Trastuzumab

Article Author:
Karl Greenblatt
Article Editor:
Karam Khaddour
Updated:
7/14/2020 12:02:24 AM
For CME on this topic:
Trastuzumab CME
PubMed Link:
Trastuzumab

Indications

Trastuzumab is a biologic antineoplastic agent that, at the time of its FDA approval in 1998, was among the first available “targeted” chemotherapies. In the United States, it is licensed for the treatment of the following:

  • HER2-positive breast cancer: adjuvant therapy - Approved for combination use with anthracycline- or taxane-based chemotherapy. The maximum recommended duration of adjuvant treatment is 1 year.
  • Metastatic HER2-positive breast cancer - Approved as monotherapy or for combination use with paclitaxel.
  • HER2-positive gastric cancer - Used in combination with cisplatin-based chemotherapy. Compared with chemotherapy alone, trastuzumab plus chemotherapy modestly improved survival (median 13.8 months vs. 11.1 months).[1]

Trastuzumab has reported efficacy for the off-label neoadjuvant treatment of HER2-positive breast cancer.[2] For the treatment of metastatic breast cancer, trastuzumab has also been used in combination with lapatinib,[3] anastrozole,[4] cyclophosphamide,[2] pertuzumab,[2] [5] and several other agents.

Mechanism of Action

Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). Trastuzumab binds to an extracellular domain of this receptor and inhibits HER2 homodimerization, thereby preventing HER2-mediated signaling. It is also thought to facilitate antibody-dependent cellular cytotoxicity, leading to the death of cells that express HER2.[6] Its mechanism differs slightly from that of the newer agent pertuzumab; the latter inhibits hetero-dimerization of HER2 with HER3, a related growth factor receptor. 

In the U.S., a biosimilar molecule is commercially available (trastuzumab-dkst). The product ado-trastuzumab emtansine is an antibody-drug conjugate consisting of trastuzumab and emtansine, an anti-microtubule cytotoxic agent.

Administration

Trastuzumab is administered as an intravenous infusion over 30 to 90 minutes. It should not be administered as a bolus and should not be administered together with D5W. Per the National Institute for Occupational Safety and Health (NIOSH) guidelines, due to trastuzumab’s status as a potentially hazardous drug, double-gloves, a gown, and closed-system transfer devices are required during administration. The recommended maintenance dose is 2 mg/kg infused weekly or 6 mg/kg infused once every 3 weeks. Initial loading doses up to 8 mg/kg may be administered. No dose adjustment is recommended for patients with mild to moderate renal insufficiency; trastuzumab has not been studied in patients with hepatic impairment or end-stage renal disease. The estimated elimination half-life of trastuzumab is 28 days;[7] a higher tumor burden may increase the elimination half-life.[8] Interpatient variability in drug clearance rates is considerable; increased body weight and decreased serum albumin have been associated with increased clearance.[9]

Adverse Effects

Trastuzumab is known to cause cardiotoxicity, usually manifested as a decrease in left-ventricular ejection fraction (LVEF). The exact pathogenesis of this event is unknown but may involve decreased clearance of reactive oxygen species in cardiac myocytes.[10] In the U.S., trastuzumab carries a black box warning regarding subclinical and clinical cardiac failure. According to the product label, a decrease in LVEF of at least 10% has been observed in up to 22% of patients, although some studies have reported an incidence as high as 44%.[11] Symptomatic congestive heart failure during treatment is less common, with an estimated incidence of 2% to 7%. The major risk factor for the development of cardiotoxicity is concurrent treatment with anthracyclines; the risk of severe cardiotoxicity is three to four times higher in patients receiving both trastuzumab and anthracyclines.[12] Increased age, hypertension, coronary artery disease, and hyperlipidemia may also contribute to increased risk. In clinical practice, most cases of trastuzumab-induced cardiotoxicity appear to be reversible upon discontinuation of treatment.[13][14] In some patients, however, long-term echocardiographic evidence of myocardial dysfunction persists.[15]

Severe infusion reactions have been observed upon administration of trastuzumab. These may include angioedema, anaphylaxis, interstitial pneumonitis, and acute respiratory distress syndrome. Trastuzumab also carries a black box warning to this effect. Most severe events have occurred within 24 hours of the initial infusion. All patients should be monitored for significant dyspnea, hypotension, or signs of angioedema; trastuzumab should be discontinued if these are observed. Some, but not all, patients have tolerated re-treatment after pre-medication (e.g., with acetaminophen and/or diphenhydramine).

Rare cases of nephrotic syndrome have been associated with trastuzumab, with the greatest incidence in patients with metastatic gastric cancer.

Other adverse effects commonly reported with trastuzumab monotherapy include:

  • Headache
  • Chills
  • Gastrointestinal symptoms (nausea and vomiting; abdominal pain, diarrhea)
  • Cough 
  • Back pain      
  • Upper respiratory symptoms (rhinitis, pharyngitis)
  • Weakness and fatigue

Contraindications

  • Pregnancy: Trastuzumab is believed to be a human teratogen. Fetal exposure has been associated with the development of oligohydramnios, leading to pulmonary hypoplasia and death. Patients of childbearing potential should use at least one form of contraception while receiving trastuzumab. It is unknown if trastuzumab is secreted in human breast milk.
  • Cardiac Dysfunction: Due to the risk of cardiotoxicity, trastuzumab should be used with extreme caution in patients with pre-existing structural heart disease.

Monitoring

Routine echocardiographic assessment is universally recommended before initiating trastuzumab treatment. Cardiac risk factors such as hypertension and smoking should also be optimized. The role of screening echocardiography for asymptomatic patients during treatment is uncertain. A reasonable, guideline-based alternative is to obtain echocardiography at baseline, at the conclusion of treatment, and 6 to 12 months following treatment.[16] In clinical practice, asymptomatic patients receiving anthracyclines or with baseline cardiac risk factors often undergo echocardiography frequently as every 2 to 3 months. Patients with metastatic disease receiving indefinite therapy may also undergo routine echocardiography.[17] Symptomatic patients should receive immediate echocardiography, cardiac biomarker testing, and referral to a cardiologist. Trastuzumab should be discontinued if LVEF is less than 50% and is decreased by more than 10% from baseline, or if LVEF is decreased by more than 16% from baseline. In select cases, trastuzumab may be restarted if there is documented recovery of LVEF.

When trastuzumab is combined with paclitaxel, increased serum concentration of trastuzumab has been observed. Serum paclitaxel concentrations may also be decreased in the presence of trastuzumab.[18] The mechanism and clinical significance of these interactions are unknown.

When added to cytotoxic chemotherapy, trastuzumab may further increase the risk of neutropenia, infections, and anemia. Trastuzumab should not be used in combination with belimumab due to an increased risk of neutropenia and infection.

Enhancing Healthcare Team Outcomes

Trastuzumab is a biologic agent primarily used in the treatment of HER2-positive breast cancer. It may be used as adjuvant therapy for localized disease or as first-line therapy for metastatic disease. The development of trastuzumab has significantly increased survival associated with HER2-positive breast cancer; notably, trastuzumab also carries considerable historical importance as one of the first “targeted” chemotherapeutic agents developed. It is typically given in combination with one or more cytotoxic agents, most commonly anthracyclines (e.g., doxorubicin) and taxanes (e.g., paclitaxel). Trastuzumab has also demonstrated efficacy in the treatment of HER2-positive metastatic gastric cancer. The most significant adverse event associated with trastuzumab is cardiotoxicity; this is usually mild and reversible with discontinuation, but it may progress to irreversible, clinically significant cardiac failure. The risk of cardiotoxicity is highest in patients receiving concomitant anthracycline therapy. All patients should receive a baseline echocardiogram before initiating therapy and must be monitored closely for the development of palpitations, dyspnea, chest pain, and/or peripheral edema. Certain patients may benefit from more frequent echocardiographic assessment. Immediate discontinuation of trastuzumab is warranted if a decreased LVEF is discovered. Clinicians and clinical staff must also be aware of the potential for serious infusion reactions, especially following the initial dose. Trastuzumab is likely a human teratogen; it should be avoided in patients who are pregnant, and patients of childbearing potential must use contraception during treatment.


References

[1] Bang YJ,Van Cutsem E,Feyereislova A,Chung HC,Shen L,Sawaki A,Lordick F,Ohtsu A,Omuro Y,Satoh T,Aprile G,Kulikov E,Hill J,Lehle M,Rüschoff J,Kang YK, Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (London, England). 2010 Aug 28     [PubMed PMID: 20728210]
[2] Gianni L,Pienkowski T,Im YH,Roman L,Tseng LM,Liu MC,Lluch A,Staroslawska E,de la Haba-Rodriguez J,Im SA,Pedrini JL,Poirier B,Morandi P,Semiglazov V,Srimuninnimit V,Bianchi G,Szado T,Ratnayake J,Ross G,Valagussa P, Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The Lancet. Oncology. 2012 Jan     [PubMed PMID: 22153890]
[3] de Azambuja E,Holmes AP,Piccart-Gebhart M,Holmes E,Di Cosimo S,Swaby RF,Untch M,Jackisch C,Lang I,Smith I,Boyle F,Xu B,Barrios CH,Perez EA,Azim HA Jr,Kim SB,Kuemmel S,Huang CS,Vuylsteke P,Hsieh RK,Gorbunova V,Eniu A,Dreosti L,Tavartkiladze N,Gelber RD,Eidtmann H,Baselga J, Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. The Lancet. Oncology. 2014 Sep     [PubMed PMID: 25130998]
[4] Kaufman B,Mackey JR,Clemens MR,Bapsy PP,Vaid A,Wardley A,Tjulandin S,Jahn M,Lehle M,Feyereislova A,Révil C,Jones A, Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Nov 20     [PubMed PMID: 19786670]
[5] Swain SM,Ewer MS,Viale G,Delaloge S,Ferrero JM,Verrill M,Colomer R,Vieira C,Werner TL,Douthwaite H,Bradley D,Waldron-Lynch M,Kiermaier A,Eng-Wong J,Dang C, Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Annals of oncology : official journal of the European Society for Medical Oncology. 2018 Mar 1     [PubMed PMID: 29253081]
[6] Namboodiri AM,Pandey JP, Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes. Clinical and experimental immunology. 2011 Dec     [PubMed PMID: 22059994]
[7] Bruno R,Washington CB,Lu JF,Lieberman G,Banken L,Klein P, Population pharmacokinetics of trastuzumab in patients with HER2 metastatic breast cancer. Cancer chemotherapy and pharmacology. 2005 Oct     [PubMed PMID: 15868146]
[8] Bernadou G,Campone M,Merlin JL,Gouilleux-Gruart V,Bachelot T,Lokiec F,Rezai K,Arnedos M,Diéras V,Jimenez M,Paintaud G,Ternant D, Influence of tumour burden on trastuzumab pharmacokinetics in HER2 positive non-metastatic breast cancer. British journal of clinical pharmacology. 2016 May     [PubMed PMID: 26714164]
[9] Cosson VF,Ng VW,Lehle M,Lum BL, Population pharmacokinetics and exposure-response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer. Cancer chemotherapy and pharmacology. 2014 Apr     [PubMed PMID: 24519752]
[10] Mohan N,Shen Y,Endo Y,ElZarrad MK,Wu WJ, Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes. Molecular cancer therapeutics. 2016 Jun     [PubMed PMID: 27197303]
[11] Farolfi A,Melegari E,Aquilina M,Scarpi E,Ibrahim T,Maltoni R,Sarti S,Cecconetto L,Pietri E,Ferrario C,Fedeli A,Faedi M,Nanni O,Frassineti GL,Amadori D,Rocca A, Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart (British Cardiac Society). 2013 May     [PubMed PMID: 23349345]
[12] Mantarro S,Rossi M,Bonifazi M,D'Amico R,Blandizzi C,La Vecchia C,Negri E,Moja L, Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer. Internal and emergency medicine. 2016 Feb     [PubMed PMID: 26712595]
[13] Hamirani Y,Fanous I,Kramer CM,Wong A,Salerno M,Dillon P, Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study. Medical oncology (Northwood, London, England). 2016 Jul     [PubMed PMID: 27334792]
[14] de Azambuja E,Procter MJ,van Veldhuisen DJ,Agbor-Tarh D,Metzger-Filho O,Steinseifer J,Untch M,Smith IE,Gianni L,Baselga J,Jackisch C,Cameron DA,Bell R,Leyland-Jones B,Dowsett M,Gelber RD,Piccart-Gebhart MJ,Suter TM, Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Jul 10     [PubMed PMID: 24912899]
[15] Tan TC,Bouras S,Sawaya H,Sebag IA,Cohen V,Picard MH,Passeri J,Kuter I,Scherrer-Crosbie M, Time Trends of Left Ventricular Ejection Fraction and Myocardial Deformation Indices in a Cohort of Women with Breast Cancer Treated with Anthracyclines, Taxanes, and Trastuzumab. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2015 May     [PubMed PMID: 25772019]
[16] Plana JC,Galderisi M,Barac A,Ewer MS,Ky B,Scherrer-Crosbie M,Ganame J,Sebag IA,Agler DA,Badano LP,Banchs J,Cardinale D,Carver J,Cerqueira M,DeCara JM,Edvardsen T,Flamm SD,Force T,Griffin BP,Jerusalem G,Liu JE,Magalhães A,Marwick T,Sanchez LY,Sicari R,Villarraga HR,Lancellotti P, Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2014 Sep     [PubMed PMID: 25172399]
[17] Davis CC,Zelnak A,Eley JW,Goldstein DA,Switchenko JM,McKibbin T, Clinical Utility of Routine Cardiac Monitoring in Breast Cancer Patients Receiving Trastuzumab. The Annals of pharmacotherapy. 2016 Sep     [PubMed PMID: 27307412]
[18] Furtlehner A,Schueller J,Jarisch I,Ostermann E,Czejka M, Disposition of paclitaxel (Taxol) and its metabolites in patients with advanced breast cancer (ABC) when combined with trastuzumab (Hercpetin). European journal of drug metabolism and pharmacokinetics. 2005 Jul-Sep     [PubMed PMID: 16250250]