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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


February 26, 2018–Abemaciclib (VERZENIO™, Eli Lilly and Company) approved in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (with Pharmacist's Applications to Practice.)

September 28, 2017–Abemaciclib (VerzenioTM, Eli Lilly and Co.) in combination with fulvestrant approved for women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy (with Pharmacist's Applications to Practice.)


February 26, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf

On February 26, 2018, the Food and Drug Administration approved abemaciclib (VERZENIO™, Eli Lilly and Company) in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Approval was based on MONARCH 3, a randomized (2:1), double-blinded, placebo-controlled, multicenter clinical trial in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. A total of 493 patients were randomized to receive either abemaciclib 150 mg or placebo orally twice daily, plus physician’s choice of letrozole or anastrozole. The estimated median progression-free survival (PFS) (RECIST 1.1) was 28.2 months (95% CI: 23.5, Not reached) for patients receiving abemaciclib and 14.8 months (95% CI: 11.2, 19.2) for those receiving placebo (HR 0.540; 95% CI: 0.418, 0.698; p<0.0001).

The most common adverse reactions in at least 20% of patients receiving abemaciclib in MONARCH 3 and more than 2% higher than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia.

The recommended starting dose of abemaciclib in combination with an aromatase inhibitor is 150 mg twice daily orally with or without food.

Full prescribing information is available:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf

FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 

Pharmacist’s Applications to Practice

Abemaciclib as Initial Endocrine-Based Therapy for Metastatic Hormone Receptor (HR)–Positive, Human Epidermal Growth Factor Receptor 2 (HER2)–Negative Breast Cancer

Author: Lesley Hall Volz, PharmD BCOP
Clinical Oncology Specialist
University of Louisville/James Graham Brown Cancer Center
Louisville KY

 What is the potential role for abemaciclib in the treatment of hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer?

  • Abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is currently approved by the U.S. Food and Drug Administration (FDA) for treating metastatic HR-positive, HER2-negative breast cancer for three separate indications.1
  • Previously, the MONARCH 1 and MONARCH 2 trials led to approval of abemaciclib for metastatic HR-positive, HER2-negative breast cancer for patients whose disease had progressed on endocrine therapy.2,3
  • On February 26, 2018, abemaciclib was approved by the FDA to be used in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for postmenopausal HR-positive, HER2-negative breast cancer patients on the basis of results of the MONARCH 3 trial. Abemaciclib is the third CDK 4/6 inhibitor approved by the FDA for such therapy, following palbociclib and ribociclib.1,4-6
  • The MONARCH 3 trial (N = 493) compared the efficacy and safety of abemaciclib plus a nonsteroidal aromatase inhibitor (AI = anastrozole 1 mg or letrozole 2.5 mg) versus placebo plus an AI in postmenopausal women with HR-positive, HER2-negative breast cancer who had not been previously treated in the metastatic setting. Patients could have received endocrine therapy in the neoadjuvant or adjuvant setting as long as they had been disease free for more than 12 months after the completion of therapy. At a preplanned interim analysis, this double-blind phase 3 trial demonstrated improved progression-free survival (PFS) with the combination versus AI alone (not reached vs. 14.7 months, respectively; hazard ratio 0.54; 95% confidence interval 0.41–0.72; p = .000021).6 Objective response rate (ORR) was improved in patients with measurable disease in the combination versus AI alone (59% vs. 44%, respectively; p = .004). The most frequent adverse event was diarrhea (81.3%), the majority of which was grade 1. In comparison to placebo, patients on abemaciclib experienced more grade 3/4 diarrhea (9.5% vs. 1.2%), neutropenia (21.1% vs. 1.2%), and leukopenia (7.6% vs. 0.6%).
  • The National Comprehensive Cancer Network (NCCN) recognizes abemaciclib plus an AI as a category 1 recommendation for first-line therapy for postmenopausal HR-positive, HER2-negative metastatic breast cancer. The NCCN also recognizes palbociclib and ribociclib in combination with an AI as category 1 recommendations for the same indication.7
  • Until randomized trials comparing CDK4/6 inhibitors have been conducted, selecting an agent in combination with an AI is challenging. A few factors to consider when selecting an agent include adverse-effect profiles, cost, and patient or clinician preference.

What role can the pharmacist play in the management of patients on abemaciclib?

  • Abemaciclib dosing varies according to the indication. When used in combination with an AI, abemaciclib is dosed 150 mg by mouth twice daily on a continuous schedule. Abemaciclib may be administered with or without food.1
  • Laboratory monitoring includes complete blood count and complete metabolic panel every 2 weeks for the first 2 months, monthly for the next 2 months, and then as clinically indicated.1
  • Dose interruptions or modifications are recommended for neutropenia (all grades, 41%; grade 3/4, 22%), diarrhea (all grades, 81%; grade 3/4, 9%), increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (all grades, 40%; grade 3/4, 9%), and any grade 3/4 toxicity. Median time to onset of adverse effect varies (for diarrhea, 8 days; for neutropenia, 33 days; and for AST/ALT elevations, 61 days). Median time to resolution for neutropenia lower than grade 3 and elevated AST/ALT levels is approximately 2 weeks. Diarrhea usually improves within 1 week.1
  • Patients should be monitored for signs and symptoms of thromboembolism, which occurred in 5% of patients in clinical trials.1,2,3,6
  • Dosing frequency should be reduced to once daily in patients with Child Pugh-C hepatic impairment.1
  • The combination of abemaciclib with strong cytochrome P450 3A4 (CYP3A4) inhibitors should be avoided, and patients should be advised not to consume grapefruit products. If abemaciclib is used concomitantly with strong CYP3A4 inhibitors, the package insert instructions for dose reductions should be followed.1

Clinical Pearls

  • Abemaciclib is supplied as a 7-day blister dose pack (14 tablets) of 200 mg, 150 mg, 100 mg, and 50 mg to accommodate various dosing schedules and dose reductions.1
  • Key differences in CDK 4/6 inhibitors include dosing schedules and side-effect profiles. Abemaciclib is the only CDK 4/6 inhibitor that is dosed continuously, rather than on a schedule of 21 days on followed by 7 days off.1,4,5
  • Although the incidence of diarrhea (all grades) with abemaciclib is three times the incidence that occurs with other CDK 4/6 inhibitors, the incidence of grade 3 or higher neutropenia with abemaciclib is one-third less.1,4,5
  • Elevations of 0.2–0.3 mg/dl in serum creatinine may occur within the first cycle of abemaciclib and remain stable throughout treatment. Abemaciclib inhibits renal tubular secretion transporters but does not alter glomerular filtration.1
  • A Verzenio Savings Card is available to patients with commercial insurance. The savings card provides patients with the first 3 months of therapy at no cost and then for $10/month after that, covering up to a maximum of $25,000/year. Uninsured and government-insured patients are ineligible.8

References

  1. Verzenio (abemaciclib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
  2. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218-5224.
  3. Sledge Jr. GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884.
  4. Ibrance (palbociclib) [package insert]. New York, NY: Pfizer Labs; March 2017.
  5. Kisqali (ribociclib) [package insert]. East Hanover, NJ: Novartis, Inc.; March 2017.
  6. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646.
  7. National Comprehensive Cancer Network. Breast Cancer. Version 1.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed April 6, 2018.
  8. Verzenio Savings Card. Available at https://www.verzenio.com. Accessed April 6, 2018.

September 28, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf

On September 28, 2017, the Food and Drug Administration approved abemaciclib (VerzenioTM, Eli Lilly and Company) in combination with fulvestrant for women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. In addition, abemaciclib was approved as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

The approval in combination with fulvestrant was based on MONARCH 2, a randomized, placebo-controlled, multicenter trial in women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. The trial randomized 669 patients to receive either abemaciclib or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Patients remained on continuous treatment with abemaciclib until development of progressive disease or unmanageable toxicity. Median progression-free survival for patients taking abemaciclib with fulvestrant was 16.4 months compared with 9.3 months for those taking placebo with fulvestrant (HR 0.553; 95% CI: 0.449, 0.681; p<0.0001). The objective response rate in patients with measurable disease taking abemaciclib with fulvestrant was 48.1% (95% CI: 42.6, 53.6) compared to 21.3% (95% CI 15.1, 27.6) in the placebo with fulvestrant treated patients.

The approval as monotherapy was based on MONARCH 1, a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received one or two prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg abemaciclib orally twice daily on a continuous schedule until progressive disease or unmanageable toxicity. Objective response rate was 19.7 percent (95% CI: 13.3, 27.5) with a median response duration of 8.6 months (95% CI: 5.8, 10.2).

The most common adverse reactions in greater than 20% of patients taking abemaciclib were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia. The most frequently reported (≥5%) grade 3 or 4 adverse reactions in patients taking abemaciclib with fulvestrant were neutropenia, diarrhea, leukopenia, anemia, and infections.

The recommended starting doses are 150 mg twice daily in combination with fulvestrant or 200 mg twice daily as monotherapy.

Full dosing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf

FDA granted priority review and Breakthrough Therapy Designation to abemaciclib for this indication. Approval was granted approximately three months prior to the due date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 

Pharmacist’s Applications to Practice

Abemaciclib for Hormone Receptor (HR)–Positive, Human Epidermal Growth Factor Receptor 2 (HER2)–Negative Advanced or Metastatic Breast Cancer That Has Progressed After Endocrine Therapy

Author: Andrea M. Clarke, PharmD
PGY-1 Pharmacy Practice Resident
University Health Shreveport
Shreveport, LA

What is the potential role for abemaciclib in the management of metastatic breast cancer?

  • Abemaciclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor approved as a treatment option for patients with HR-positive HER2-negative advanced or metastatic breast cancer (MBC) whose disease has progressed after endocrine therapy.1
  • Approval by the FDA is based on evidence from the single-arm phase 2 MONARCH 1 study in which treatment with abemaciclib as monotherapy demonstrated an overall response rate of 19.7%, median progression-free survival (PFS) of 6 months, and median overall survival of 17.7 months.2
  • Abemaciclib in combination with fulvestrant was examined in the phase 3 MONARCH 2 study, which demonstrated improved PFS of 16.4 months versus 9.3 months when compared to fulvestrant alone.3
  • Abemaciclib is the third CDK 4/6 inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for MBC. Abemaciclib is the only CDK 4/6 inhibitor to be approved for use as monotherapy. Palbociclib is approved for use with fulvestrant following endocrine therapy progression but is also approved in the first-line setting when used in combination with letrozole. Ribociclib is approved in the first-line setting when used in combination with letrozole.4
  • The National Comprehensive Cancer Network has not yet weighed in on abemaciclib’s role in therapy for MBC.

What role can the pharmacist play in the management of patients on abemaciclib?

  • Pharmacists need to be aware of two different dosing recommendations for abemaciclib.  When used as monotherapy, abemaciclib is dosed as 200 mg twice daily. When used in combination with fulvestrant, abemaciclib is dosed as 150 mg twice daily.1
  • In pre- and perimenopausal patients on abemaciclib in combination with fulvestrant, a gonadotropin-releasing hormone agonist such as goserelin should be added to the regimen.1
  • Dosing for patients with severe hepatic impairment (Child-Pugh C) should be reduced to once daily.1
  • Monitor for hematologic and nonhematologic toxicities to determine the need for dose modifications as provided in the package insert. Dose modifications are recommended for neutropenia (46% incidence; all grades), diarrhea (90% incidence; all grades), alanine aminotransferase/aspartate aminotransferase (ALT/AST) increases (30% incidence; all grades). Grade 3 or higher neutropenia occurred in nearly one-third of patients, with a median time of onset of 29 days and median duration of 15 days.1-3
  • Monitor for signs and symptoms of venous thromboembolism, which has been reported in patients treated with abemaciclib in combination with fulvestrant.1-3
  • Abemaciclib is metabolized by cytochrome P450 3A4 (CYP3A4), and patients should be screened for concomitant use with CYP3A4 inhibitors and inducers. If strong CYP3A4 inhibitors are used, dose reduction of abemaciclib to 100 mg twice daily is recommended.1
  • Patients should be counseled to take abemaciclib at approximately the same time each day with or without food.1

Clinical Pearls

  • A complete blood count with differential, ALT, AST, and serum bilirubin should be assessed prior to the start of therapy and then monitored every 2 weeks for the first 2 months, monthly for 2 months, and then as clinically indicated.1
  • When compared with palbociclib and ribociclib, abemaciclib has a lower frequency of hematologic toxicities, in particular neutropenia, but a higher incidence of fatigue and gastrointestinal toxicities, possibly because of abemaciclib’s greater selectivity for CDK4 over CDK6. The lower incidence of neutropenia with abemaciclib allows for continuous dosing, whereas palbociclib and ribociclib are dosed 21 days on and 7 days off.1-3,5,6
  • Elevations in serum creatinine (SCr) occurred in most patients (98.5%); however, abemaciclib has been found to inhibit renal efflux transporters that mediate active secretion of creatinine in the kidneys. Therefore, elevation in SCr may not accurately reflect renal function, and other methods of estimating glomerular filtration rate (GFR) that do not reflect active tubular secretion by renal efflux transporters, such as cystatin C-calculated GFR, may reflect renal function more accurately.2,7
  • Abemaciclib and its active metabolites cross the blood-brain barrier and reach concentrations in the cerebrospinal fluid that are comparable to unbound plasma concentrations, which may make this an attractive option for patients with brain metastases.1,7,8
  • Abemaciclib is supplied as 50 mg, 100 mg, 150 mg, and 200 mg tablets.1
  • Although no patient assistance program is currently available to the uninsured, a Verzenio Savings Card is available to patients with commercial insurance and will cover the remaining out-of-pocket costs, providing patients with the first 3 months of therapy at no cost and then for $10/month after that, covering up to a maximum of $25,000/year. Uninsured and government-insured patients are ineligible.9

References

  1. Verzenio (abemaciclib) [package insert]. Indianapolis, IN: Eli Lilly and Co.; September 2017.
  2. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. 2017; 23(17):5218-5224.
  3. Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017; 35:2875-2884.
  4. Breast Cancer. Version 2.2017. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed October 15, 2017.
  5. Ibrance (palbociclib) [package insert]. New York, NY: Pfizer Labs; March 2017.
  6. Kisqali (ribociclib) [package insert]. East Hanover, NJ: Novartis, Inc.; March 2017.
  7. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 2016; 6(7):740-753.
  8. Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos. 2015;43(9):1360-1371.
  9. Verzenio Savings Card. Available at https://www.verzenio.com. Accessed  October 15, 2017.
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