Trastuzumab is a recombinant DNA-derived humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody and antineoplastic agent.1, 50, 51, 52, 53, 54, 55
Trastuzumab and hyaluronidase-oysk is a fixed combination of trastuzumab (a recombinant DNA-derived humanized anti-HER2 monoclonal antibody) and hyaluronidase (an endoglycosidase); the hyaluronidase component is used to increase the absorption of trastuzumab.56
Trastuzumab-anns (Kanjinti®), trastuzumab-dkst (Ogivri®), trastuzumab-dttb (Ontruzant®), trastuzumab-pkrb (Herzuma®), trastuzumab-qyyp (Trazimera®), and trastuzumab-strf (Hercessi®) are biosimilar to trastuzumab (Herceptin®).50, 51, 52, 53, 54, 55, 172 FDA defines a biosimilar as a biological product highly similar to an FDA-licensed reference biologic with the exception of minor differences in clinically inactive components, and for which there are no clinically meaningful differences in safety, purity, or potency.170, 171 The claim of biosimilarity is based on a totality-of-evidence approach, which includes consideration of data from analytical, animal, and clinical studies (e.g., human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity assessment, additional comparative clinical studies).171 Therefore, biosimilarity may be established even when there are formulation or minor structural differences as long as these differences are not clinically meaningful.171 Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between the proposed biologic and the reference biological, but does not independently establish safety and effectiveness of the proposed biosimilar biological.171 In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product; these requirements include demonstrating the biological product can be expected to produce the same clinical results as the reference product in any given patient and, for a biological product administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is no greater than the risk of using the reference product without such alteration or switch.169 Biosimilar products that are interchangeable can be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.169 None of the currently available trastuzumab biosimilars have interchangeable data at this time.172
Several trastuzumab biosimilars are available.50, 51, 52, 53, 54, 55 Biosimilarity of these products has been demonstrated for the indications described in Table 1.50, 51, 52, 53, 54, 55 Biosimilarity to originator trastuzumab is additionally supported by comparative clinical studies in patients with breast cancer (trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, and trastuzumab-strf).58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71
FDA-labeled Indication | Adjuvant Breast Cancer | Metastatic Breast Cancer | Gastric Cancer |
|---|---|---|---|
Trastuzumab-anns (Kanjinti®) | X | X | X |
Trastuzumab-dkst (Ogivri®) | X | X | X |
Trastuzumab-dttb (Ontruzant®) | X | X | X |
Trastuzumab-pkrb (Herzuma®) | X | X | X |
Trastuzumab-qyyp (Trazimera®) | X | X | X |
Trastuzumab-strf (Hercessi®) | X | X | X |
Trastuzumab, trastuzumab biosimilars, and trastuzumab/hyaluronidase-oysk are used for the adjuvant treatment of HER2-overexpressing node-positive or node-negative (estrogen receptor [ER]/progesterone receptor [PR] negative or with one high risk feature) breast cancer in adults; these products are used as single agents following multi-modality anthracycline-based therapy, as part of a treatment regimen with docetaxel and carboplatin, or as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel.1, 50, 51, 52, 53, 54, 55, 56
Trastuzumab, its biosimilars, and trastuzumab/hyaluronidase-oysk are also used in combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer in adults.1, 50, 51, 52, 53, 54, 55, 56
Trastuzumab, its biosimilars, and trastuzumab/hyaluronidase-oysk are also used as single agents for HER2-overexpressing breast cancer in adults who have received one or more chemotherapy regimens for metastatic disease.1, 50, 51, 52, 53, 54, 55, 56
Patients should be selected for treatment with trastuzumab, trastuzumab biosimilars, or trastuzumab/hyaluronidase-oysk based on an FDA-approved companion diagnostic test.1, 50, 51, 52, 53, 54, 55, 56
Adjuvant Therapy for Early-stage Breast Cancer
The current indication for trastuzumab as adjuvant therapy for HER2-overexpressing breast cancer is based on the results of 4 randomized controlled trials (NSABP B31, NCCTG N9831, HERA, and BCIRG006).1, 28, 29, 44, 72, 73, 74, 75
The NSABP B31 and NCCTG N9831 trials were randomized open-label trials.1 Patients were eligible for enrollment if they had operable breast cancer identified as HER2-positive with either 3+ HER2 overexpression according to the immunohistochemistry (IHC) assay or positive results for amplification of the HER2 gene according to the fluorescent in situ hybridization (FISH) assay.1, 28 HER2 testing was performed at a reference laboratory (NSABP B31) or HER2 test results were confirmed by a central laboratory prior to randomization (NCCTG N9831).1
In the NSABP B31 trial, 2043 women were randomly assigned to receive either doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with trastuzumab given concurrently with paclitaxel.28 In the NCCTG N9831 trial, 1633 of the 2766 patients enrolled were randomly assigned to receive either doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with trastuzumab given concurrently with paclitaxel.28 In both trials, for the comparison groups receiving trastuzumab given concurrently with paclitaxel, an initial dose of trastuzumab 4 mg/kg was administered with the first dose of paclitaxel, followed by trastuzumab 2 mg/kg once weekly for 51 weeks.1, 28 The same regimen of adjuvant chemotherapy with doxorubicin and cyclophosphamide was used in both trials (four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2), but the regimens for paclitaxel differed: 80 mg/m2 once weekly or 175 mg/m2 once every 3 weeks for a total of 12 weeks in NSABP B31 and 80 mg/m2 once weekly in NCCTG N9831.1, 28 When administered, radiation therapy was initiated following completion of chemotherapy.1 Patients with ER-positive and/or PR-positive tumors also received hormonal therapy.1
A total of 3752 patients were randomly assigned to treatment in the 2 trials prior to a planned interim analysis.1 Most patients in the NSABP B31 and NCCTG N9831 trials (91%) had node-positive disease.1, 28 Median age was 49 years (range: 22-80 years), and most were white (84%).1 Most patients had intermediate-grade (27%) or high-grade (66%) breast tumors, and 53% had hormone receptor-positive disease.1 In a combined analysis of data from patient groups from the 2 trials at a median follow-up of 2 years, disease-free survival at 3 years was prolonged (hazard ratio: 0.48, absolute disease-free survival rate: 87 versus 75%) in patients receiving trastuzumab in combination with standard adjuvant chemotherapy compared with those receiving standard adjuvant chemotherapy alone.1, 28 Subgroup analysis from the NCCTG N9831 trial exploring efficacy according to HER2 overexpression showed a strong effect on disease-free survival (hazard ratio: 0.42) for the addition of trastuzumab to adjuvant chemotherapy in patients with disease that was 3+ HER2-overexpressing and FISH-positive.1 Because of the small number of events in the other subgroups, it is not known whether adjuvant therapy including trastuzumab would benefit patients with breast tumors that are FISH-positive but lack 3+ HER2 overexpression.1 A final overall survival analysis (which included a total of 4063 patients from the 2 trials) was performed at a median follow-up of 8.3 years; in this analysis, survival was prolonged (hazard ratio: 0.64, absolute survival rate: 86.9% versus 79.4%) in patients receiving trastuzumab in combination with standard adjuvant chemotherapy compared with those receiving standard adjuvant chemotherapy alone.1, 72 Overall survival results were consistent across subgroups based on age, hormone receptor status, number of positive lymph nodes, tumor size/grade, and surgery/radiation therapy.1
Trastuzumab also was used as adjuvant therapy for operable HER2-positive breast cancer in a third multicenter randomized trial (HERA).1, 29 In the HERA trial, 5081 women received trastuzumab (1 or 2 years) or underwent observation following neoadjuvant and/or adjuvant chemotherapy for operable HER2-positive breast cancer.1, 29 Differing regimens of neoadjuvant and/or adjuvant chemotherapy (including both anthracyclines and taxanes in about 26% of patients) were followed by an initial dose of trastuzumab 8 mg/kg, then trastuzumab 6 mg/kg once every 3 weeks.29 Patients were eligible to enroll in HERA if they had breast cancer that was identified as HER2-positive with either 3+ HER2 overexpression according to the IHC assay or positive results for amplification of the HER2 gene according to the FISH assay as determined at a central laboratory.1 The median age was 49 years (range: 21-80 years); about one-third of the patients had node-negative breast cancer, and 50% had hormone receptor-negative tumors.1 Among the patients with node-negative disease, 96% had at least 1 high-risk feature (i.e., hormone receptor-negative disease, pathological tumor size >2 cm, tumor grade 2-3, age <35 years).1
At a median follow-up of 12.6 months among 3386 patients receiving either 1 year of trastuzumab therapy or observation, the rate of disease-free survival was prolonged in patients receiving trastuzumab (hazard ratio for an event: 0.54).1, 29 Overall survival was not substantially prolonged with 1 year of trastuzumab compared to observation at a median follow-up of 12.6 months.1 However, at a median follow-up of 2 years, prolonged survival was observed in patients receiving 1 year of trastuzumab therapy compared with observation (hazard ratio for death: 0.66, absolute difference in death rate at 3 years of 2.7 percentage points).44 At a median follow-up of 11 years, continued survival benefits were observed with 1 year of trastuzumab therapy versus observation (hazard ratio: 0.74).73 An analysis comparing 1 year and 2 years of trastuzumab treatment was performed with a median follow-up of 8 years; in this analysis, there was no additional benefit for 2 years of trastuzumab versus 1 year of trastuzumab in terms of disease-free survival or overall survival.1, 74
A fourth randomized, open-label trial (BCIRG006) enrolled 3222 patients with HER2-overexpressing breast cancer as determined by the presence of HER2 gene amplification according to the FISH assay.1, 75 FISH assays were conducted at a central laboratory.1 Patients with node-positive disease were eligible for enrollment; patients with node-negative disease were also eligible for enrollment if they had ≥1 high-risk feature (i.e., hormone receptor-negative disease, tumor size >2 cm, tumor grade 2-3, age <35 years).1 All patients underwent primary surgery for breast cancer prior to randomization.1 Patients were randomly assigned to receive doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab (AC-TH), or docetaxel and carboplatin plus trastuzumab (TCH).1, 75 In the AC-T and AC-TH groups, all patients received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles; this was followed by docetaxel 100 mg/m2 administered every 3 weeks for 4 cycles.1 In the AC-TH group, trastuzumab was administered concurrently with docetaxel at a dosage of 4 mg/kg initially, then 2 mg/kg weekly; after docetaxel therapy was complete, trastuzumab monotherapy was continued at a dosage of 6 mg/kg every 3 weeks for a total of 52 weeks.1 In the TCH group, patients received docetaxel 75 mg/m2 and carboplatin (target AUC of 6 mg/mL per minute) every 3 weeks for 6 cycles.1 Trastuzumab was administered at a dosage of 4 mg/kg initially, then 2 mg/kg weekly while the patient was receiving docetaxel and carboplatin; after docetaxel and carboplatin therapy was complete, trastuzumab monotherapy was continued at a dosage of 6 mg/kg every 3 weeks for a total of 52 weeks.1
The median age was 49 years (range: 22-74 years).1 Most patients (71%) had node-positive disease, and 54% had hormone receptor-positive disease.1 Disease-free survival was prolonged in the TCH group (hazard ratio: 0.67) and the AC-TH group (hazard ratio: 0.6) compared with the AC-T group.1 Overall survival was also improved with the trastuzumab-containing regimens compared to AC-T.75 Rates of disease-free survival and overall survival at 5 years were 75 and 87% in the AC-T group, 84 and 92% in the AC-TH group, and 81 and 91% in the TCH group.75
The current indication for trastuzumab/hyaluronidase-oysk as adjuvant therapy for HER2-overexpressing breast cancer is based on the results of 2 clinical studies with trastuzumab/hyaluronidase-oysk (HannaH and SafeHER) as well as data from clinical studies of IV trastuzumab.56, 76, 77, 78, 79
The HannaH study was a randomized, multicenter, open-label trial enrolling 596 patients with HER2-positive operable or locally advanced breast cancer.56, 76, 77 Patients were eligible for enrollment if they had either 3+ HER2 overexpression according to the IHC assay or positive results for amplification of the HER2 gene according to the in situ hybridization (ISH) assay.56, 76 Patients were randomized to receive 8 cycles of treatment with either trastuzumab/hyaluronidase-oysk or IV trastuzumab concurrently with chemotherapy (docetaxel 75 mg/m2 every 3 weeks for 4 cycles followed by 5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks for 4 cycles); this was followed by surgery and continued therapy with trastuzumab/hyaluronidase-oysk or IV trastuzumab (as treated prior to surgery) for an additional 10 cycles.56, 76 Trastuzumab/hyaluronidase-oysk was administered subcutaneously at a fixed dosage of 600 mg/10,000 units every 3 weeks, while IV trastuzumab was administered as an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks.76 The primary goal of the HannaH study was to establish noninferiority of trastuzumab/hyaluronidase-oysk to IV trastuzumab based on pharmacokinetic parameters and pathological complete response rates at the time of definitive surgery.56 Event-free survival and overall survival rates were also examined.56
Most patients enrolled were white (69%), and the median age was 50 years (range: 24-81 years).56 Pathological complete response rates were 45.4% among patients treated with trastuzumab/hyaluronidase-oysk and 40.7% among patients treated with IV trastuzumab.56, 76 At a median follow-up exceeding 70 months, no differences in event-free survival or overall survival were observed between patients who received IV trastuzumab and patients who received trastuzumab/hyaluronidase-oysk.56 Event-free survival rates at 6 years were 65% in both study groups, while 6-year overall survival rates were 84% in both groups.77
The SafeHER study was a nonrandomized, open-label study designed to assess safety and tolerability of trastuzumab/hyaluronidase-oysk with chemotherapy in 1864 patients with HER2-positive breast cancer.56, 78, 79 Efficacy was evaluated as a secondary objective.56 Patients were eligible for enrollment if they had either 3+ HER2 overexpression according to the IHC assay or positive results for amplification of the HER2 gene according to the ISH assay.56 Patients received trastuzumab/hyaluronidase-oysk 600 mg every 3 weeks for a total of 18 cycles throughout the study; trastuzumab/hyaluronidase-oysk was initiated either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination with neoadjuvant chemotherapy followed by trastuzumab.56
The majority were white (76%), and median age was 54 years (range: 20-88 years).56 In the intention-to-treat population of 1867 patients, 7% had a disease-free survival event (recurrence, contralateral invasive breast cancer, or death), and 1.5% had an overall survival event at the time of clinical cutoff.56
An additional randomized study (PrefHER) assessed treatment preferences among 240 patients with HER2-positive breast cancer undergoing neoadjuvant or adjuvant treatment; patients were randomized to receive 4 cycles of trastuzumab/hyaluronidase-oysk followed by 4 cycles of IV trastuzumab or 4 cycles of IV trastuzumab followed by 4 cycles of trastuzumab/hyaluronidase-oysk.56, 80, 81, 82 After cycle 8, the majority of patients (86%) stated that they preferred trastuzumab/hyaluronidase-oysk over IV trastuzumab; the most common reason for their preference was the reduced clinic administration time for trastuzumab/hyaluronidase-oysk.56 Only 13% of patients reported they preferred IV trastuzumab; the most common reason for preferring trastuzumab was the lower incidence of local injection reactions.56 Rates of event-free survival at 3 years were consistent with those observed in previous trials of adjuvant trastuzumab therapy.82
First-line Therapy for Advanced Breast Cancer
The current indication for trastuzumab in combination with paclitaxel for the initial treatment of metastatic breast cancer is based on data from a randomized, controlled, multicenter clinical trial (H0648g) involving 469 patients with 2+ or 3+ HER2 -overexpressing metastatic breast cancer.1, 3 Patients were randomized to receive combination therapy with trastuzumab (4 mg/kg IV initial dose followed by once-weekly doses of 2 mg/kg IV) and chemotherapy or chemotherapy alone.1, 3 For patients who had received prior adjuvant therapy with an anthracycline, chemotherapy consisted of paclitaxel 175 mg/m2 IV over 3 hours every 21 days for at least 6 cycles; for all other patients, chemotherapy consisted of an anthracycline (doxorubicin hydrochloride 60 mg/m2 or epirubicin hydrochloride 75 mg/m2 every 21 days) and cyclophosphamide (600 mg/m2 every 21 days) for 6 cycles.1
Longer time to disease progression (7.2 versus 4.5 months), higher overall response rate (45 versus 29%), longer median duration of response (8.3 versus 5.8 months), and longer median survival (25.1 versus 20.3 months) were reported in patients receiving trastuzumab in combination with chemotherapy compared with those receiving chemotherapy alone.1, 3 These treatment effects were observed in both patients who received trastuzumab plus paclitaxel and those who received trastuzumab plus an anthracycline and cyclophosphamide; however, the magnitude of effect was greater in the subgroup treated with paclitaxel.1, 3 The benefits of trastuzumab treatment were primarily observed in the subgroup of patients with the highest level of HER2 protein overexpression (3+).1, 3
The efficacy of trastuzumab/hyaluronidase-oysk administered subcutaneously for this indication was based on the previously summarized studies conducted with IV trastuzumab.56, 78, 79
Second-line or Salvage Therapy for Advanced Breast Cancer
The current indication for trastuzumab as monotherapy for metastatic breast cancer is based on data from a single-arm, open-label, multicenter clinical trial (H0649g) in 222 patients with 2+ or 3+ HER2-overexpressing metastatic breast cancer that relapsed following 1 or 2 previous chemotherapy regimens.1, 4 Among patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received 2 prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative therapy with hematopoietic rescue.1 About 72% had visceral disease (i.e., lung or liver metastases), and patients with only bone metastases, a characteristic that generally is associated with an indolent course of disease, were ineligible for enrollment in the trial.4
Patients received an initial dose of trastuzumab 4 mg/kg IV followed by once-weekly doses of 2 mg/kg IV; the overall response rate was 14% (2% complete responses, 12% partial responses), the median duration of response was 9 months, and median survival was 13 months.1, 4 Complete responses to trastuzumab were observed only in patients with metastatic breast disease limited to the skin and the lymph nodes.1 Response rates varied based on degree of HER2 overexpression, with an overall response rate of 18% in patients with 3+ overexpressing tumors versus 6% in those with 2+ overexpressing tumors.1, 4
The efficacy of trastuzumab/hyaluronidase-oysk administered subcutaneously for this indication was based on the previously summarized studies conducted with IV trastuzumab.56, 78, 79
In the 2020 American Society of Clinical Oncology (ASCO) guidelines on selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer, adjuvant trastuzumab is recommended for patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after receiving standard preoperative chemotherapy and HER2-targeted therapy.10060 Adjuvant trastuzumab is recommended in combination with chemotherapy for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer with tumors greater than 1 cm.10060 Trastuzumab may also be considered for patients with small, node-negative tumors (≤1 cm).10060 Trastuzumab may be administered with any acceptable adjuvant chemotherapy regimen (consult the guideline for additional details).10060 Because the risk for cardiotoxicity is increased when trastuzumab is administered concurrently with an anthracycline, it is not recommended to administer trastuzumab concurrently with anthracycline-based regimens.10060 Instead, trastuzumab should be preferentially administered concurrently with a non-anthracycline chemotherapy regimen.10060 For patients at increased risk of cardiotoxicity, a regimen of docetaxel-carboplatin-trastuzumab is recommended.10060 Patients should be offered a total of 1 year of adjuvant trastuzumab, with regular assessments of cardiac function during that period.10060 Any trastuzumab product (including biosimilars) or trastuzumab/hyaluronidase-oysk may be used for adjuvant therapy.10060
In the 2022 ASCO guidelines on systemic treatment for advanced HER2-positive breast cancer, first-line recommended treatment includes a combination of trastuzumab, pertuzumab, and a taxane.11000 Trastuzumab is recommended for second-line treatment of patients whose breast cancer progresses after initial HER2-targeted treatment.11000 Multiple potential treatment options are recommended for third-line treatment, including some trastuzumab-containing regimens.11000 Selection of an appropriate regimen should be made after discussing treatment schedules, routes of administration, and adverse effects with the patient.11000
Trastuzumab and its biosimilars are used in combination with cisplatin and capecitabine or 5-fluorouracil for adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.1, 50, 51, 52, 53, 54, 55 Trastuzumab has been designated an orphan drug by FDA for treatment of this cancer.57
Patients should be selected for treatment with trastuzumab or trastuzumab biosimilars based on an FDA-approved companion diagnostic test.1, 50, 51, 52, 53, 54, 55
The current indication for trastuzumab for gastric cancer is based on data from an open-label, multicenter trial (ToGA) enrolling 594 patients with previously untreated metastatic gastric or gastroesophageal junction adenocarcinoma.1, 83 All patients were either HER2 gene amplified (FISH-positive) or HER2-overexpressing (IHC 3+).1, 83 Patients were randomized to receive trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) or chemotherapy with cisplatin and a fluoropyrimidine alone.1, 83 Trastuzumab was administered as an IV infusion with an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression.1, 83 Cisplatin was administered at a dosage of 80 mg/m2 every 3 weeks for 6 cycles.1, 83 Fluoropyrimidine therapy was administered as capecitabine 1000 mg/m2 orally twice daily for 14 days of each 21-day cycle for 6 cycles or as a continuous infusion of 5-fluorouracil 800 mg/m2 per day on days 1-5 every 3 weeks for 6 cycles.1, 83 The primary outcome measure was overall survival.1, 83
Median age was 60 years (range: 21-83 years); 76% were male, 53% were Asian, 38% were white, 82% had primary gastric cancer, and 18% had primary gastroesophageal adenocarcinoma.1, 83 Most patients had not received previous neoadjuvant and/or adjuvant therapy or previous radiotherapy; 23% had undergone prior gastrectomy.1, 83 At the time of interim analysis, median overall survival was prolonged in the trastuzumab plus chemotherapy group (13.5 months versus 11 months); an updated overall survival analysis conducted 1 year after the interim analysis found similarly improved overall survival in the trastuzumab plus chemotherapy group (median 13.1 months versus 11.7 months).1, 83 In an exploratory subgroup analysis, the benefit of trastuzumab added to chemotherapy was most pronounced among patients with 3+ HER2 overexpression.1, 83
The 2023 ASCO guideline on immunotherapy and targeted therapy for advanced gastroesophageal cancer provides recommendations for HER2-positive gastric and gastroesophageal junction cancer.11001 The recommended first-line treatment for patients with previously untreated unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma is trastuzumab plus pembrolizumab, given in conjunction with fluoropyrimidine- and oxaliplatin-based chemotherapy.11001 This recommendation is based on the KEYNOTE-811 trial, which found a benefit with the addition of pembrolizumab to the traditional regimen of trastuzumab plus chemotherapy.11001 Of note, although this recommendation applies to all patients regardless of tumor proportion score (TPS) or combined positive score (CPS), most patients in the KEYNOTE-811 trial (87%) had a programmed death-ligand 1 (PD-L1) CPS ≥1.11001 In the trial, HER2 positivity was defined as immunohistochemistry (IHC) 3+ or in situ hybridization (IHC) 2+ with positive ISH.11001 Trastuzumab is recommended for HER2-positive patients who have progressed after first-line therapy.11001
Dispensing and Administration Precautions
Trastuzumab and biosimilars are administered by IV infusion only.1, 50, 51, 52, 53, 54, 55, 56 These products should not be administered by rapid IV injection, such as IV push or bolus, and should not be mixed with other medications.1, 50, 51, 52, 53, 54, 55, 56
Trastuzumab/hyaluronidase-oysk is administered by subcutaneous injection only and should not be administered IV.56
IV Administration (Trastuzumab and Biosimilars)
The initial dose of trastuzumab or biosimilars should be administered as an IV infusion over 90 minutes; if the first infusion is well tolerated, subsequent doses may be administered by IV infusion over 30 minutes.1, 50, 51, 52, 53, 54, 55
If a dose of trastuzumab or biosimilar is missed by 1 week or less, then the usual maintenance dose should be administered as soon as possible; do not wait until the next planned cycle.1, 50, 51, 52, 53, 54, 55 Subsequent maintenance doses should be administered 7 days or 21 days later, according to the weekly or once every 3-week schedules, respectively.1, 50, 51, 52, 53, 54, 55 If a dose of trastuzumab or biosimilar is missed by more than 1 week, a re-loading dose should be administered over 90 minutes as soon as possible.1, 50, 51, 52, 53, 54, 55 Subsequent maintenance doses should be administered 7 days or 21 days later, according to the weekly or once every 3-week schedules, respectively.1, 50, 51, 52, 53, 54, 55
Trastuzumab and biosimilars are supplied as lyophilized powders for injection and must be reconstituted and diluted prior to administration.1, 50, 51, 52, 53, 54, 55 Trastuzumab is supplied in single-dose vials containing 150 mg of trastuzumab powder for injection.1 Biosimilars are supplied in single-dose 150-mg vials and multiple-dose 420-mg vials.50, 51, 52, 53, 54, 55
Unopened vials of trastuzumab and biosimilars should be stored in the refrigerator at 2-8°C in the original carton until time of reconstitution.1, 50, 51, 52, 53, 54, 55 Vials of trastuzumab-strf should not be frozen or shaken.50 If needed, unopened vials of trastuzumab-qyyp may be stored at room temperature (up to 30°C) for a single period of up to 3 months in the original carton to protect from light; once removed from the refrigerator, vials should not be returned to refrigeration.55
Reconstitution and Dilution of Single-dose Vials
Reconstitute single-dose vials with 7.4 mL of sterile water for injection to yield a solution containing 21 mg/mL that delivers 7.15 mL (150 mg).1, 50, 51, 52, 53, 54, 55 Using a sterile syringe, slowly inject 7.4 mL of sterile water for injection into the vial of lyophilized powder; direct the stream of diluent onto the cake of powder.1, 50, 51, 52, 53, 54, 55 Swirl the vial gently to assist with reconstitution, but do not shake the vial.1, 50, 51, 52, 53, 54, 55 Slight foaming may occur upon reconstitution; allow the vial to stand undisturbed for approximately 5 minutes following reconstitution.1, 50, 51, 52, 53, 54, 55 The reconstituted solution should be free of visible particulates, clear to slightly opalescent, and colorless to pale yellow.1, 50, 51, 52, 53, 54, 55 The reconstituted solution should be used immediately following reconstitution, because it does not contain a preservative.1, 50, 51, 52, 53, 54, 55 If it is not used immediately, it may be stored for up to 24 hours at 2-8°C.1, 50, 51, 52, 53, 54, 55 Do not freeze the reconstituted solution.1, 50, 51, 52, 53, 54, 55 Reconstituted solutions of trastuzumab-strf should be protected from light.50
Reconstituted solutions must be further diluted prior to administration.1, 50, 51, 52, 53, 54, 55 Calculate the volume of the 21-mg/mL solution needed to obtain the required dose.1, 50, 51, 52, 53, 54, 55 Withdraw the calculated amount of solution from the vial and add to 250 mL of 0.9% sodium chloride injection.1, 50, 51, 52, 53, 54, 55 Do not use dextrose 5% solution.1, 50, 51, 52, 53, 54, 55 Use a bag made of either polyvinylchloride (for trastuzumab, trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, and trastuzumab-strf), polypropylene (for trastuzumab-qyyp and trastuzumab-strf), polyethylene (for trastuzumab, trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, and trastuzumab-qyyp), or ethylene vinyl acetate (for trastuzumab-qyyp).1, 50, 51, 52, 53, 54, 55 Glass IV bottles can be used for the preparation of trastuzumab-qyyp.55 Gently invert the container to mix the solution.1, 50, 51, 52, 53, 54, 55 Diluted solutions may be stored at 2-8°C for no more than 24 hours prior to use; storage time is additional to the time allowed for the reconstituted vials.1, 50, 51, 52, 53, 54, 55 Do not freeze the diluted solution.1, 50, 51, 52, 53, 54, 55 Diluted solutions of trastuzumab-strf may be stored at 30-35°C for no more than 6 hours.50
Reconstitution and Dilution of Multiple-dose Vials
Reconstitute multiple-dose vials with 20 mL of bacteriostatic water for injection containing 0.9-1.1% benzyl alcohol to yield a solution containing 21 mg/mL that delivers 20 mL (420 mg).50, 51, 52, 53, 54, 55 Depending on the specific presentation, a vial of bacteriostatic water for injection may or may not be supplied with the vial of lyophilized drug powder; use the supplied vial of diluent if present.50, 51, 52, 53, 54, 55 Alternatively, in patients with known hypersensitivity to benzyl alcohol, 20 mL of sterile water for injection may be used to reconstitute the multiple-dose vial and yield a single-use solution.50, 51, 52, 53, 54, 55 Using a sterile syringe, slowly inject 20 mL of diluent into the vial of lyophilized powder; direct the stream of diluent onto the cake of powder.50, 51, 52, 53, 54, 55 Swirl the vial gently to assist with reconstitution, but do not shake the vial.50, 51, 52, 53, 54, 55 Slight foaming of the product may occur upon reconstitution; allow the vial to stand undisturbed for approximately 5 minutes following reconstitution.50, 51, 52, 53, 54, 55 The reconstituted solution should be free of visible particulates, clear to slightly opalescent, and colorless to pale yellow.50, 51, 52, 53, 54, 55 If reconstituted with bacteriostatic water for injection, the reconstituted solution may be stored at 2-8°C for up to 28 days.50, 51, 52, 53, 54, 55 If reconstituted with sterile water for injection, the reconstituted solution should be used immediately following reconstitution, because it does not contain a preservative.50, 51, 52, 53, 54, 55 Do not freeze the reconstituted solution.50, 51, 52, 53, 54, 55
Reconstituted solutions must be further diluted prior to administration.50, 51, 52, 53, 54, 55 Calculate the volume of the 21-mg/mL solution needed to obtain the required dose.50, 51, 52, 53, 54, 55 Withdraw the calculated amount of solution from the vial and add to 250 mL of 0.9% sodium chloride injection.50, 51, 52, 53, 54, 55 Do not use dextrose 5% solution.50, 51, 52, 53, 54, 55 Use a bag made of either polyvinylchloride (for trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, and trastuzumab-strf), polyethylene (for trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, and trastuzumab-qyyp), polypropylene (for trastuzumab-qyyp and trastuzumab-strf), or ethylene vinyl acetate (for trastuzumab-qyyp).50, 51, 52, 53, 54, 55 Glass IV bottles can be used for the preparation of trastuzumab-qyyp.55 Gently invert the container to mix the solution.50, 51, 52, 53, 54, 55 The diluted solution may be stored at 2-8°C for no more than 24 hours prior to use; storage time is additional to the time allowed for the reconstituted vials.50, 51, 52, 53, 54, 55 Do not freeze the diluted solution.50, 51, 52, 53, 54, 55
Subcutaneous Administration (Trastuzumab/Hyaluronidase-oysk)
Trastuzumab/hyaluronidase-oysk is administered subcutaneously over approximately 2-5 minutes by a healthcare professional.56 If a dose is missed, the next dose should be administered as soon as possible; the interval between subsequent doses should not be less than 3 weeks.56
Trastuzumab/hyaluronidase-oysk is supplied in single-dose vials and does not require reconstitution prior to administration.56 Unopened vials should be stored at 2-8°C in the original carton to protect from light.56 Vials should not be shaken or frozen.56 Once removed from refrigeration, trastuzumab/hyaluronidase-oysk must be administered within 4 hours and should not be kept above 30°C.56
Prepare the dosing syringe in controlled and validated aseptic conditions.56 After the solution has been withdrawn from the vial and into the syringe, replace the transfer needle with a syringe closing cap.56 Label the syringe with the peel-off sticker.56 To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration, followed by volume adjustment to 5 mL.56 Trastuzumab/hyaluronidase-oysk is compatible with polypropylene and polycarbonate syringes as well as stainless steel transfer and injection needles.56 If the syringe containing trastuzumab/hyaluronidase-oysk is not used immediately, the syringe may be stored at 2-8°C for up to 24 hours and subsequently at room temperature (20-25°C) for up to 4 hours.56 Protect from light, and do not shake or freeze.56
Administer trastuzumab/hyaluronidase-oysk into the left and right thighs in an alternating manner.56 New injections should be given at least 2.5 cm from the previous site on healthy skin and never into skin that is red, bruised, tender, hard, or covered by moles or scars.56 Avoid injecting other medicinal products for subcutaneous injection into the same sites used for trastuzumab/hyaluronidase-oysk.56
Adjuvant Therapy for Early-stage Breast Cancer - IV Trastuzumab and Biosimilars
For adjuvant treatment of HER2-overexpressing node-positive or node-negative (estrogen receptor [ER]/progesterone receptor [PR] negative or with one high risk feature) breast cancer, the recommended dosage of IV trastuzumab or biosimilars (trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, and trastuzumab-strf) depends on the chemotherapy regimen used.1, 50, 51, 52, 53, 54, 55
When trastuzumab or biosimilars are given during and following paclitaxel, docetaxel, or docetaxel/carboplatin, the recommended dosage is 4 mg/kg IV initially, followed by 2 mg/kg IV once weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).1, 50, 51, 52, 53, 54, 55 Then, one week following the last weekly dose of trastuzumab or biosimilars, begin dosing trastuzumab or biosimilars at 6 mg/kg IV every 3 weeks for a total of 52 weeks of therapy.1, 50, 51, 52, 53, 54, 55
When trastuzumab or biosimilars are given as single agents within 3 weeks following completion of multimodality anthracycline-based chemotherapy regimens, the recommended dosage is 8 mg/kg IV initially, then 6 mg/kg every 3 weeks for a total of 52 weeks of therapy.1, 50, 51, 52, 53, 54, 55 Extending treatment beyond 1 year is not recommended.1, 50, 51, 52, 53, 54, 55
Adjuvant Therapy for Early-stage Breast Cancer - Trastuzumab and Hyaluronidase-oysk
For adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR negative or with one high risk feature) breast cancer, the recommended dosage of trastuzumab/hyaluronidase-oysk is 600 mg trastuzumab/10,000 units hyaluronidase administered subcutaneously every 3 weeks for 52 weeks or until disease recurrence (whichever occurs first).56 Extending treatment beyond 1 year is not recommended.56
Therapy for Advanced Breast Cancer - IV Trastuzumab and Biosimilars
When used for HER2-overexpressing metastatic breast cancer, either as monotherapy for treatment of disease that has relapsed following prior chemotherapy or in combination therapy with paclitaxel for initial treatment, the recommended dosage of IV trastuzumab or biosimilars (trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, and trastuzumab-strf) is 4 mg/kg IV initially, followed by once-weekly doses of 2 mg/kg IV.1, 50, 51, 52, 53, 54, 55 Therapy is administered until disease progression occurs.1, 50, 51, 52, 53, 54, 55
Therapy for Advanced Breast Cancer - Trastuzumab and Hyaluronidase-oysk
When used for HER2-overexpressing metastatic breast cancer, either as monotherapy for treatment of disease that has relapsed following prior chemotherapy or in combination with paclitaxel for initial treatment, the recommended dosage of trastuzumab/hyaluronidase-oysk is 600 mg trastuzumab/10,000 units hyaluronidase administered subcutaneously every 3 weeks until disease progression.56
Metastatic Gastric Cancer - IV Trastuzumab and Biosimilars
For metastatic gastric cancer, the recommended dosage of IV trastuzumab or biosimilars (trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, and trastuzumab-strf) is 8 mg/kg IV initially, followed by 6 mg/kg IV every 3 weeks until disease progression.1, 50, 51, 52, 53, 54, 55
Dosage Modification for Toxicity and Contraindications for Continued Therapy
Left ventricular function should be assessed before initiation of trastuzumab (or biosimilars) and trastuzumab/hyaluronidase-oysk; it should also be monitored frequently during therapy.1, 50, 51, 52, 53, 54, 55, 56 If left ventricular ejection fraction decreases by ≥16 percentage points from the baseline value, or if left ventricular ejection fraction decreases by ≥10 percentage points from the baseline value to a value that is below the lower limit of normal, treatment should be discontinued for 4 weeks.1, 50, 51, 52, 53, 54, 55, 56 After 4 weeks, cardiac function should be reassessed; if there are no clinical manifestations of cardiotoxicity, left ventricular ejection fraction returns to normal limits, and the absolute decrease in left ventricular ejection fraction from baseline is ≤15 percentage points, therapy can be resumed.1, 50, 51, 52, 53, 54, 55, 56 If left ventricular ejection fraction decline is persistent (greater than 8 weeks), or if therapy has been interrupted on more than 3 occasions for cardiomyopathy, therapy should be discontinued permanently.1, 50, 51, 52, 53, 54, 55, 56
The safety of continuing or restarting treatment in patients who have developed trastuzumab-induced left ventricular cardiac dysfunction has not been fully evaluated.1, 56
Infusion Reactions and Pulmonary Toxicity (IV Trastuzumab and Biosimilars)
Infusion of IV trastuzumab (or biosimilars) should be interrupted in all patients experiencing dyspnea or clinically important hypotension, and appropriate medical therapy, which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen, should be instituted.1, 50, 51, 52, 53, 54, 55 Patients should be evaluated and monitored carefully until signs and symptoms have resolved completely.1 Permanent discontinuance of therapy should be strongly considered in all patients experiencing severe or life-threatening infusion reactions.1, 50, 51, 52, 53, 54, 55 Discontinuance of treatment is recommended in patients with infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome (ARDS).1 For mild or moderate infusion reactions, the rate of infusion may be slowed.1, 50, 51, 52, 53, 54, 55
The most appropriate method for identifying patients who may safely receive additional infusions following a severe infusion-related reaction to the medication has not been determined.1 Following complete recovery from a severe infusion-related reaction, some patients have tolerated subsequent infusions, typically accompanied by prophylactic treatment including antihistamines and/or corticosteroids, but others have experienced severe reactions to additional infusions despite the use of premedication.1
Hypersensitivity and Administration-related Reactions (Trastuzumab and Hyaluronidase-oysk)
Trastuzumab/hyaluronidase-oysk should be permanently discontinued in patients who experience anaphylaxis or severe hypersensitivity reactions, as well as patients who experience angioedema, interstitial pneumonitis, or ARDS.56 For patients who experience reversible grade 1 or 2 hypersensitivity reactions, premedicate with an analgesic, antipyretic, and/or antihistamine prior to subsequent infusions.56
The manufacturers make no specific dosage recommendations for patients with hepatic impairment.1, 56
The manufacturers make no specific dosage recommendations for patients with renal impairment.1, 56
The manufacturers make no specific dosage recommendations for geriatric patients.1, 56
A boxed warning about the risk of cardiomyopathy is included in the prescribing information for trastuzumab, biosimilars, and trastuzumab/hyaluronidase-oysk.1, 56 Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death.1, 56 It may also cause asymptomatic decreases in left ventricular ejection fraction.1, 56 Patients receiving trastuzumab have a 4-6 fold increased risk of symptomatic myocardial dysfunction compared with those not receiving trastuzumab.1, 56 Symptomatic myocardial dysfunction can occur in patients receiving trastuzumab as a single agent or in combination with other agents; the highest absolute incidence is observed among patients receiving trastuzumab with an anthracycline.1, 56
In the NSABP B31 trial, 15% of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in left ventricular ejection fraction after a median follow-up duration of 8.7 years.1 In the HERA trial, 2.6% of patients discontinued trastuzumab due to cardiac toxicity at a median follow-up duration of 12.6 months.1 In the BCIRG006 trial, discontinuations due to cardiac toxicity occurred in 2.9% of patients receiving docetaxel and carboplatin plus trastuzumab (TCH) and 5.7% receiving doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab (AC-TH).1 The incidence of grade 3/4 cardiac ischemia/infarction was higher among patients receiving AC-TH (0.3%) and TCH (0.2%) compared with patients receiving a regimen that did not contain trastuzumab (0%).1
Congestive heart failure (CHF) was reported in 3.2% of patients receiving trastuzumab in the NSABP B31 and NCCTG N9831 trials, 2% of patients receiving trastuzumab in the HERA trial, and 2 and 0.4% receiving AC-TH and TCH, respectively, in the BCIRG006 trial.1 Among the 64 patients in the NSABP B31 and NCCTG N9831 trials who developed CHF, 1 patient died of cardiomyopathy, 1 patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up.1 Approximately 24% of surviving patients had recovery to left ventricular ejection fraction ≥50% and no symptoms on continuing medical management at the time of last follow-up.1 In the HERA trial, at a median follow-up duration of 8 years, severe CHF (New York Heart Association [NYHA] class III or IV) was reported in 0.8% of patients, and mild symptomatic or asymptomatic left ventricular dysfunction was reported in 4.6%.1
In patients with metastatic breast cancer, cardiac dysfunction (defined as CHF or significant asymptomatic decrease in left ventricular ejection fraction) was reported in 28% of patients who received trastuzumab plus anthracycline/cyclophosphamide chemotherapy in the H0648g trial, 11% who received trastuzumab plus paclitaxel in the H0648g trial, and 7% who received trastuzumab in the H0649g trial.1 Rates of NYHA class III or IV CHF were 19, 4, and 5%, respectively.1
In the HannaH study, the rate of cardiac disorders was similar between trastuzumab/hyaluronidase-oysk and trastuzumab (15 versus 14%, respectively).56 The most frequent cardiac adverse reactions in the trastuzumab/hyaluronidase-oysk and trastuzumab arms were left ventricular dysfunction (3.4 and 4%), tachycardia (2 and 3%), and palpitations (2 and 1.3%).56 Cardiac failure and CHF occurred in 1% of patients receiving trastuzumab/hyaluronidase-oysk and <1% of patients receiving trastuzumab.56 The proportion of patients with a significant decrease in left ventricular ejection fraction (defined as a drop ≥10 percentage points to a left ventricular ejection fraction <50%) was similar in the trastuzumab/hyaluronidase-oysk and trastuzumab groups (3.8 and 4.2% ).56 The fixed dosage of trastuzumab/hyaluronidase-oysk was not associated with an increased risk of cardiac events or significant drop in left ventricular ejection fraction in patients with lower body weights (<59 kg).56
In the SafeHER trial, 17% of patients receiving trastuzumab/hyaluronidase-oysk reported a cardiac disorder during treatment.56 Decreased ejection fraction was the most frequent cardiac disorder, reported in 4.5%.56 During the treatment period, CHF was reported in <1% of patients, and cardiac failure was reported in <1% of patients.56 One patient reported CHF during the follow-up period.56 A left ventricular ejection fraction <50% with a decrease of ≥10 percentage points from baseline was noted in 6% of patients treated with trastuzumab/hyaluronidase-oysk.56
Thorough cardiac assessment, including history, physical examination, and determination of left ventricular ejection fraction by echocardiogram or multigated acquisition (MUGA) scan, should be performed prior to and during trastuzumab or trastuzumab/hyaluronidase-oysk therapy.1, 56 The manufacturer recommends measuring left ventricular ejection fraction at baseline (immediately prior to treatment initiation), every 3 months during treatment, and upon completion of therapy.1, 56 Left ventricular ejection fraction should be assessed every 6 months for at least 2 years after completion of trastuzumab or trastuzumab/hyaluronidase-oysk as a component of adjuvant therapy.1, 56
Trastuzumab and trastuzumab/hyaluronidase-oysk should be withheld in patients who experience a ≥16% absolute decrease in left ventricular ejection fraction from baseline.1, 56 They should also be withheld in patients with a left ventricular ejection fraction below institutional limits of normal and a ≥10% absolute decrease from baseline.1, 56 If trastuzumab or trastuzumab/hyaluronidase-oysk is withheld for significant left ventricular cardiac dysfunction, left ventricular ejection fraction should be reassessed at 4-week intervals.1, 56 The safety of continuing or resuming trastuzumab or trastuzumab/hyaluronidase-oysk in patients with trastuzumab-induced left ventricular cardiac dysfunction has not been studied.1, 56 Receipt of anthracyclines after stopping trastuzumab or trastuzumab/hyaluronidase-oysk may also increase the risk of cardiac dysfunction.1, 56
A boxed warning about the risk of infusion reactions is included in the prescribing information for trastuzumab.1 Infusion reactions are characterized by fever and chills and, on occasion, other symptoms (e.g., nausea, vomiting, pain [including pain at tumor sites], headache, dizziness, dyspnea, hypotension, rash, and asthenia).1 Serious and fatal infusion reactions have been reported in the post-marketing setting.1 Severe reactions (e.g., bronchospasm, anaphylaxis, angioedema, hypoxia, severe hypotension) are usually reported during or immediately following the initial infusion; however, onset and clinical course may vary.1 Progressive worsening, initial improvement followed by clinical deterioration, and delayed post-infusion events with rapid clinical deterioration have been observed.1 Deaths have been reported within hours to days following a serious infusion reaction.1
Trastuzumab infusions should be interrupted in all patients experiencing dyspnea or clinically significant hypotension, and appropriate medical therapy should be administered (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen).1 Monitor patients carefully until signs and symptoms have completely resolved.1 Permanent discontinuation of trastuzumab should be strongly considered in all patients who experience severe infusion reactions.1 The most appropriate method of identifying patients who may be safely retreated with trastuzumab after a severe infusion reaction has not been established.1 Before resuming trastuzumab, the majority of patients who experienced a severe infusion reaction were premedicated with antihistamines and/or corticosteroids.1 Some of these patients were able to tolerate subsequent trastuzumab infusions, while others had recurrent severe infusion reactions despite premedication.1
Fetal/Neonatal Morbidity and Mortality
A boxed warning about the risk of embryofetal toxicity is included in the prescribing information for trastuzumab and trastuzumab/hyaluronidase-oysk.1, 56 Trastuzumab and trastuzumab/hyaluronidase-oysk can cause fetal harm if administered to a pregnant females.1, 56 In post-marketing reports, use of trastuzumab during pregnancy has been associated with cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.1, 56
Verify the pregnancy status of females of reproductive potential prior to initiating trastuzumab or trastuzumab/hyaluronidase-oysk therapy.1, 56 Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose.1, 56 If either product is administered during pregnancy, or if a patient becomes pregnant during or within 7 months following the last dose of trastuzumab or trastuzumab/hyaluronidase-oysk, healthcare providers and patients should immediately report the exposure to the manufacturer (Genentech) at 1-888-835-2555.1, 56
A boxed warning about the risk of pulmonary toxicity is included in the prescribing information for trastuzumab and trastuzumab/hyaluronidase-oysk.1, 56 Pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome (ARDS), and pulmonary fibrosis, has been reported.1, 56 In some cases, pulmonary toxicity may be serious or fatal.1, 56 Pulmonary toxicity may occur as part of an infusion reaction.1 Toxicity may be more severe in patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest.1, 56
Exacerbation of Chemotherapy-induced Neutropenia
Trastuzumab and trastuzumab/hyaluronidase-oysk may exacerbate chemotherapy-induced neutropenia.1, 56 In randomized controlled trials, the per-patient incidences of grade 3 or 4 neutropenia and febrile neutropenia were higher among patients receiving IV trastuzumab in combination with myelosuppressive chemotherapy than among patients receiving chemotherapy alone.1, 56 Rates of septic death were not increased among patients receiving trastuzumab compared with those not receiving trastuzumab.1, 56
Hypersensitivity and Administration-related Reactions
Severe administration-related reactions, including hypersensitivity and anaphylaxis, have been reported with trastuzumab/hyaluronidase-oysk.56 In clinical trials, 9 and 4.2% of patients receiving trastuzumab/hyaluronidase-oysk experienced hypersensitivity and anaphylaxis, respectively.56 Grade 3 or 4 hypersensitivity and anaphylactic reactions occurred in 1 and <1% of patients, respectively.56 In one trial, 2 patients required permanent discontinuation of therapy as a result of a severe hypersensitivity reaction.56 Serious and fatal reactions have been reported with IV trastuzumab products.56
Closely monitor patients for systemic hypersensitivity reactions, especially when trastuzumab/hyaluronidase-oysk is first administered.56 Patients with dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or fatal administration-related reaction.56 Medications and emergency equipment for severe administration-related reactions should be available for immediate use.56 Permanently discontinue trastuzumab/hyaluronidase-oysk in patients who experience anaphylaxis or severe hypersensitivity reactions.56 For patients experiencing reversible grade 1 or 2 hypersensitivity reactions, premedicate with an analgesic, antipyretic, and/or antihistamine prior to readministration of trastuzumab/hyaluronidase-oysk.56
Among 903 females with metastatic breast cancer who were tested for human anti-human antibodies (HAHA) to trastuzumab, anti-trastuzumab antibodies were detected in 1 patient.1 This patient did not experience an allergic reaction.1 Samples for the assessment of HAHA were not collected in studies of trastuzumab in adjuvant breast cancer patients.1 The clinical relevance of anti-trastuzumab antibodies is not known.1
In a clinical trial of IV trastuzumab and trastuzumab/hyaluronidase-oysk, the incidence of treatment-induced/enhanced anti-trastuzumab antibodies at a median follow-up exceeding 60 months was 10% in patients treated with IV trastuzumab and 16% in patients treated with trastuzumab/hyaluronidase-oysk.56 Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 patients in the IV trastuzumab group and 3 patients in the trastuzumab/hyaluronidase-oysk group.56 The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 21% among patients treated with trastuzumab/hyaluronidase-oysk.56 None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies.56 The clinical relevance of anti-trastuzumab or anti-recombinant human hyaluronidase antibodies in patients treated with trastuzumab/hyaluronidase-oysk is not known.56
Trastuzumab and trastuzumab/hyaluronidase-oysk may cause fetal harm if administered to a pregnant females.1, 56 In post-marketing reports and published literature, use of trastuzumab during pregnancy has been associated with cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.1, 56 In these case reports, oligohydramnios occurred in pregnant females who received trastuzumab either alone or in combination with chemotherapy.1, 56 In most cases, amniotic fluid index increased after trastuzumab was stopped.1, 56 In cases where trastuzumab was resumed after amniotic index improved, oligohydramnios recurred.1, 56
Verify the pregnancy status of females of reproductive potential prior to initiating trastuzumab or trastuzumab/hyaluronidase-oysk.1, 56 Apprise patients of the potential risks to a fetus.1, 56 If either product is administered during pregnancy, or if a patient becomes pregnant during or within 7 months following the last dose of trastuzumab or trastuzumab/hyaluronidase-oysk, healthcare providers and patients should immediately report the exposure to the manufacturer's pregnancy pharmacovigilance program at 1-888-835-2555.1, 56 Monitor females who received trastuzumab or trastuzumab/hyaluronidase-oysk during pregnancy or within the 7 months prior to conception for oligohydramnios; if oligohydramnios occurs, perform fetal/neonatal testing as appropriate for gestational age and consistent with community standards of care.1, 56
Studies in Cynomolgus monkeys have shown that trastuzumab crosses the placenta during the early (gestation days 20-50) and late (gestation days 120-150) phases of gestation.1 Trastuzumab concentrations in fetal serum and amniotic fluid were approximately 33 and 25%, respectively, of those present in maternal serum but were not associated with adverse developmental effects.1 No evidence of teratogenicity was observed when subcutaneous recombinant human hyaluronidase was administered to pregnant mice during the period of organogenesis at doses >7,200 times the human dose.56
There are no data regarding the presence of trastuzumab or hyaluronidase in human milk, the effects on the breast-fed infant, or effects on milk production.1, 56 Data suggest human immunoglobulin G (IgG) is present in human milk but does not enter neonatal or infant circulation in substantial amounts.1, 56 Trastuzumab is present in the milk of Cynomolgus monkeys but not associated with neonatal toxicity.1, 56
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for trastuzumab or trastuzumab/hyaluronidase-oysk and any potential adverse effects on the breast-fed child from the medication or from the underlying maternal condition.1, 56 This consideration should also take into account the 7-month washout period for trastuzumab and trastuzumab/hyaluronidase-oysk.1, 56
Females and Males of Reproductive Potential
Trastuzumab and trastuzumab/hyaluronidase-oysk may cause fetal harm if administered to a pregnant females.1, 56 Verify the pregnancy status of females of reproductive potential prior to initiating therapy.1, 56 Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose.1, 56
The safety and efficacy of trastuzumab and trastuzumab/hyaluronidase-oysk have not been established in pediatric patients.1, 56
In clinical trials, trastuzumab was administered to 386 patients with breast cancer who were ≥65 years of age (253 patients in the adjuvant treatment setting and 133 patients in the metastatic treatment setting).1 In studies of trastuzumab/hyaluronidase-oysk, 19% of patients were ≥65 years of age, and 4.7% were ≥75 years of age.56
The risk of cardiac dysfunction is increased in geriatric patients compared with younger patients;1, 56 however, limitations in data collection and differences in study design preclude a determination of whether the toxicity profile of trastuzumab in older patients is different from that observed in younger patients.1 Other differences in safety or efficacy were not observed between older patients and younger patients.56
In a clinical trial of trastuzumab in patients with metastatic gastric cancer, 108 patients (37%) were ≥65 years of age and 13 patients (4.4%) were ≥75 years of age.1 No overall differences in safety and efficacy were observed in older patients compared with younger patients.1
No pharmacokinetic studies have been conducted in patients with hepatic impairment.1, 56
No significant differences in trastuzumab pharmacokinetics were observed in patients with mild (creatinine clearance [Clcr] 60-90 mL/minute) or moderate (Clcr 30-60 mL/minute) renal impairment.1 The pharmacokinetics of trastuzumab in patients with severe renal impairment or end-stage renal disease (with or without hemodialysis) have not been studied.1 The pharmacokinetics of trastuzumab/hyaluronidase-oysk have not been specifically studied in patients with renal impairment.56
In patients receiving trastuzumab for adjuvant treatment of breast cancer, the most common adverse reactions (≥5%) were headache, diarrhea, nausea, and chills.1
In patients receiving trastuzumab/hyaluronidase-oysk for adjuvant treatment of breast cancer, the most common adverse reactions (≥10%) were fatigue, arthralgia, diarrhea, injection site reaction, upper respiratory tract infection, rash, myalgia, nausea, headache, edema, flushing, pyrexia, cough, and pain in extremity.56
In patients receiving trastuzumab for metastatic breast cancer, the most common adverse reactions (≥10%) were fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash.1
In patients receiving trastuzumab for metastatic gastric cancer, the most common adverse reactions (≥10%) were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infection, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.1
Anthracycline Antineoplastic Agents
The risk of trastuzumab-induced cardiotoxic effects is increased in patients receiving an anthracycline concomitantly.1 Patients who receive an anthracycline after stopping trastuzumab or trastuzumab/hyaluronidase-oysk may be at increased risk of cardiac dysfunction because of the long washout period for trastuzumab and trastuzumab/hyaluronidase-oysk; the manufacturers recommend avoiding anthracycline-based therapy for up to 7 months after stopping trastuzumab or trastuzumab/hyaluronidase-oysk.1, 56 If anthracyclines are used, closely monitor the patient's cardiac function.1, 56
Concentrations of doxorubicin and its major metabolite doxorubicinol were not altered in the presence of trastuzumab when used as combination therapy in clinical trials; trastuzumab concentrations were also not altered as part of this combination therapy.1
The pharmacokinetics of capecitabine and its metabolites were not altered when administered in combination with trastuzumab.1
The plasma concentrations of carboplatin and trastuzumab were not altered when administered in combination.1
The pharmacokinetics of cisplatin and its metabolites were not altered when administered in combination with trastuzumab.1
Plasma concentrations of docetaxel and trastuzumab were not altered when administered in combination.1
Plasma concentrations of paclitaxel and its major metabolite, 6-alpha hydroxyl-paclitaxel, were not altered when administered in combination with trastuzumab in clinical trials; trastuzumab concentrations were also not altered when administered in combination.1
Trastuzumab, a recombinant DNA-derived humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is an antineoplastic agent.1 Trastuzumab inhibits proliferation of tumor cells that overexpress HER2.1 The HER2 proto-oncogene (also known as c-erbB2 or neu) encodes a 185-kd transmembrane tyrosine kinase receptor known as p185HER2 or HER2, which is structurally related to the epidermal growth factor receptor.1 Trastuzumab, a recombinant humanized murine monoclonal antibody, binds specifically to the extracellular domain of the HER2 receptor or HER2/neu protein.1 Results from in vitro assays and animal studies have shown trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2/neu protein.1, 7 Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) also has been demonstrated and, according to in vitro studies, occurs preferentially in cells that overexpress the HER2 protein compared with cells that do not.1
Hyaluronidase, a component of trastuzumab/hyaluronidase-oysk, is a recombinant human endoglycosidase used to increase the dispersion and absorption of co-administered medications when administered subcutaneously.56 Hyaluronidase depolymerizes hyaluronan, a polysaccharide found in the extracellular matrix of subcutaneous tissue; this leads to increased permeability of subcutaneous tissues.56 Hyaluronidase acts transiently and locally; effects are reversible, and permeability of the subcutaneous tissue is restored within 24-48 hours.56 Hyaluronidase was shown to increase absorption rate of a trastuzumab product in animal studies.56
Trastuzumab is eliminated via parallel linear and non-linear elimination pathways; as a result, total trastuzumab clearance increases with decreasing concentrations.1 Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the every-3-week schedule compared to the weekly schedule of IV trastuzumab, the average steady-state exposure was essentially the same at both dosages.1 The average trastuzumab exposure following the first cycle at steady state, as well as the time to steady state, was higher in breast cancer patients compared with metastatic gastric cancer patients at the same dosa the reason for this difference is unclear.1 Time to steady state with IV trastuzumab administration was approximately 12 weeks in breast cancer patients and 9 weeks in patients with metastatic gastric cancer.1 Following discontinuation of IV trastuzumab, trastuzumab concentrations will decrease to approximately 3% of the population predicted steady-state trough serum concentration (97% washout) by 7 months in most patients.1 Pharmacokinetics of IV trastuzumab are not significantly affected by age or race (Asian versus non-Asian evaluated in studies).1
Trastuzumab exposure following subcutaneous administration of trastuzumab/hyaluronidase-oysk 600 mg/10,000 units every 3 weeks is comparable to that observed with a regimen of IV trastuzumab 8 mg/kg (loading dose) followed by 6 mg/kg every 3 weeks.56 In a pharmacokinetic study comparing trastuzumab/hyaluronidase-oysk to IV trastuzumab, the mean maximum plasma concentration of trastuzumab was 32% lower with trastuzumab/hyaluronidase-oysk, and the mean AUC following the cycle 7 dose and cycle 12 dose was approximately 10 and 20% higher, respectively.56 Following subcutaneous administration of trastuzumab/hyaluronidase-oysk, trastuzumab concentrations reached steady state after the cycle 7 dose, with a <15% increase in concentration up to cycle 13.56 The absolute bioavailability of subcutaneous trastuzumab/hyaluronidase-oysk is 77%, and the time to maximum concentration is 3 days.56 Trastuzumab is estimated to reach concentrations <1 mcg/mL by 7 months after discontinuation in the majority of patients.56 In patients with body weight 50 kg and under, the mean steady state AUC of trastuzumab was approximately 80% higher with trastuzumab/hyaluronidase-oysk than with IV trastuzumab; in patients with body weight >90 kg, the AUC was approximately 20% lower with trastuzumab/hyaluronidase-oysk than with IV trastuzumab.56 However, the manufacturer of trastuzumab/hyaluronidase-oysk does not recommend any dosage adjustments based on body weight at this time, as these changes in drug exposure are not thought to be clinically relevant.56
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 150 mg | Kanjinti® | Amgen |
420 mg | Kanjinti® | Amgen |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 150 mg | Ogivri® | Biocon Biologics |
420 mg | Ogivri® (supplied with or without 20 mL bacteriostatic water for injection containing 1.1% benzyl alcohol) | Biocon Biologics |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 150 mg | Ontruzant® | Organon |
420 mg | Ontruzant® (supplied with or without 20 mL bacteriostatic water for injection containing 1.1% benzyl alcohol) | Organon |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 150 mg | Herzuma® | Teva Pharmaceuticals |
420 mg | Herzuma® (supplied with 20 mL bacteriostatic water for injection containing 1.1% benzyl alcohol) | Teva Pharmaceuticals |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 150 mg | Trazimera® | Pfizer |
420 mg | Trazimera® (supplied with 20 mL bacteriostatic water for injection containing 1.1% benzyl alcohol) | Pfizer |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 150 mg | Hercessi® | Accord BioPharma |
420 mg | Hercessi® | Accord BioPharma |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for subcutaneous use only | Trastuzumab 600 mg and hyaluronidase 10,000 units/5 mL (120 mg/2000 units/mL) | Herceptin Hylecta® | Genentech |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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