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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.  

December 20, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125409s113s118lbl.pdf

On December 20, 2017, the Food and Drug Administration granted regular approval to pertuzumab (PERJETA®, Genentech, Inc.) for use in combination with trastuzumab and chemotherapy as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

Approval was based on data from APHINITY (NCT01358877), a multicenter, randomized, double-blind, placebo-controlled trial in 4804 patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization. Patients were then randomized to receive pertuzumab or placebo, in combination with adjuvant trastuzumab and chemotherapy. The main efficacy outcome was invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.

After a median follow-up of 45.4 months, the proportion of IDFS events in the intent-to-treat population was 7.1% (n=171) in the pertuzumab arm and 8.7% (n=210) for those receiving placebo (HR 0.82; 95% CI: 0.67, 1.00; p=0.047). High-risk patients included patients such as those with hormone receptor negative or those with node positive breast cancer. The proportion of IDFS events in patients with hormone receptor negative disease was 8.2% (n=71) and 10.6% (n=91) in the pertuzumab and placebo arms, respectively (HR 0.76, 95% CI 0.56, 1.04). The proportion of IDFS events for patients with node positive disease was 9.2% (n=139) and 12.1% (n=181) in the pertuzumab and placebo arms, respectively (HR 0.77, 95% CI 0.62, 0.96). Overall survival data are not yet mature.

Adverse reactions reported in at least 30% of patients receiving pertuzumab in combination with trastuzumab and chemotherapy in APHINITY were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. The most common grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell count decreased, leukopenia, fatigue, nausea, and stomatitis.

The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125409s113s118lbl.pdf

In 2012, FDA granted regular approved to pertuzumab for use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

FDA granted accelerated approval to pertuzumab in 2013 as neoadjuvant treatment. With this latest adjuvant approval, the accelerated approval post-marketing requirement is fulfilled and regular approval is granted to pertuzumab for use in combination with trastuzumab and chemotherapy as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

FDA granted priority review to pertuzumab for this application. 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

Pertuzumab for Adjuvant Treatment of Human Epidermal Growth Factor Receptor-2 (HER2)–Positive Early-Stage Breast Cancer

Author: Jennifer de los Angeles, PharmD BCOP
Clinical Oncology Pharmacist
Stephenson Cancer Center, University of Oklahoma
Oklahoma City, OK

What is the potential role for adjuvant pertuzumab (Perjeta) in the treatment of HER2-positive early-stage breast cancer?

  • HER2 gene amplification and protein overexpression are demonstrated in approximately 15%–20% of all breast cancer (BC) cases.1 Gene amplification and protein overexpression are often associated with a worse prognosis. Therefore, the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend determination of HER2 status for all newly diagnosed invasive BCs and at time of recurrence.1,2 Prior evidence has shown that adding trastuzumab to adjuvant chemotherapy has improved outcomes and survival for patients with HER2-positive BC.1
  • Trastuzumab was the first monoclonal antibody approved for treatment for HER2-positive BC. This approval was based on evidence showing significant disease-free survival (DFS) prolongation and reduction in recurrence for those who received chemotherapy and trastuzumab compared to chemotherapy alone.3 Following the approval of trastuzumab, pertuzumab was developed as an additional monoclonal antibody for treatment of HER2-positive BC. Pertuzumab binds to a portion of the HER2 protein epitope different from the one that trastuzumab binds to, preventing dimerization. Binding of both trastuzumab and pertuzumab provides more complete inhibition of HER2 signaling pathways.
  • Pertuzumab was initially approved in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic BC who have not received prior anti-HER2 therapy or chemotherapy.4 Pertuzumab’s indication was then broadened for use in combination with trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2-positive, locally advanced inflammatory, or early-stage BC (lesion greater than 2 cm in diameter or node positive).4 Most recently, the pertuzumab indication was further broadened to include adjuvant treatment of patients with HER2-positive early BC at high risk of recurrence.4
  • Pertuzumab was approved for adjuvant treatment in early BC following the results of the APHINITY trial. The APHINITY trial assigned patients with HER2-positive early BC to receive either pertuzumab or placebo in addition to standard adjuvant chemotherapy (see below) followed by 1 year of trastuzumab treatment.5
    • Standard chemotherapy regimens included these three: 3-4 cycles of 5-fluorouracil + epirubicin or doxorubicin + cyclophosphamide followed by 3-4 cycles of docetaxel or 12 cycles of weekly paclitaxel; 4 cycles of cyclophosphamide + doxorubicin or epirubicin followed by 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; 6 cycles of docetaxel + carboplatin.
    • The 3-year rate of invasive-DFS was found to be slightly improved in the pertuzumab group, compared to the placebo group (94.1% vs. 93.2%, respectively; p = .045).5
    • Significant results were found in the node-positive cohort, where 3-year invasive-DFS was found to favor the pertuzumab group compared to the placebo group (92% vs. 90.2%; p = .02).5 However, patients with node-negative disease were not found to have any difference in 3-year invasive-DFS when pertuzumab was compared to placebo.5  
    • Hormone receptor positivity/negativity cohorts also did not show a significant difference in 3-year invasive-DFS.5
    • Of note, eligibility included patients with node-positive HER2 BC with a tumor diameter greater than 1 cm. Patients with node-negative HER2 BC were initially enrolled if tumor diameter was between 0.5 and 1 cm and if the patient had at least one high-risk feature (histologic grade 3, estrogen/progesterone negativity, age less than 35 years). However, enrollment of patients with node-negative disease was stopped early because of the initial trial design in order to ensure that the patient population had nodal-status distribution.5

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

  • Pharmacists should ensure that patients receive a loading dose of 840 mg with cycle 1 of administration and that all subsequent doses are reduced to 420 mg.4
  • Prior to administration, pharmacists may ensure that appropriate cardiac function tests are performed and that the patient’s left ventricular ejection fraction (LVEF) is appropriate for treatment (greater than or equal to 50% for metastatic BC and greater than or equal to 55% for early BC).4
    • Ensure that these tests are performed approximately every 12 weeks.
    • Withhold pertuzumab and trastuzumab if LVEF falls below desired levels (less than 40% or 40%–45% with a fall of 10% points or greater below pretreatment value for metastatic BC or less than 50% with a fall 10% points or greater below pretreatment value for early BC).4
  • Prior to administration, female patients should have a negative pregnancy test, because pertuzumab can cause embryo-fetal mortality and birth defects.4
  • Pertuzumab and trastuzumab in combination are minimally emetogenic and will likely not require anti-emetics.
    • Appropriate anti-emetic regimens should be selected when combined with adjuvant chemotherapy.
  • Pharmacists should counsel patients on the adverse effects of pertuzumab, including diarrhea (all grades, 46%–67%). Pharmacists should provide patients with treatment options if diarrhea becomes problematic.
  • Pharmacists should also educate patients on the possibility of fatigue (26%–38%), skin rash (11%–34%), headache (11%–21%), and infusion-related reactions or hypersensitivity reactions (5% in the APHINITY trial).4
  • Patient assistance can be found through Genentech at https://www.genentech-access.com/hcp/brands/perjeta.html.

Clinical Pearls

  • Patients treated with pertuzumab must have HER2-positive BC.
    • HER2 determination is initially performed by immunohistochemistry (IHC) and measured HER2 protein expression.
      • The degree of staining is correlated with a scale of 0–3+.
      •  0 and 1+ results are interpreted as negative.
      • 2+ results are referred to as equivocal.
        • Any equivocal result should be validated through fluorescent in-situ hybridization (FISH) testing.1
      • 3+ results are interpreted as positive.
  • Pertuzumab is FDA-approved for treating early-stage BC in patients who are at high risk for recurrence. Risk factors discussed included nodal involvement, age less than 35 years, histological grade 3, and negative hormone receptor status.5
  • On the basis of the APHINITY trial, pertuzumab shows benefit in patients with node-positive disease. However, pertuzumab’s use in patients with early-stage node-negative disease may need further investigation, given the lack of benefit observed in node-negative patients in the APHINITY trial.

References

  1. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline update. J Clin Oncol. 2013;31(31):3997-4013.
  2. National Comprehensive Cancer Network. Breast Cancer Version 4.2017. Accessed February 27, 2018.
  3. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-3752.
  4. Perjeta [package insert]. December 2017. South San Francisco, CA: Genentech, Inc.
  5. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122-131.
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