Hormone receptor-positive (HR-positive) breast cancer is the most common subtype of invasive breast cancer. Treatment has been focused on targeting the estrogen receptor pathway, and endocrine therapy (ET) has remained the mainstay treatment for these patients. However, up to 50% of patients with HR-positive metastatic breast cancer (MBC) develop resistance to ET.1 The recent development of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, as well as alpelisib (Piqray), a phosphoinositide 3-kinase (PI3K) inhibitor, has changed the way patients with HR-positive MBC are treated.

CDK4/6 Inhibitors 
Loss of normal cell cycle regulation allows cancer cells to develop and grow. In the cell cycle, the progression from G1 (pre-DNA synthesis) to S (DNA synthesis) is controlled by the tumor suppressor retinoblastoma (Rb) protein and is a crucial transition to prevent abnormal cell growth. Growth signals occurring during the G1 phase can lead to cyclin D binding to CDK4/6, which causes phosphorylation of Rb, release of E2F transcription factors and, ultimately, cell cycle progression. The CDK4/6-Rb pathway is particularly important in HR-positive breast cancer, as estrogen has been shown to increase the rate of progression from the G1 to the S phase. CDK 4/6 inhibitors work synergistically with antiestrogen therapy to block this transition.1-3 

Three CDK4/6 inhibitors were recently approved by the FDA for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2) MBC: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). These medications are oral, highly potent, and selective for CDK4/6.2 All 3 agents are approved for use in the first-line setting of MBC in combination with an aromatase inhibitor and in the second-line setting in combination with fulvestrant. There are 2 main differences in the indications of these agents4-6
  1. Ribociclib is also approved in the first-line setting in premenopausal MBC in combination with an aromatase inhibitor plus ovarian suppression or tamoxifen. 
  2. Abemaciclib is the only CDK4/6 inhibitor approved for use as monotherapy in the second-line setting. 

The CDK4/6 inhibitors are generally well tolerated, even in individuals ≥65 years, which accounts for many of these patients.7 Older patients generally have more comorbidities. As a result, they take more medications that may interact with a CDK4/6 inhibitor, which must be considered when selecting which CDK4/6 inhibitor to use. Toxicities can have an impact on quality of life, which is an important factor and not to be overlooked. Fortunately, toxicities from these agents are manageable with dose modifications and/or supportive therapy. 

Hematologic toxicities, notably neutropenia, are common with the CDK4/6 inhibitors, especially palbociclib and ribociclib. Because of this, both agents are dosed for 21 days on followed by 7 days off to allow for neutrophil count recovery. If counts do not recover appropriately, a dose reduction is usually necessary.2,4-6 The occurrence of febrile neutropenia is rare. 

Abemaciclib has unique pharmacologic properties compared with palbociclib and ribociclib. It can efficiently pass through the blood-brain barrier and has shown clinical benefit in patients with MBC to the brain. Abemaciclib is being further studied in this specific patient population.8 Additionally, it has higher affinity to cyclin-dependent kinase 9, which results in gastrointestinal toxicity and a different adverse effect (AE) profile from its counterparts, which allows for continuous dosing. Abemaciclib’s most common toxicity is diarrhea, which is managed as needed with loperamide. Dose reductions may be needed if diarrhea persists despite optimal loperamide use or if it becomes intolerable and affects quality of life. Preventive use of loperamide has not been studied and warrants further investigation.3,4-6,9 



Selection of which CDK4/6 inhibitor largely depends on a patient’s treatment history, cancer-specific factors (such as brain metastases), and comorbidities (Table).4-6 Patients with gastrointestinal comorbidities may want to avoid abemaciclib, and those who are prone to dose-limiting neutropenia from previous therapies may want to avoid treatment with palbociclib and ribociclib. Meanwhile, patients with a prolonged QT interval at baseline and/or who are taking other medications that prolong the QT interval may want to avoid ribociclib. For any of the above-mentioned instances, if a provider determines that a specific CDK4/6 inhibitor is best for treatment of the patient’s MBC, these patients are often started at a lower dose and titrated to the full dose depending on their tolerability, with close monitoring for toxicity. 



PI3K Inhibitor 
The PI3K signaling pathway impacts cancer cell growth, survival, motility, and metabolism.10 Activation of this pathway in breast cancer is associated with resistance to ET, disease progression, and poorer prognosis.11 The PI3K pathway is broken down into isoforms; genetic mutations that activate the alpha isoform are PIK3CA mutations.12 These mutations occur in approximately 40% of patients with HR+, HER2- negative breast cancer.13 Alpelisib is a selective oral PI3K inhibitor used in combination with fulvestrant for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced breast cancer as detected by an FDA approved test following progression on or after ET.14 

It is the first and only PI3K inhibitor approved for use in breast cancer. Alpelisib works synergistically with ET and has been shown to be most effective in patients harboring the PIK3CA mutation.15 It inhibits the phosphorylation of PI3K downstream targets, including protein kinase B, which affects growth and survival of cancer cells (Figure).10 Alpelisib can be used in patients with disease progression on a CDK4/6 inhibitor. 

Alpelisib’s recommended starting dose is 300 mg orally once daily with food. It is available in 50-, 150-, and 200-mg tablets supplied in blister packs. Doses can be modified to 250 or 200 mg once daily for toxicity. Alpelisib’s most common toxicities (>30%) include rash, hyperglycemia, diarrhea, nausea, decreased appetite, fatigue, increased liver enzymes, and increased serum creatinine.14 

Monitor patients for these toxicities while on therapy, as they are manageable with supportive therapy, dose adjustments, or therapy holds. Loperamide is recommended to be used as needed for diarrhea associated with alpelisib. Antihistamines and corticosteroids are used for the treatment of rash, the incidence of which has been found to be lower when taken with an antihistamine as a preventive measure.15 

Patient glucose levels should be monitored while on treatment with alpelisib, and fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) prior to treatment initiation. Also monitor blood glucose and/or FBG at least once each week for the first 2 weeks, then at least once every 4 weeks and as clinically indicated, and HbA1c every 3 months and as clinically indicated. Initiation or adjustments of antidiabetic medications may be required to manage hyperglycemia, especially in patients with diabetes requiring closer monitoring. Signs and symptoms of pneumonitis, a rare but serious AE, should be tracked. Additionally, as with any oral oncology agent, monitor adherence to therapy.14 

The role of oncology pharmacists in the clinic and specialty setting is critical as additional oral oncology agents come to market. At Partners HealthCare Specialty Pharmacy (PHSP), the pharmacy is integrated within our health system, which improves patient care, removes the office administrative burden, and streamlines patient and provider communication. At PHSP, oncology pharmacists have a patient management program that closely monitors for toxicities and adherence. Integrated into the care team, PHSP pharmacists monitor patients’ labs, check for drug interactions, and check their progress/tolerability via access to the electronic medical record. 

The following case helps illustrate the benefits to the patient: PHSP received an abemaciclib prescription for a 73-year-old patient at a reduced dose of 150 mg twice daily due to her comorbidity of diabetes insipidus. Abemaciclib was the drug of choice by the provider due to the patient’s brain metastases and increased penetration of the blood-brain barrier compared with the other CDK4/6 inhibitors. A specialty pharmacist followed up with the patient about a week after she started therapy to check in and assess tolerability. The patient reported she had a few episodes of diarrhea that kept her up all night despite using loperamide. The pharmacist informed the patient’s provider team of this AE and recommended the patient take loperamide as a preventive measure with her evening dose. 

A few weeks later, the on-call pharmacist received a call from this patient because she was having a hard time contacting her physician’s office. The patient’s diarrhea had continued despite optimal loperamide use, and the pharmacist was concerned for dehydration because of the diabetes insipidus. So, the pharmacist contacted the patient’s provider team and helped coordinate the patient to have labs and intravenous fluids. Her dose was reduced to 100 mg twice daily. The pharmacist then created a care plan and checked with the patient weekly to follow up on her diarrhea, which improved and was manageable with the lower dose. 

This case illustrates the importance of follow-up phone calls and close communication with providers for patients starting on a new oral chemotherapy regimen. Patients on oral chemotherapy are usually not coming into the clinic as often as patients who are receiving intravenous chemotherapy. If a patient is experiencing a toxicity at home and is unsure of how to manage it, this may lead to an emergency department visit, hospitalization, or a lack of adherence, all of which can increase health care cost and affect the efficacy of the medication. 

Summary 
CDK4/6 inhibitors and alpelisib have changed the way patients with MBC are treated. There are numerous ongoing trials looking at other ways to use these agents in patients with breast cancer, such as in combination with other chemotherapy agents and immunotherapy, in the neoadjuvant and adjuvant setting, continuation after progression, and the combination of alpelisib and CDK4/6 inhibitors. 

The CDK4/6 inhibitors and alpelisib have shown superior disease outcomes compared with ET alone; however, they do come with greater toxicity. These toxicities are manageable and reversible, but require close monitoring and early intervention. For patients with MBC, quality of life is very important to maintain. Oncology pharmacists have a unique opportunity to manage patients on oral chemotherapy because they possess the clinical knowledge of these agents and management of their toxicities, and the clinic providers often do not have the capacity to follow up with these patients. Oncology pharmacists can greatly improve patient care and outcomes and should seek to become involved in their care. 
 
Amanda Manoogian, PharmD, BCOP, is coordinator, Specialty Pharmacy - Clinical Services at Partners HealthCare. 

REFERENCES
  1. Preusser M, De Mattos-Arruda L, Thill Met al. CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. ESMO Open. 2018;3(5):e000368. doi: 10.1136/esmoopen-2018-000368.
  2. Spring LM, Wander SA, Zangardi M, Bardia A. CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions. Curr Oncol Rep. 2019;21(3):25. doi: 10.1007/s11912-019-0769-3.
  3. Pernas S, Tolaney SM, Winer EP, Goel S. CDK4/6 inhibition in breast cancer: current practice and future directions.Ther Adv Med Oncol. 2018;10:1758835918786451. doi: 10.1177/1758835918786451.
  4. Lexicomp Online, Palbociclib: Wolters Kluwer Clinical Drug Information, last updated Sept 16, 2019; Accessed Sept 20, 2019.
  5. Lexicomp Online, Ribociclib: Wolters Kluwer Clinical Drug Information, last updated Sept 20, 2019; Accessed Sept 20, 2019.
  6. Lexicomp Online, Abemaciclib: Wolters Kluwer Clinical Drug Information, last updated Sept 16, 2019; Accessed Sept 20, 2019.
  7. Battisti NML, De Glas N, Sedrak MS, et al. Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper. Ther Adv Med Oncol. 2018;10:1758835918809610. doi: 10.1177/1758835918809610.
  8. Anders CK, Le Rhun E, Bachelot TD, et al. A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC). J Clin Oncol. 2019;37(suppl 15):1017. bit.ly/2WAVfA4.  
  9. Marra A Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer. 2019;5:27; doi: 10.1038/s41523-019-0121-y.
  10. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as a drug target in human cancer. J Clin Oncol. 2010;28(6):1075-1083. doi: 10.1200/JCO.2009.25.3641.
  11. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the Phosphatidylinositol 3-Kinase Pathway: Role in Tumor Progression and Therapeutic Implications in Breast Cancer. Breast Cancer Res. 2011;13(6):224. doi: 10.1186/bcr3039.
  12. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation, and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7-24. doi: 10.1038/nrc3860.
  13. Sabisne V, Crozier C, Brookes C, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J Clin Oncol. 2014;32(27):2951-2958.
  14. Alpelisib [package insert]. East Hanover, NJ: Novartis; 2019.  
  15. Andre F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone ReceptorPositive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940. doi: 10.1056/NEJMoa1813904