SIZE XSSIZE SMSIZE MDSIZE LG

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


October 31, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf

On October 31, 2017, the Food and Drug Administration granted accelerated approval to acalabrutinib (Calquence™, AstraZeneca Pharmaceuticals Inc. under license of Acerta Pharma BV) for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Approval was based on Study LY-004, an open-label, phase 2 trial (NCT02213926) enrolling 124 patients with MCL who received at least one prior therapy. Patients received acalabrutinib, 100 mg orally twice daily, until disease progression or unacceptable toxicity. The overall response rate (investigator assessed), which was the primary endpoint, was 81% (95% CI: 73%, 87%); and the complete response rate was 40%(95% CI: 31%, 49%). There was excellent concordance (91%) between the ORR as determined by investigator assessment and independent review committee. The median duration of response has not been reached with 15.2 months of follow-up. The median time to best response was 1.9 months.

The most common adverse reactions in greater than 20% of patients taking acalabrutinib were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia and bruising. Dose reductions or discontinuations due to adverse reactions were reported in 1.6% and 6.5% of patients, respectively. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, thrombocytopenia and anemia.

The recommended dose is 100 mg orally twice daily, approximately every 12 hours.

Full prescribing information is available at
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf

FDA granted Breakthrough Therapy, Orphan Drug designation, and priority review to acalabrutinib for this indication. Approval was granted approximately 14 weeks 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

Acalabrutinib (Calquence) for the Treatment of Adult Patients with Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy

Author: Robert Walchack, PharmD
PGY-2 Oncology Pharmacy Resident
WVU Medicine
Morgantown, WV

What is the potential role for acalabrutinib in the treatment of mantle cell lymphoma?1-6

  • On October 31, 2017, the U.S. Food and Drug Administration (FDA) granted acalabrutinib accelerated approval for the treatment of adult patients with mantle cell lymphoma (MCL) who had received at least one prior therapy.
    • Continued approval is contingent upon phase 4 confirmatory trials illustrating anticipated clinical benefit.
  • The National Comprehensive Cancer Network (NCCN) lists acalabrutinib, a bruton tyrosine kinase (BTK) inhibitor, as a second-line treatment option with a category 2A recommendation.
    • Several second-line treatment options are listed, including ibrutinib.
      • Overall response rates (ORRs) for selected second-line treatment options
        • Ibrutinib: 67% (23% complete response [CR])
        • Bendamustine plus rituximab: 92% (41% CR)
      • Note: Both the acalabrutinib and ibrutinib studies evaluated patients with MCL who had received at least one prior therapy. The median number of prior treatments was two for acalabrutinib and three for ibrutinib. Median age and performance status were similar in both studies. The bendamustine plus rituximab study evaluated patients with relapsed CD20-positive mantle cell lymphoma or indolent B-cell lymphoma, and a maximum of three prior, unique chemotherapy regimens were allowed. The median number of prior treatments was one.
  • Acalabrutinib is a second-generation BTK inhibitor and was created to possess more potency and selectivity than ibrutinib. It does not inhibit epidermal growth factor receptor (EGFR), interleukin-2-inducible T-cell (ITK), or TEC kinases, nor does it inhibit platelet aggregation, lending itself to a potentially more favorable safety profile.
    • Grade 3 or higher bleeding
      • Acalabrutinib: 2%
      • Ibrutinib: 6%
    • All grades of thrombocytopenia
      • Acalabrutinib: 44% (grade 3 or greater: 12%)
      • Ibrutinib – not reported (grade 3 or greater: 13%)
    • Grades 3 and 4 neutropenia
      • Acalabrutinib: 23%
      • Ibrutinib: 17%
    • Note: All percentages for adverse events associated with ibrutinib reported in this PAP are from the trial evaluating its use in MCL as referenced below.
  • Approval was based on abstract data from the phase 2 ACE-LY-004 study, which evaluated 124 adults with confirmed MCL who had relapsed after or were refractory to 1–5 prior therapies (median = 2).
    • Acalabrutinib 100 mg twice daily by mouth was given until the disease progressed or an unacceptable level of toxicity was reached.
    • The primary end point of ORR = 81% (95% confidence interval [CI], 73%–87%), with 40% (95% CI, 31%–49%) achieving CR and 41% achieving a partial response (PR) per investigator assessment.
      • Median time to response was 1.9 months (range 1.5–4.4).
    • 12-month progression-free survival was 67% (95% CI, 58%–75%).
    • 12-month overall survival was 87% (95% CI, 79%–92%).
  • No data reporting central nervous system (CNS) penetration of acalabrutinib were available at the time of this publication. Meanwhile, ibrutinib has been shown to cross the blood-brain barrier and induce rapid, sustained responses in MCL patients with CNS relapse.

What role can the pharmacist play in the management of patients on acalabrutinib?2-3

  • Counsel patients on the importance of adherence and administration of doses 12 hours apart.
  • Monitor for drug-drug interactions and recommend safe and effective therapeutic alternatives.
    • Strong CYP3A inhibitors: avoid co-administration with acalabrutinib; otherwise, interrupt treatment if the inhibitor will be used over a short term.
    • Moderate CYP3A inhibitors: reduce acalabrutinib dose to 100 mg once daily.
    • Strong CYP3A inducers: avoid co-administration with acalabrutinib; otherwise, increase acalabrutinib dose to 200 mg twice daily.
    • Decreased plasma concentrations of acalabrutinib may occur with concomitant acid suppression. Avoid concomitant use with proton pump inhibitors. Administer acalabrutinib 2 hours prior to H2-receptor antagonists and separate from antacids by at least 2 hours.
  • Attend to risks of a secondary malignancy.
    • Acalabrutinib: 11%
    • Ibrutinib: 5%
    • The most frequent second primary malignancy was skin cancer. Advise patients to protect from sun exposure.
  • Monitor for atrial fibrillation and flutter and manage accordingly.
    • Any grade of atrial fibrillation and atrial flutter
      • Acalabrutinib: 3% (grade 3 or higher: 1%)
      • Ibrutinib: 11% (grade 3 or higher: 6%)
  • Monitor for and counsel patients on the signs and symptoms of the following:
    • Common adverse reactions, such as anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).
    • Grades 3–4 adverse events such as neutropenia (10%), anemia (9%), and pneumonia (5%).
  • No dosing adjustments are recommended in cases of renal and hepatic impairment.
  • The AstraZeneca Patient Savings Program (https://www.astrazenecaspecialtysavings.com/pdf/CALQUENCE_Affordability_Brochure.pdf) is available for patients who have commercial health insurance that covers medication costs for acalabrutinib, but not the full cost to the patient. Patients are ineligible if prescriptions are paid by any state or federally funded programs.

Clinical Pearls2-4,7

  • Acalabrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, although the mechanism is not well understood.
    • The patient should be monitored for signs of bleeding.
    • The study excluded patients treated with a BTK or BCL-2 inhibitor and concomitant warfarin.
    • Consider the risk-benefit ratio of withholding acalabrutinib for 3–7 days pre- and postsurgery depending on the type of surgery and risk of bleeding.
  • Consider antiviral prophylaxis (entecavir and tenofovir are preferred agents) and monitor for infections due to hepatitis B virus (HBV) reactivation in high-risk patients.
    • Hepatitis B surface antigen (HBsAg)-positive
    • Prior HBV infection
    • Increasing HBV viral load in patients planned for allogeneic hematopoietic cell transplant or anti-CD20 or anti-CD52 monoclonal antibody therapy
  • If patient is HBsAg-positive or hepatitis B core antibody (HBcAb)-positive:
    • Use baseline quantitative polymerase chain reaction (PCR) for HBV DNA to determine viral load.
    • Administer prophylactic antiviral therapy or preemptive antivirals upon detection of increasing viral load.
  • During antitumor therapy
    • Monitor HBV viral load via PCR monthly, then every 3 months after treatment is completed.
    • Antiviral prophylaxis should be continued for up to 12 months after completion of antitumor therapy if viral load remains undetectable.
      • Monitoring of viral load and transaminases should be considered for patients without active HBV infection who are not receiving antiviral prophylaxis.
  • Consider antimicrobial prophylaxis in patients who are at increased risk for opportunistic infections.
    • Infections of grade 3 or higher
      • Acalabrutinib: 18%
      • Ibrutinib: 28%
  • Acalabrutinib temporarily increased lymphocyte counts in 31.5% of patients.
    • Lymphocytosis generally presents within 7 days of starting acalabrutinib and persists for 6–7 weeks.

References

  1. National Comprehensive Cancer Network. B-cell Lymphomas (Version 6.2017). https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf . Accessed November 15, 2017.
  2. Calquence (acalabrutinib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  3. Wang M, Rule S, Zinzani P, et al. Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase 2 ACE-LY-004 study. ASH Meeting Abstracts 2017: Abstract 155.
  4. Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 2015;126:739-745.
  5. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:4473-4479.
  6. Bernard S, Goldwirt L, Amorim S, et al. Activity with ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood 2015;126(14):1695-1698.
  7. National Comprehensive Cancer Network. Prevention and Treatment of Cancer-Related Infections. (Version 2.2017). https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf . Accessed November 23, 2017.
xs
sm
md
lg