend survival by a median year or longer. Such use is included in leading treatment guidelines (Ann Oncol 2024;35[8]:718-727; J Natl Compr Canc Netw 2024;22[5]:331-357; Ann Oncol 2020;31[12]:1623-1649). Now, CDK4/6+ET has expanded to early-stage BC. Recent clinical trials show that at least one CDK4/6 inhibitor significantly decreases the risk for invasive BC recurrence and distant metastasis in high-risk patients with early-stage HR-positive, HER2-negative BC with nodal involvement, Dr. Roman noted. The FDA approved abemaciclib (Verzenio, Eli Lilly and Company) plus tamoxifen or an aromatase inhibitor for this indication in March 2023.
The monarchE randomized, phase 3 clinical trial included 5,637 patients from 603 sites in 38 countries. All participants had at least four positive lymph nodes or one to three positive lymph nodes with an additional high-risk feature. Five years after treatment, 83.6% of the cohort receiving abemaciclib plus ET, or ET alone, for 24 months did not have an invasive BC recurrence and 86% did not develop distant metastases, compared with 76% and 79.2%, respectively, who only received ET (J Clin Oncol 2020;38[34]:3987-3998).
The trade-off of abemaciclib’s benefits is a 98% chance of experiencing one or more of five adverse events and 19 toxicities identified during the monarchE trial. During the study, 43% of the CDK4/6 group of patients developed one or more grade 3 or higher toxicities, requiring dose reduction modifications. The most common toxicities included diarrhea (about 82%), neutropenia (45%), fatigue (38%), leukopenia (37%), abdominal pain (34%), nausea (28%) and anemia (23%).
“Because four-year data analysis reveals that the benefit of abemaciclib is consistent at doses of 150 mg, 100 mg or 50 mg, oncologic pharmacists will need to work with physicians and patients to manage side effects and reduce dropout,” Dr. Roman told Specialty Pharmacy Continuum. At Allegheny Health, oncology clinical pharmacists often provide recommendations for adverse effect management, based on published studies and patient-specific characteristics. Dr. Roman added that she and her colleagues “keep in close contact with patients and ask them about any toxicities, grading toxicities one to two weeks after starting the medication and prior to each refill.”
Data suggest that ribociclib (Kisqali, Novartis) is another effective CDK4/6 inhibitor for HR-positive, HER2-negative early-stage BC patients with high recurrence risk. Interim results of NATALEE, an ongoing phase 3 clinical trial for the drug, showed a significant 25.2% reduction in invasive disease–free survival (iDFS) in patients randomized to a three-year ribociclib+ET regimen compared with ET alone (Int J Mol Sci 2023;24[22]:16366). This trial included participants with no nodal involvement. In an independent analysis, German researchers at the University of Ulm and University of TÜbingen retrospectively applied the NATALEE criteria to 1,738 patients and reported that 32% of premenopausal and 13% of postmenopausal patients would potentially benefit from ribociclib (Ther Adv Med Oncol 2023;15:1-16; Int J Mol Sci 2023;24[22]:16366).
Dr. Roman pointed out that many questions remain about how to optimize CDK4/6 inhibitors for early-stage BC. Similarly designed, randomized, phase 3 clinical trials PALLAS and PENELOPE-B evaluating the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) combined with ET did not produce any iDFS benefit (J Clin Oncol 2022;40[3]:282-293; J Clin Oncol 2021;39[14]:1518-1530).
Cleveland Clinic Experience
Sowmya Takkellapati, PharmD, BCOP, an oncology pharmacy clinical specialist at Cleveland Clinic, works with a multidisciplinary team to determine patient eligibility for treatment with CDK4/6 inhibitors. “This includes discussions of comorbidities, drug interactions, and laboratory parameters and other required tests, such as blood counts, organ function tests and echocardiograms,” she said. “Financial coverage may vary based on the CDK4/6 inhibitor chosen, and this may be an evolving landscape with any upcoming approvals.”
As with any cancer treatment, Dr. Takkellapati said, she discusses the data related to reducing recurrence risk and expectations of tolerability with the patient. “We [cover] administration instructions, potential adverse effects and any patient-specific concerns,” including access issues and financial challenges. “Cancer treatments can be financially toxic, even with health insurance coverage, [so] our specialty pharmacy and care teams explore eligibility for financial assistance programs.”
For patients already being treated with CDK4/6 inhibitors, Dr. Takkellapati assesses lab values, corrected QT level results and the grade of toxicities experienced to guide dose reductions and holding/restarting the medication. “For patients continuing treatment,” she added, “we have also modified supportive care strategies for adverse effect management.”
Dr. Roman is an advisory board consultant to Astellas and Daiichi Sankyo. Dr. Takkellapati has participated in Gilead and Novartis advisory board meetings.
