8 minute read
Materia Medica
by TEAM
KaRen m. FanCheR, PhaRmD, BCoP
Advertisement
Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) breast cancer represents nearly 70% of breast cancer cases.1 The vast majority such breast cancers are diagnosed in early stages. The 5-year relative survival for this cohort of patients exceeds 94% when all stages are considered together. However, this figure drops from 100% for localized disease at presentation to 89.9% with regional disease, and further to 30.6% for metastatic disease.2 Treatment of early-stage HR+ breast cancer varies by stage and typically includes combinations of surgery, radiation and chemotherapy. Following initial treatment, adjuvant endocrine therapy with aromatase inhibitors or tamoxifen with or without ovarian suppression is the standard of care and has been associated with a significant reduction in risk of recurrence and death.1,3
Unfortunately, approximately 20% of patients treated with adjuvant endocrine therapy will develop a breast cancer recurrence within 10 years.4 Such recurrences are often at distant sites and disease cure is no longer feasible.1,4 As a result, much work is being done to identify approaches to enhance or escalate treatment of high-risk HR+ early breast cancer.
CDK4/6 Inhibitors
One of the hallmarks of cancer cells is the ability to evade extracellular and intracellular signals that limit proliferation.5 Within the cell cycle, cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK 4 and 6 mediate the transition from the G1 phase into the S phase of the cell cycle. These kinases phosphorylate the retinoblastoma protein (pRb), which ultimately allows the cell cycle to progress to the S phase of cell division.6 In HR+ breast cancers, upon binding of estrogen to the estrogen receptor, CDKs are activated. Therefore, CKD4 and CDK6 inhibitors are important drug targets in HR+ breast cancer due to the ability to arrest the cell cycle and block cell growth.7
CDK4/6 inhibitors are already a mainstay in the treatment of metastatic HR+ breast cancer.3 Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have all demonstrated improvements in progressionfree survival and/or overall survival when used in combination with endocrine therapy for the first-line treatment of HR+, HER2– advanced breast cancer.5 More recently, the addition of a CDK4/6 inhibitor to adjuvant endocrine therapy has been investigated in several key trials.
The monarchE Trial
Abemaciclib (Verzenio®) is a selective small molecule inhibitor or CDK4/6.6,8 Abemaciclib is structurally different than palbociclib and ribociclib, resulting in a greater selectivity for CDK4 compared to CDK6. CDK4 plays a greater role in breast tumorigenesis, making it an attractive compound for study.9
The phase 3 monarchE trial randomized high-risk HR+ patients (n=5637) to two years of abemaciclib combined with 5-10 years of endocrine therapy, or endocrine therapy alone.1 Inclusion criteria were the findings of at least four positive lymph nodes or one to three positive nodes with one of the following additional risk factors: tumor size ≥5 cm or grade 3 histology (Cohort 1), or one to three positive nodes and a Ki-67 proliferation index of ≥ 20% (Cohort 2). Patients were of a median age of 51 years and the majority were post-menopausal at diagnosis (56.5%). Patients may have received up to 12 weeks of endocrine therapy prior to randomization. Radiation, adjuvant, and neoadjuvant chemotherapy were received in 95.4%, 58.3%, and 37.0% of the study population, respectively. Aromatase inhibitors were the most prescribed endocrine therapy (68.3%, including 14.2% treated concurrently with ovarian suppression).
The monarchE trial reported a benefit in invasive disease-free survival (IDFS).1,11 At two years, the addition of abemaciclib to endocrine therapy improved IDFS from 89.3% to 92.3% (p=0.0009) in the intent-to-treat population. Furthermore, distant recurrence-free survival (DRFS) was increased from 90.8% to 93.8% (p=0.0009).10 This benefit was maintained at three years for both IDFS (88.8% vs. 83.4%, p<0.0001) and DRFS (86.1% vs 90.3%, p<0.0001).11
When patients in Cohort 1 were stratified based on Ki-67 index, those who were Ki-67high had an absolute benefit in three-year IDFS of 7.1% (HR 0.63, 91% CI 0.49-0.80).1,11 In contrast, patients in Cohort 1 with a low Ki-67 index demonstrated a less pronounced absolute benefit of 4.5% (HR 0.70, 91% CI 0.51-0.98). While both subsets of patients derived a benefit from abemaciclib, the magnitude of benefit was reduced based on this biomarker.
Based on the results of the monarchE trial, the FDA approved abemaciclib, in combination with endocrine therapy, for the adjuvant treatment of adult patients with HR+, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20% on October 12, 2021.12 The Ki-67 IHC MIB-1 pharmDx assay was approved as a companion diagnostic. Importantly, the FDA-approved indication may expand pending additional follow-up data such as overall survival in the intent-to-treat population.
Dosage and Administration
The dose of abemaciclib in the monarchE trial was 150 mg by mouth twice daily.1 In contrast to palbociclib and ribociclib, which are taken for 21 days out of 28-day cycles, abemaciclib is taken continuously. Doses may be taken with or without food.8
Abemaciclib is extensively metabolized by cytochrome P450 (CYP) 3A4, and therefore the concomitant use of strong CYP3A4 inhibitors
Continued on Page 24
From Page 23
or inducers should be avoided if possible; specific dose adjustments are recommended by the manufacturer if concomitant therapy is required.6,8
Adverse Effects and Management
As previously noted, abemaciclib is more potent against CDK4 than CDK6. This difference in potency results in a different spectrum of adverse effects than palbociclib and ribociclib.9 In clinical trials of abemaciclib, the most common adverse effects were diarrhea and fatigue; this is in contrast to trials of palbociclib and ribociclib, where hematologic effects such as neutropenia were frequently noted.
Diarrhea has been noted in up to 90% of patients who receive abemaciclib, commonly occurring within the first week of treatment initiation.9 This effect is often self-limiting, with resolution in approximately 7 days.6,9 Most cases of such diarrhea can be managed with increased oral fluid intake and antidiarrheal therapy, and do not require treatment modification or dose reduction.6 However, up to 10% of patients develop severe diarrhea. In the monarchE trial, diarrhea of any grade was reported in 82.2% of patients who received abemaciclib, with 7.6% of patients having grade ≥3 symptoms.1 Patients should be educated that at the first sign of loose stools, antidiarrheal therapy such as loperamide should be initiated, oral fluids intake should be increased, and the healthcare provider should be contacted for further instructions and appropriate follow-up.8
Other events frequently reported with abemaciclib include neutropenia, nausea, fatigue, abdominal pain, and decreased appetite.6 In the monarchE trial, other commonly reported adverse effects included neutropenia (44.6%), fatigue (38.4%), abdominal pain (34%), nausea (27.9%), anemia (22.9%), and arthralgia (20.5%).1
Due to the risk of neutropenia, complete blood counts should be monitored prior to the start of abemaciclib, every two weeks for the first two months, monthly for the next two months, and then as clinically indicated.8 Patients should also be educated regarding the possibility of developing neutropenia and to immediately contact their healthcare provider should a fever occur. According to the prescribing information, if white blood cell growth factors are required for the treatment of neutropenia and/or febrile neutropenia, abemaciclib should be held for at least 48 hours after the last dose of white blood cell growth factor and until toxicity resolves to less than grade 2. Abemaciclib should be resumed at the next lower dosage recommendation, unless dosage reduction had already performed for the toxicity that led to the use of the growth factor. The initiation, dosage and duration of white blood cell growth factor therapy should be administered as per current treatment guidelines.
In clinical trials of abemaciclib, hepatotoxicity was infrequently reported (<5%).8 In the monarchE trial, increases in aspartate aminotransferase (AST) and/ or alanine aminotransferase (ALT) occurred in approximately 10% of patients. The manufacturer recommends that liver function tests (LFTs) should be monitored prior to the start of therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated, with dosage adjustments as appropriate.
Future Directions
The landscape of treatment options for early-stage HR+ breast cancer continues to evolve as we learn how to best tailor individual treatment based on risk stratification. Identifying high-risk patients for escalation of therapy is now a major focus of clinical research. The monarchE data supports incorporating two years of adjuvant abemaciclib therapy in select high-risk patients, making abemaciclib the first drug to receive FDA-approval for adjuvant hormonereceptor positive breast cancer in over 15 years.12 However, there have also been trials of palbociclib and ribociclib in this setting, with results varying across trials. No direct comparisons have been made between the CDK4/6 inhibitors in this setting to date, and therefore the most appropriate use of these agents in HR+ early breast cancer remains undefined. Comparative studies and longerterm follow-up are eagerly awaited.
Dr. Fancher is an associate professor of pharmacy practice at Duquesne University School of Pharmacy. She also serves as a clinical pharmacy specialist in oncology at the University of Pittsburgh Medical Center at Passavant Hospital. She can be reached at fancherk@duq.edu or (412) 396-5485.
REFERENCES 1. Johnston SR, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2–, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2021;38:3987-98. 2. Cancer Stat Facts: Female Breast Cancer Subtypes. Available at https://seer.cancer.gov/ statfacts/html/breast-subtypes.html . Accessed March 26, 2022. 3. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 2.2022. https://www.nccn. org/professionals/physician_gls/pdf/breast.pdf. Accessed March 26, 2022. 4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials Lancet. 2015;386:1341-52. 5. Murphy CG. The role of CDK4/6 inhibitors in breast cancer. Curr Treat Options in Oncol. 2019;20:52. 6. Palumbo A, Lau G and Saraceni M. Abemaciclib: the newest CDK4/6 inhibitor for the treatment of breast cancer. Ann Pharmcother. 2019;53:178-85. 7. Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from discovery to therapy.Cancer Discov. 2016;6:353-67. 8. Verzenia [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2017. 9. Thill M and Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Ther Adv Med Oncol. 2018;10:1758835918793326. 10. O’Shaughnessy JA, Johnson S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancerSan Antonio Breast Cancer Symposium. 2020;Abstract GS1-01. 11. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021; 32: 1571-81. 12. US Food and Drug Administration. FDA approves abemaciclib with endocrine therapy for early breast cancer. https://www.fda.gov/drugs/ resources-information-approved-drugs/fdaapproves-abemaciclib-endocrine-therapy-earlybreast-cancer. Accessed March 26, 2022.
