Pertuzumab, Trastuzumab, and Docetaxel for HER2-Positive Breast Cancer

Abstract

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases.

Indication(s)

The pertuzumab, trastuzumab, and docetaxel regimen (see Table 1 ) has been studied in neoadjuvant treatment of patients with HER2-positive early stage, locally advanced, metastatic, and inflammatory breast cancer.^1,2 Current guidelines include pertuzumab, trastuzumab, and docetaxel as one of the recommended regimens for neoadjuvant or adjuvant therapy of HER2-positive breast cancer and as one of the preferred first-line regimens for HER2-positive metastatic breast cancer. ³

Table 1.

Docetaxel, trastuzumab, and pertuzumab^1,2

Drug	Dose	Route of administration	Administered on day(s)	Total dose/cycle
Pertuzumab	420 mg a	IV	1	420 mg
Trastuzumab	6 mg/kg b	IV	1	6 mg/kg
Docetaxel	75 to 100 mg/m2	IV	1	75 to 100 mg/m2

Cycle repeats every 3 weeks.

^a Cycle 1, day 1 only 840 mg.

^b Cycle 1, day 1 only 8 mg/kg.

Note: IV = intravenous.

Regimen name:	Pertuzumab, Trastuzumab, and Docetaxel
Synonym:	None
Origin of name:	The regimen is named for the 3 medications in the regimen.

Drug Preparation

Follow institutional policies for preparation of hazardous medications when preparing pertuzumab, trastuzumab, and docetaxel.

• A.
  Pertuzumab

  • 1.
    Use pertuzumab injection, 30 mg/mL.
  • 2.
    Dilute in 0.9% sodium chloride (NS). The manufacturer recommends using 250 mL. ⁴
  • 3.
    Pertuzumab is reported to be incompatible with dextrose solutions. ⁴
  • 4.
    Diluted solutions may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours. ⁴
• B.
  Trastuzumab

  • 1.
    Use trastuzumab powder for injection.
  • 2.
    Reconstitute with bacteriostatic water for injection (BSWI) to a concentration of 21 mg/mL.
  • 3.
    Dilute in NS. The manufacturer recommends using 250 mL. ⁵
  • 4.
    Trastuzumab is reported to be incompatible with dextrose solutions. ⁵
  • 5.
    Diluted solutions should be used within 24 hours.
  • 6.
    Partially used vials may be stored under refrigeration 2°C to 8°C (36°F to 46°F) for up to 28 days.
  • 7.
    Pertuzumab and trastuzumab are reported to be stable when mixed in the same container for infusion. ⁶
• C.
  Docetaxel

  • 1.
    Use docetaxel injection 10 mg/mL or 20 mg/mL. If vials are stored refrigerated, allow the vials to stand at room temperature for 5 minutes. ⁷
  • 2.
    Dilute in NS or 5% dextrose injection (D5W) to a final concentration of 0.3 to 0.74 mg/mL. The manufacturer recommends using 250 mL of NS or D5W unless dose of docetaxel is greater than 200 mg, in which case a larger bag should be used. ⁷
  • 3.
    Docetaxel should be prepared and dispensed in non–polyvinyl chloride (PVC) containers.
  • 4.
    Solutions for infusion are stable for 6 hours if stored between 2°C to 25°C (36°F to 77°F) and for 48 hours if stored between 2°C to 8°C (36°F to 46°F). ⁷

Drug Administration

• A.Pertuzumab: Infuse pertuzumab over 60 minutes for the initial dose, then as a 30- to 60-minute infusion for the maintenance doses.
• B.Trastuzumab: Infuse trastuzumab over 30 to 90 minutes.
• C.Pertuzumab and trastuzumab may be mixed in the same container, and infused simultaneously over 60 to 90 minutes. ⁶
• D.Docetaxel: Infuse over 60 minutes through a non-PVC (low-sorbing) infusion set. ⁷

Supportive Care

• A.
  Acute and Delayed Emesis Prophylaxis: The regimen is predicted to cause acute emesis in 10% to 30% of patients.^7,8 The studies reviewed reported nausea in 38% to 42% of patients,^1,2 with no reported cases of grade 3 or 4 nausea^1,2 and no reported cases of vomiting.^1,2 Prophylactic antiemetic therapy with one of the following regimens is suggested^8,9:

  • 1.
    Serotonin (5HT-3) antagonists (choose one):

    • a.
      Ondansetron 8 to 16 mg orally (PO) 30 minutes before day 1 of regimen,
    • b.
      Granisetron 1 or 2 mg PO 30 minutes before day 1 of regimen,
    • c.
      Dolasetron 100 mg PO 30 minutes before day 1 of regimen, or
  • 2.
    Dexamethasone 12 mg PO 30 minutes before day 1 of regimen, or
  • 3.
    Metoclopramide 10 to 40 mg PO/IV, then every 4 to 6 hours as needed, or
  • 4.
    Prochlorperazine 10 mg PO/IV, then every 6 hours as needed with a maximum dose of 40 mg/day.
• B.
  Breakthrough Nausea and Vomiting: If breakthrough nausea or vomiting occurs, patients should receive an antiemetic agent from a different class than the current therapy^8,9:

  • 1.
    Metoclopramide 0.5 to 2 mg/kg PO every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 6 hours if needed.
  • 2.
    Prochlorperazine 10 mg PO every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 6 hours if needed.
  • 3.
    Prochlorperazine 25 mg rectally every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours if needed.
  • 4.
    Promethazine 25 to 50 mg PO every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours if needed.
• C.Hypersensitivity Precautions and Reduction of Incidence in Fluid Retention: The manufacturer of docetaxel recommends oral dexamethasone 8 mg twice daily for 3 days, beginning the day before docetaxel administration to reduce the severity of hypersensitivity and the incidence of fluid retention. ⁷

  Some clinicians administer a histamine₂ antagonist ± a histamine1 antagonist in addition to the steroid. If additional prophylaxis against hypersensitivity is chosen, the following regimen is suggested: (1) famotidine 20 mg or ranitidine 50 mg and (2) diphenhydramine 50 mg, both given intravenously over 30 minutes prior to docetaxel.

• D.Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic analysis suggest that an antineoplastic regimen have a greater than 20% incidence of febrile neutropenia before prophylactic use of colony-stimulating factors (CSFs) is warranted. For regimens with an incidence of febrile neutropenia between 10% and 20%, use of CSFs should be considered. For regimens with an incidence of febrile neutropenia less than 10%, routine prophylactic use of CSFs is not recommended. ¹⁰

  From the studies reviewed, neutropenia was reported in 50% to 53%^1,2 of patients. Grade 3 or higher neutropenia was reported in 45% to 49%^1,2 of patients, and grade 3 or higher febrile neutropenia in 8% to 14%^1,2 of patients. Prophylactic use of CSFs should be considered with the regimen. CSFs may also be considered if a patient experiences febrile neutropenia or grade 4 neutropenia in a prior cycle of the regimen.

Major Toxicities

Most of the toxicities listed below are presented according to their degree of severity. Higher grades represent more severe toxicities. Although there are several grading systems for cancer chemotherapy toxicities, all are similar. One of the frequently used systems is the National Cancer Institution Common Terminology Criteria for Adverse Events. ¹¹ Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities; but they make, or consider, dosage reductions or therapy changes for grade 3 or 4 toxicities. Incidence values are rounded to the nearest whole percent unless incidence was less than or equal to 0.5%.

• A.Cardiovascular: Left ventricular dysfunction (grade 3 or higher) 1%, ¹ (all grades) 4% ¹ ; peripheral edema (all grades) 23%. ¹
• B.Dermatologic: Alopecia (all grades) 61% to 64%^1,2; dry skin (all grades) 11% ¹ ; rash (grade 3 and 4) 2%, ² (all grades) 26% to 34%.^1,2
• C.Gastrointestinal: Constipation (all grades) 15% ¹ ; diarrhea (grades 3 and 4) 6% to 8%,^1,2 (all grades) 46%^1,2; mucositis (all grades) 26% to 28%^1,2; nausea (all grades) 38% to 42%.^1,2
• D.Hematologic: Anemia (grade 3 or 4) 3% ¹ ; febrile neutropenia (grade 3 or 4) 8% to 14%, (all grades)^1,2; leukopenia (grades 3 and 4) 5% to 12%^1,2; neutropenia (all grades) 50% to 53%,^1,2 (grades 3 and 4) 45% to 49%^1,2; granulocytopenia (grade 3 or 4) 1% to 2%.^1,2
• F.Infections: Neutropenic infection 1%. ³
• G.Metabolic: Fatigue (grades 3 and 4) 2%, ¹ (all grades) 26% to 38%.^1,2
• H.Musculoskeletal: Myalgia (all grades) 22%. ²
• I.Neurologic: Asthenia (all grades) 21% to 26%,^1,2 (grades 3 and 4) 2% to 3%^1,2; headache (all grades) 11% ² ; peripheral neuropathy (grade 3 and 4) 3%. ¹
• J.Pulmonary: Dyspnea (grade 3 or 4) 1%. ¹
• K.Treatment-Related Death: Fulminant hepatitis 1%. ¹

Pretreatment Laboratory Studies Needed

• A.
  Baseline

  • 1.
    Aspartate aminotransferase/alanine amino-transferase (AST/ALT)
  • 2.
    Total bilirubin
  • 3.
    Serum creatinine
  • 4.
    Complete blood cell count (CBC) with differential
  • 5.
    Left ventricular ejection fraction (LVEF)
• B.Prior to each treatment: CBC with differential.
• C.
  Recommended pretreatment values: The minimally acceptable pretreatment CBC values required to begin a cycle with full-dose therapy in the protocols reviewed were:

  • 1.
    Absolute neutrophil count (ANC):

    • a.
      Greater than or equal to 1,500 cells/mcL. ¹
    • b.
      In clinical practice, a pretreatment ANC of 1,000 cells/mcL is usually considered acceptable.
  • 2.
    AST/ALT, less than or equal to 2.5 times the ULN. ¹
  • 3.
    AST/ALT plus alkaline phosphatase, less than or equal to 1.5 times the ULN if alkaline phosphatase levels were greater than 2.5 times the UNL, unless bone metastases was present ¹
  • 4.
    Bilirubin, within normal limits, unless patient has documented Gilbert's Syndrome. ¹
  • 5.
    Creatinine, less than or equal to 2 mg/dL. ¹
  • 6.
    East cooperative oncology group (ECOG) performance status, 0 or 1.^1,2
  • 7.
    Hemoglobin, greater than or equal to 9 g/dL. ¹
  • 8.
    LVEF:

    • a.
      Greater than or equal to 50%. ¹
    • b.
      Greater than 55%. ²
  • 9.
    Platelet count:

    • a.
      Greater than or equal to 100,000 cells/ mcL.^1,3
    • b.
      In clinical practice, a pretreatment platelet level of 75,000 cells/mcL is usually considered acceptable.

Dosage Modifications

• A.
  Renal Function

  • 1.
    Pertuzumab:

    • a.
      Dosage adjustments are not needed with mild or moderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min). ⁴
    • b.
      No dosage recommendations in severe renal impairment (CrCl < 30 mL/min). ⁴
  • 2.
    Trastuzumab:

    • a.
      Dosage adjustments are not needed with mild or moderate renal impairment (CrCl ≥ 30 mL/min). ⁵
    • b.
      No dosage recommendations in severe renal impairment (CrCl < 30 mL/min). ⁵
  • 3.
    Docetaxel: No adjustment is required. ⁷
• B.
  Liver Function

  • 1.
    Pertuzumab: No information is available. ⁴
  • 2.
    Trastuzumab: No information is available. ⁵
  • 3.
    Docetaxel:

    • a.
      If the bilirubin is greater than the ULN and the ALT/AST are greater than 1.5 times the ULN or the alkaline phosphatase is greater than 2.5 times the ULN, do not give the drug. ⁷
    • b.
      If the ALT/AST are:

      • (1)
        Greater than 1.6 times the ULN and less than or equal to 6 times the ULN, reduce dose 25%. ¹²
      • (2)
        Greater than 6 times the ULN, use clinical judgement. ¹²
      • (3)
        Greater than or equal to 2 times the ULN and less than or equal to 3 times the ULN, reduce dose 50%. ¹³
• C.
  Myelosuppression

  • 1.
    Docetaxel:

    • a.
      Febrile neutropenia or neutrophils less than 500 cells/mcL for more than 1 week, wait for neutrophil count 1,500 cells/mcL or greater, then reduce docetaxel dose by 25%. ⁷
    • b.
      Platelet count less than100,000 cells/mcL, wait for a platelet count 100,000 cells/mcL or greater, then reduce docetaxel dose by 25%. ⁷