Pertuzumab, a recombinant humanized anti-human epidermal growth factor receptor type 2 (anti-HER2/ERBB2) monoclonal antibody, is an antineoplastic agent.1, 2, 8, 13, 16
Pertuzumab is used in combination with trastuzumab and docetaxel for the treatment of human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer in patients who have not received prior anti- HER2 therapy or chemotherapy for metastatic disease.1
The current indication for pertuzumab in the treatment of metastatic breast cancer is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (CLEOPATRA) in adults with HER2-positive metastatic breast cancer.1, 2 Patients were eligible for enrollment in the study if they had disease demonstrating an immunohistochemistry (IHC) assay score of 3+ or a fluorescent in situ hybridization (FISH) amplification ratio of 2 or higher.1 In addition, patients with prior adjuvant or neoadjuvant chemotherapy were required to have a disease-free interval of more than 12 months before diagnosis of metastatic breast cancer and enrollment into the study;1 patients may have received one prior hormonal treatment for metastatic disease before study enrollment.2
In this study, 808 patients were randomized (stratified according to prior treatment and geographic region) in a 1:1 ratio to receive either pertuzumab (840 mg by IV infusion initially, followed by 420 mg by IV infusion every 3 weeks thereafter) in combination with trastuzumab (8 mg/kg by IV infusion initially, followed by 6 mg/kg by IV infusion every 3 weeks thereafter) and docetaxel (75 mg/m2 by IV infusion initially, followed by 75 or 100 mg/m2 every 3 weeks thereafter) or placebo in combination with trastuzumab and docetaxel.1, 2 Patients received pertuzumab and trastuzumab until disease progression, withdrawal of patient consent, or unacceptable toxicity occurred; docetaxel was continued for at least 6 cycles.1 The primary measure of efficacy was progression-free survival as assessed by an independent review facility (IRF-assessed progression-free survival); secondary end points included overall survival, progression-free survival as assessed by the investigator (investigator-assessed progression-free survival), objective response rate, and duration of response.1, 2 The median age of patients enrolled in the study was 54 years (range: 22-89 years).1, 2 Approximately half of the patients had received prior adjuvant or neoadjuvant chemotherapy, including regimens consisting of an anthracycline (39%), taxane (23%), trastuzumab (11%), or hormonal therapy (25%);2 approximately 11% of patients with hormone receptor-positive tumors had received hormonal therapy for metastatic disease.1 All except 2 of the enrolled patients were women.1, 2 Approximately 89% of patients had an IHC score of 3+, and approximately 95% of patients had FISH-positive tumors.2
Patients randomized to receive pertuzumab in combination with trastuzumab and docetaxel had a longer median IRF-assessed progression-free survival compared with patients receiving placebo in combination with trastuzumab and docetaxel (18.5 versus 12.4 months, respectively).1, 2 Effects of pertuzumab on investigator-assessed progression-free survival and IRF-assessed progression-free survival were comparable.1 Prolonged progression-free survival was observed in pertuzumab-treated patients regardless of age, race, geographic region, or prior adjuvant or neoadjuvant therapy.1, 2 In addition, patients receiving pertuzumab in combination with trastuzumab and docetaxel appeared to have a higher objective response rate (80.2 versus 69.3%, respectively) and a longer median duration of response (20.2 versus 12.5 months, respectively) compared with those receiving placebo in combination with trastuzumab and docetaxel.1, 2 The median follow-up period at the time of interim analysis was 19.3 months in both treatment arms; the median duration of treatment was estimated to be 18.1 months for pertuzumab-treated patients and 11.8 months for placebo-treated patients.1, 2 At the time of interim analysis, pertuzumab- or placebo-treated patients had received a mean of 19.9 or 16.2 treatment cycles, respectively; both groups received a median of 8 docetaxel cycles.3 In the final analysis of overall survival at a median follow-up of 50 months, median overall survival was prolonged in pertuzumab-treated patients compared with placebo-treated patients (56.5 versus 40.8 months).1, 19 Results of an exploratory subgroup analysis (based on age, geographic region, race or ethnic group, presence of visceral metastases, hormone receptor status, HER2 status, prior adjuvant or neoadjuvant therapy) suggested that the effect of pertuzumab on overall survival was generally consistent across all subgroups; however, overall survival benefit for pertuzumab-treated patients was not apparent in the subgroup of patients with disease limited to nonvisceral metastasis (hazard ratio 1.11; 95% confidence interval of 0.66-1.85).1, 19
Pertuzumab is used in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage breast cancer (either node-positive or tumor size exceeding 2 cm in diameter) as part of a complete treatment regimen.1, 20, 21, 23
The current indication for pertuzumab for the neoadjuvant treatment of HER2-positive early-stage breast cancer is based principally on the results of 2 randomized, open-label, phase 2 studies (NeoSphere, TRYPHAENA) in adults with operable, locally advanced, or inflammatory early-stage HER2-positive breast cancer and a supportive open-label, multicenter, nonrandomized phase 2 study (BERENICE) evaluating the cardiac safety of anthracycline- and taxane-based neoadjuvant chemotherapy regimens in combination with pertuzumab and trastuzumab.1, 20, 21, 22 In the NeoSphere, TRYPHAENA, and BERENICE studies, HER2 overexpression was defined as a score of 3+ on IHC assay or a FISH amplification ratio of 2 or greater.1, 20, 21, 23 The primary measure of efficacy was pathological complete response (pCR) in the breast (defined as the absence of invasive cancer in the breast and axillary nodes).1, 20, 21, 23, 31
In the NeoSphere study, 417 patients were randomized (stratified according to breast cancer type and hormone receptor status) to 1 of 4 neoadjuvant chemotherapy regimens prior to surgery (trastuzumab and docetaxel; pertuzumab, trastuzumab, and docetaxel; pertuzumab and trastuzumab; or pertuzumab and docetaxel). 1, 20 In this study, pertuzumab 840 mg was administered by IV infusion initially, followed by 420 mg by IV infusion every 3 weeks for 4 cycles; trastuzumab 8 mg/kg was administered by IV infusion initially, followed by 6 mg/kg by IV infusion every 3 weeks for 4 cycles; and docetaxel 75 mg/m2 was administered by IV infusion initially, followed by 100 mg/m2, if the initial dose was tolerated, every 3 weeks for 4 cycles).1, 20 Following surgery, all patients received fluorouracil (600 mg/m2), epirubicin hydrochloride (90 mg/m2), and cyclophosphamide (600 mg/m2) (also referred to as FEC) by IV infusion every 3 weeks for 3 cycles and trastuzumab IV every 3 weeks to complete 1 year of therapy;1, 20 however, patients assigned to the pertuzumab and trastuzumab group received docetaxel every 3 weeks for 4 cycles prior to administration of the FEC regimen.1, 20
The median age of patients enrolled in the study was 49-50 years; 71% of the patients were Caucasian, 100% were female, 7% had inflammatory cancer, 32% had locally advanced cancer, and 61% had operable cancer.1, 20 Approximately one-half of the patients enrolled in the study had estrogen receptor-positive and/or progesterone receptor-positive disease.1, 20 Patients randomized to receive pertuzumab in combination with trastuzumab and docetaxel had a higher pCR rate compared with patients receiving trastuzumab and docetaxel, pertuzumab and trastuzumab, or pertuzumab and docetaxel (39.3% versus 21.5, 11.2, or 17.7%, respectively).1 The magnitude of benefit with pertuzumab was lower in the subgroup of patients with hormone receptor-positive tumors compared with those with hormone receptor-negative tumors.1, 20 At the time of the final analysis at a median follow-up of approximately 60 months, the 5-year progression-free survival rate was 86% in patients receiving pertuzumab in combination with trastuzumab and docetaxel, 81% in those receiving trastuzumab and docetaxel, 73% in those receiving pertuzumab and trastuzumab, and 73% in those receiving pertuzumab and docetaxel.25 Exploratory analysis suggested prolonged 5-year progression-free survival in patients who achieved a total pCR (defined as the absence of invasive cancer in the breast) compared with those who did not achieve a total pCR (85 versus 76%).25
In the TRYPHAENA study, 225 patients were randomized (stratified according to breast cancer type and hormone receptor status) to 1 of 3 neoadjuvant regimens prior to surgery: fluorouracil (500 mg/m2 IV ), epirubicin hydrochloride (100 mg/m2 IV ), and cyclophosphamide (600 mg/m2 IV ) (also referred to as FEC) in combination with pertuzumab (840 mg IV during cycle 1, followed by 420 mg thereafter) and trastuzumab (8 mg/kg IV during cycle 1, followed by 6 mg/kg thereafter) every 3 weeks for 3 cycles, followed by docetaxel (75 mg/m2 by IV infusion initially, followed by 100 mg/m2 by IV infusion every 3 weeks, if the initial dose was tolerated) in combination with the same dosage of pertuzumab and trastuzumab for 3 cycles; FEC for 3 cycles followed by pertuzumab in combination with trastuzumab and docetaxel for 3 cycles; or pertuzumab in combination with docetaxel (75 mg/m2 by IV infusion every 3 weeks), carboplatin (dose required to obtain an area under the plasma concentration-time curve [AUC] of 6 mg/mL per minute by IV infusion), and trastuzumab every 3 weeks for 6 cycles.1, 21 All patients received trastuzumab every 3 weeks to complete 1 year of therapy following surgery.1, 21 The median age of patients enrolled in the study was 49-50 years; 76% were Caucasian, 100% were female, 6% of patients had inflammatory cancer, 25% had locally advanced cancer, and 69% had operable cancer.1 Approximately one-half of patients enrolled in the study had estrogen receptor-positive and/or progesterone receptor-positive disease.1 Pathological complete response was achieved in 56.2% of patients receiving pertuzumab in combination with trastuzumab and FEC followed by pertuzumab in combination with trastuzumab and docetaxel, 54.7% of those receiving pertuzumab in combination with trastuzumab and docetaxel followed by FEC, and 63.6% of those receiving pertuzumab in combination with docetaxel, carboplatin, and trastuzumab.1, 21 The pCR rate was lower in the subgroup of patients with hormone receptor-positive tumors compared with those with hormone receptor-negative tumors.1, 21 At a follow-up of 3 years, similar progression-free survival (87-89%), disease-free survival (87-90%), and overall survival (93-94%) rates were observed in each of the treatment groups.26 Disease-free survival appeared to be improved in patients who achieved a total pCR compared with those who did not achieve total pCR (hazard ratio: 0.27; 95% confidence interval of 0.11-0.64).26
In the BERENICE study, 401 patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer received an investigator's choice of a neoadjuvant anthracycline- and taxane-based regimen prior to surgery. 1, 23 In this study, patients received either dose-dense doxorubicin hydrochloride (60 mg/m2 IV ) and cyclophosphamide (600 mg/m2 IV ) every 2 weeks for 4 cycles, followed by pertuzumab (840 mg by IV infusion during cycle 1, followed by 420 mg by IV infusion every 3 weeks during cycles 2-4) in combination with trastuzumab (8 mg/kg by IV infusion during cycle 1, followed by 6 mg/kg by IV infusion every 3 weeks during cycles 2-4) and paclitaxel (80 mg/m2 IV weekly for 12 weeks), or fluorouracil (500 mg/m2 IV ), epirubicin hydrochloride (100 mg/m2 IV), and cyclophosphamide (600 mg/m2 IV) every 3 weeks for 4 cycles, followed by pertuzumab in combination with trastuzumab and docetaxel (75 mg/m2 by IV infusion initially, followed by 100 mg/m2, if the initial dose was tolerated) every 3 weeks for 4 cycles.1, 23 All patients received pertuzumab and trastuzumab every 3 weeks to complete 1 year of therapy following surgery.1, 23 In this study, HER2 overexpression was defined as a score of 3+ on IHC assay or a FISH amplification ratio of 2 or greater.1, 23 The median age of patients enrolled in the study was 49 years; 83% were Caucasian, and all but one patient were female.1, 23 Pathological complete response was achieved in 61.8% of patients receiving dose-dense doxorubicin and cyclophosphamide followed by pertuzumab in combination with trastuzumab and paclitaxel and 60.7% of those receiving fluorouracil, epirubicin, and cyclophosphamide followed by pertuzumab in combination with trastuzumab and docetaxel.1, 23 The pCR rate was lower in the subgroup of patients with hormone receptor-positive tumors compared with those with hormone receptor-negative tumors.1, 23
Pertuzumab is used in combination with trastuzumab and chemotherapy for the adjuvant treatment of early-stage HER2-positive breast cancer at high risk of recurrence.1
The current indication for pertuzumab for the adjuvant treatment of breast cancer is based principally on the results of a randomized, double-blind, placebo-controlled trial (APHINITY) in 4804 adults with operable early-stage HER2-positive (defined as an IHC assay score of 3+ or amplification of HER2 by in situ hybridization) breast cancer.1, 24 In this study, patients were randomized (stratified by nodal status, adjuvant chemotherapy regimen, hormone receptor status, geographic region, and protocol) to receive an investigator's choice of adjuvant chemotherapy (fluorouracil-epirubicin-cyclophosphamide for 3 or 4 cycles or fluorouracil-doxorubicin-cyclophosphamide for 3 or 4 cycles, followed by docetaxel for 3 or 4 cycles or weekly paclitaxel for 12 cycles; doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide for 4 cycles, followed by docetaxel for 4 cycles or weekly paclitaxel for 12 cycles; or docetaxel-carboplatin for 6 cycles) in combination with trastuzumab (8 mg/kg IV initially, followed by 6 mg/kg by IV infusion every 3 weeks) and either pertuzumab (840 mg IV initially, followed by 420 mg IV every 3 weeks) or placebo for 1 year.1, 24 The majority of patients (78%) received an anthracycline-containing regimen.1, 24 Trastuzumab was administered on day 1 of the first taxane-containing cycle and continued for a total of 1 year (up to 18 cycles) or until disease recurrence, withdrawal of consent, or unacceptable toxicity occurred.1, 24
In the APHINITY study, the primary measure of efficacy was invasive disease-free survival (DFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.1, 24 The median age of patients enrolled in the study was 51 years; 71% were Caucasian, over 99% were female, 63% had node-positive disease, and 64% had hormone receptor-positive disease.1, 24
At a median follow-up duration of 45.4 months, invasive DFS was higher in pertuzumab-treated patients compared with placebo-treated patients (93 versus 91%).1, 24 The invasive disease-free survival rate, when defined to include development of a second primary non-breast cancer, was 92% in pertuzumab-treated patients and 90% in placebo-treated patients.1, 24 An exploratory subgroup analysis suggested that the magnitude of benefit (i.e., invasive DFS) was greater in patients with node-positive disease receiving pertuzumab.1, 24 At the time of the interim analysis, no difference in overall survival was observed between pertuzumab-treated patients and placebo-treated patients.1, 24 Pertuzumab-treated patients and those assigned to placebo received a median of 18 cycles of anti-HER2 therapy.1
Patients should be selected for pertuzumab therapy based on HER2 protein overexpression or HER2 gene amplification in tumor specimens.1
Because infusion or hypersensitivity reactions may occur, patients should be closely observed for 30-60 minutes after each infusion of pertuzumab.1 Subsequent administration of trastuzumab (IV or subcutaneous) or a taxane should not be started until after the 30- to 60-minute observation period following pertuzumab administration.1 (See Infusion-related Reactions under Cautions.)
Pertuzumab, trastuzumab, and a taxane should be administered sequentially.1 Pertuzumab and trastuzumab (IV or subcutaneous) can be given in any order; however, a taxane should be given after pertuzumab and trastuzumab (IV or subcutaneous).1 In patients receiving an anthracycline-based regimen, pertuzumab and trastuzumab (IV or subcutaneous) should be administered after completion of the anthracycline.1
Pertuzumab can only be obtained through select specialty distributors.3 The manufacturer should be contacted for additional information.4
Pertuzumab is administered by IV infusion only.1 Pertuzumab solutions should not be administered by rapid IV injection, such as IV push or bolus. 1
Prior to administration, pertuzumab injection concentrate must be diluted using proper aseptic technique.1 Pertuzumab injection concentrate is diluted by adding the appropriate volume of the concentrated pertuzumab 30-mg/mL solution to a polyvinyl chloride (PVC) or non-PVC polyolefin infusion bag containing 250 mL of 0.9% sodium chloride injection; the bag should be inverted gently to mix the solution and should not be shaken.1 Pertuzumab injection concentrate should not be diluted in 5% dextrose injection.1 Any unused portion left in the vial should be discarded since the injection concentrate contains no preservative.1 Pertuzumab solutions should be inspected visually for particulate matter and discoloration prior to dilution and administration.1 Following dilution, pertuzumab infusion solution may be administered immediately or stored at 2-8°C for up to 24 hours.1 Diluted pertuzumab solution should not be admixed with any other drug.1
Unopened vials of pertuzumab injection concentrate should be protected from light and stored in the original carton at 2-8°C until use; vials should not be frozen or shaken.1
Procedures for proper handling (e.g., use of gloves) and disposal of antineoplastic drugs should be followed when preparing or administering pertuzumab.18
The initial dose of pertuzumab should be administered by IV infusion over 60 minutes; subsequent doses may be administered by IV infusion over 30-60 minutes.1 (See General under Dosage and Administration.)
Dispensing and Administration Precautions
Single-entity pertuzumab and trastuzumab preparations should not be substituted for or used with the fixed combination of pertuzumab, trastuzumab, and hyaluronidase (Phesgo®).28
Clinicians should consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with pertuzumab.
Pertuzumab should be discontinued if trastuzumab is discontinued.1 If a dose of pertuzumab and trastuzumab is missed or delayed, and the time between 2 sequential infusions of the combination is less than 6 weeks, the maintenance dose of pertuzumab and trastuzumab should be administered as soon as possible; waiting until the next scheduled dose is not recommended.1 If the time between 2 sequential infusions of the combination is 6 weeks or longer, the initial pertuzumab and trastuzumab (IV only) dose should be re-administered (see Table 1).1
Time Between Sequential Doses | Pertuzumab | Trastuzumab (IV) |
|---|---|---|
≥6 weeks | Administer 840 mg by IV infusion over 60 minutes, followed by 420 mg by IV infusion over 30-60 minutes every 3 weeks thereafter | Administer 8 mg/kg by IV infusion over approximately 90 minutes, followed by 6 mg/kg by IV infusion over 30 or 90 minutes every 3 weeks thereafter |
For the treatment of HER2-positive metastatic breast cancer, the recommended initial dose of pertuzumab is 840 mg IV in combination with trastuzumab (IV or subcutaneous) and docetaxel (IV), followed by pertuzumab 420 mg IV in combination with trastuzumab (IV or subcutaneous) and docetaxel (IV) every 3 weeks thereafter.1
In the CLEOPATRA study, pertuzumab and trastuzumab were continued for a mean of 19.9 cycles,1 and docetaxel was continued for a median of 8 cycles.3
Neoadjuvant Treatment of Early-stage Breast Cancer
For the neoadjuvant treatment of HER2-positive early-stage breast cancer, the recommended initial dose of pertuzumab is 840 mg IV in combination with trastuzumab (IV or subcutaneous), followed by pertuzumab 420 mg IV in combination with trastuzumab (IV or subcutaneous) every 3 weeks for 3-6 cycles as part of one of the following chemotherapy regimens:1
Following surgery, pertuzumab and trastuzumab should be continued to complete 1 year of therapy (up to 18 cycles).1
Adjuvant Treatment of Early-stage Breast Cancer
For the adjuvant treatment of HER2-positive early-stage breast cancer, pertuzumab is administered in combination with trastuzumab (IV or subcutaneous) as part of a complete regimen, including standard anthracycline- and/or taxane-based chemotherapy regimens.1
The recommended initial dose of pertuzumab is 840 mg IV in combination with trastuzumab (IV or subcutaneous).1 Pertuzumab and trastuzumab therapy should begin on day 1 of the first taxane-containing cycle.1 The initial regimen should be followed by pertuzumab 420 mg IV in combination with trastuzumab (IV or subcutaneous) every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or intolerable toxicity occurs.1
Dosage Modification for Toxicity and Contraindications for Continued Therapy
Dosage reductions are not recommended for pertuzumab.1 If toxicities occur, reduction in infusion rate or temporary or permanent discontinuance of pertuzumab should be considered based on causality.1 The prescribing information for individual chemotherapy agents used in combination with pertuzumab should be consulted for detailed information on dosage modifications.1
Metastatic Breast Cancer: Baseline left ventricular ejection fraction (LVEF) should be 50% or higher prior to starting pertuzumab therapy.1 If LVEF decreases to less than 40% or to 40-45% with an absolute decrease from baseline of 10% or more, pertuzumab and trastuzumab should be withheld for at least 3 weeks.1 (See Left Ventricular Dysfunction under Cautions.) LVEF should be reassessed within approximately 3 weeks.1 If LVEF has recovered to greater than 45% or to 40-45% with an absolute decrease from baseline of less than 10%, pertuzumab and trastuzumab therapy may be resumed.1 If LVEF has not improved or has declined further, discontinuance of pertuzumab and trastuzumab should be strongly considered.1
Early-stage Breast Cancer: Baseline LVEF should be 55% or higher prior to starting pertuzumab therapy; however, for patients receiving anthracycline-based chemotherapy, an LVEF of 50% or higher is required prior to starting pertuzumab and trastuzumab.1 If LVEF decreases to less than 50% with an absolute decrease from baseline of 10% or more, pertuzumab and trastuzumab should be withheld for at least 3 weeks.1 (See Left Ventricular Dysfunction under Cautions.) LVEF should be reassessed within approximately 3 weeks.1 If LVEF has recovered to greater than 50% or to an absolute decrease from baseline of less than 10%, pertuzumab and trastuzumab therapy may be resumed.1 If LVEF has not improved or has declined further, discontinuance of pertuzumab and trastuzumab should be strongly considered.1
If clinically important infusion-related reactions occur, the infusion rate should be slowed or the infusion should be interrupted, and appropriate medical therapy should be initiated.1 (See Infusion-related Reactions under Cautions.)
If serious hypersensitivity reactions occur, the pertuzumab infusion should be immediately discontinued, and the drug should be permanently discontinued.1 (See Hypersensitivity Reactions under Cautions.)
Dosage adjustment is not necessary based on body weight or baseline albumin concentration.1 (See Description.)
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1 (See Hepatic Impairment under Cautions.)
No dosage adjustment is necessary in patients with mild (creatinine clearance of 60-90 mL/minute) or moderate (creatinine clearance of 30-60 mL/minute) renal impairment.1
The manufacturer makes no specific dosage recommendations for patients with severe renal impairment (creatinine clearance less than 30 mL/minute) because data are limited in this population.1 (See Renal Impairment under Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Cautions.)
Pertuzumab is contraindicated in patients with known hypersensitivity to the drug or any ingredients in the formulation.1
Decreases in left ventricular ejection fraction (LVEF) have been reported with inhibitors of human epidermal growth factor receptor type 2 (HER2), including pertuzumab.1, 6, 9 In the CLEOPATRA study evaluating pertuzumab in combination with trastuzumab and docetaxel in patients with metastatic breast cancer, the combination regimen was not associated with an increased incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel.1, 2 LVSD occurred in 4% of pertuzumab-treated patients and in 8% of placebo-treated patients; symptomatic LVSD (congestive heart failure) occurred in 1 and 2% of patients, respectively.1, 2 Pooled analysis of data from several studies evaluating use of pertuzumab as a single agent or in combination with either chemotherapy or targeted therapy for the treatment of various malignancies demonstrated that the median time to development of LVSD and symptomatic heart failure was around cycle 4, with 87% of the events occurring between cycles 1 and 7.3, 6 In this pooled analysis, no substantial increases in cardiac dysfunction were observed following use of pertuzumab in combination with trastuzumab or non-anthracycline-based chemotherapy.6
In the NeoSphere study evaluating pertuzumab in combination with trastuzumab and docetaxel as neoadjuvant therapy, the combination regimen was associated with an increased incidence of LVSD compared with the trastuzumab- and docetaxel-treated groups.1 An increased incidence of decreased LVEF also was observed in patients treated with pertuzumab in combination with trastuzumab and docetaxel.1 The incidence of asymptomatic and symptomatic LVSD and decreases in LVEF varied with each of the neoadjuvant regimens containing pertuzumab in the NeoSphere, TRYPHAENA, and BERENICE studies.1, 20, 21, 23 (See Tables 2, 3, and 4.) In the TRYPHAENA study, recovery of LVEF to 50% or more occurred in all but one patient.1
In the APHINITY study evaluating pertuzumab for the adjuvant treatment of early-stage breast cancer, the incidence of symptomatic heart failure (New York Heart Association [NYHA] class III/IV) with an LVEF less than 50% and an absolute decrease in LVEF of 10% or more was 0.6% in pertuzumab-treated patients and 0.2% in placebo-treated patients.1 Among the patients who developed symptomatic heart failure, LVEF recovery (defined as 2 consecutive LVEF measurements above 50%) occurred in 47 or 67% of patients receiving pertuzumab or placebo, respectively.1 The majority of patients who developed symptomatic heart failure (86%) received an anthracycline-based chemotherapy regimen.1 Asymptomatic or mildly symptomatic (NYHA class II) decreases in LVEF to less than 50% and an absolute decrease in LVEF of 10% or more occurred in 3% of patients in each treatment group.1
Findings | Neoadjuvant Chemotherapy Regimen | |
|---|---|---|
Pertuzumab, Trastuzumab, and Docetaxel | Trastuzumab and Docetaxel | |
Decreased LVEFa | 8% | 2% |
LVSD | 3% | 0.9% |
Symptomatic LVSD | 0.9% | 0% |
aLVEF decrease to less than 50% with an absolute decrease from baseline of greater than 10%.
Findings | Neoadjuvant Chemotherapy Regimen | ||
|---|---|---|---|
Pertuzumab, Trastuzumab, and FECb Followed by Pertuzumab, Trastuzumab, and Docetaxel | FECb Followed by Pertuzumab, Trastuzumab, and Docetaxel | Pertuzumab, Docetaxel, Carboplatin, and Trastuzumab | |
Decreased LVEFa | 7% | 16% | 11% |
LVSD | 6% | 4% | 3% |
Symptomatic LVSD | 0% | 4% | 1% |
aLVEF decrease to less than 50% with an absolute decrease from baseline of greater than 10%.
Findings | Neoadjuvant Chemotherapy Regimen | |
|---|---|---|
Dose-dense Doxorubicin and Cyclophosphamide Followed by Pertuzumab, Trastuzumab, and Paclitaxel | FECc Followed by Pertuzumab, Trastuzumab, and Docetaxel | |
Decreased LVEFa | 7% | 2% |
Asymptomatic LVSD | 7% | 4% |
Symptomatic LVSDb | 2% | 0% |
aLVEF decrease to less than 50% with an absolute decrease from baseline of greater than 10% as measured by echocardiogram or multigated acquisition (MUGA) scan.
bNew York Heart Association (NYHA) class III/IV congestive heart failure.
Pertuzumab has not been studied in patients with a baseline LVEF of less than 50%, prior history of congestive heart failure, decreases in LVEF to less than 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function (e.g., uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment, cumulative prior anthracycline exposure greater than 360 mg/m2 of doxorubicin or its equivalent).1 However, patients who have received prior anthracycline therapy or who have had prior radiation therapy to the chest area may be at greater risk for development of LVSD.1
LVEF should be assessed prior to initiation of pertuzumab and at regular intervals (e.g., every 3 months) during treatment.1 If substantial decreases in LVEF occur, temporary or permanent discontinuance of pertuzumab may be required.1 (See Left Ventricular Dysfunction under Dosage and Administration.)
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies to date evaluating pertuzumab in pregnant women; however, pertuzumab may cause embryofetal mortality and/or teratogenicity if administered to pregnant women based on its mechanism of action and animal studies.1 Oligohydramnios and oligohydramnios sequence manifesting as pulmonary hyperplasia, skeletal abnormalities, and neonatal death have been reported in patients receiving the anti-human epidermal growth factor receptor type 2 (anti-HER2) antibody trastuzumab during pregnancy in postmarketing experience.1 In pregnant cynomolgus monkeys, exposure to pertuzumab at concentrations 2.5-20 times that of human clinical exposure (based on peak plasma concentrations) resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death.1
The manufacturer states that a pregnancy test should be performed prior to initiation of pertuzumab, and females of reproductive potential should be advised to use effective contraceptive methods during therapy and for 7 months after discontinuance of the drug.1
If pertuzumab is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1 (See Pregnancy under Cautions.) Patients who become pregnant during pertuzumab therapy should be monitored for development of oligohydramnios; if oligohydramnios occurs, appropriate fetal testing within the standards of care should be performed.1
Infusion-related reactions, including fatal events, have been reported in patients receiving pertuzumab.1 In the CLEOPATRA study in which the initial dose of pertuzumab was administered one day before trastuzumab and docetaxel during the first cycle (to allow for evaluation of pertuzumab-related infusion reactions), infusion reactions were reported in 13% of patients receiving pertuzumab compared with 10% of those receiving placebo; the most common infusion reactions were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.1 During the second cycle when pertuzumab, trastuzumab, and docetaxel were administered on the same day, the most common infusion reactions included fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.1
Patients should be observed closely for 60 minutes after the first infusion of pertuzumab and for 30 minutes after subsequent infusions of the drug.1 If infusion-related reactions occur, reduction in infusion rate or temporary or permanent discontinuance of pertuzumab may be required.1 (See Infusion-related Reactions under Dosage and Administration.)
In the APHINITY study, infusion-related reactions occurred in 21 or 18% of patients on the first day of receiving pertuzumab or placebo, respectively.1 The incidence of grade 3 or 4 infusion-related reactions was 1 or 0.7% in patients receiving pertuzumab or placebo, respectively.1 In this study, patients randomized to pertuzumab received the drug on the same day as other treatment drugs.1
Severe hypersensitivity, including anaphylaxis and fatal events, has been reported in patients receiving pertuzumab.1 Angioedema has been reported in postmarketing experience.1 In the CLEOPATRA study, hypersensitivity or anaphylactic reactions occurred in 11 or 9% of patients receiving pertuzumab or placebo, respectively; grade 3-4 hypersensitivity or anaphylactic reactions occurred in 2 or 3% of patients, respectively.1 Anaphylaxis occurred in 4 patients receiving pertuzumab and 2 patients receiving placebo.1
The frequencies of hypersensitivity or anaphylactic events observed in the NeoSphere, TRYPHAENA, BERENICE, and APHINITY studies were consistent with those observed in the CLEOPATRA study.1 In the NeoSphere study, anaphylaxis occurred in 2 patients receiving pertuzumab, trastuzumab, and docetaxel.1 In the APHINITY study, anaphylaxis occurred in 5 or 4% of patients receiving pertuzumab or placebo, respectively.1 The incidence of hypersensitivity or anaphylaxis was 8% in patients treated with pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH); 1% of these reactions were grade 3 or 4 in severity.1
Pertuzumab is contraindicated in patients with known hypersensitivity to the drug or any ingredients in the formulation.1 Patients should be observed closely for hypersensitivity reactions, including anaphylaxis.1 If serious hypersensitivity reactions occur, pertuzumab therapy should be discontinued.1 Pertuzumab should be administered in a setting where emergency equipment and appropriate medical support are available for the management of potential reactions.1 (See Hypersensitivity Reactions under Dosage and Administration.)
Other Warnings and Precautions
Patients should be selected for pertuzumab therapy based on HER2 protein overexpression or HER2 gene amplification.1 In clinical practice and clinical research studies, the methods of HER2 evaluation most commonly used are immunohistochemistry (IHC) assays, which directly measure overexpression of the HER2 protein, and fluorescent in situ hybridization (FISH), which measures amplification of the HER2 oncogene.3, 5 (See Evaluation of HER2/neu in Breast Cancer under Uses: Breast Cancer, in Trastuzumab 10:00.) In clinical trials evaluating pertuzumab, patients with breast cancer were required to have disease demonstrating an IHC score of 3+ or a FISH amplification ratio of 2 or higher.1, 2, 20, 21, 23, 24
Assessment of HER2 status should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency in the specific technology being used.1 Improper assay performance, including use of suboptimally fixed tissue, failure to use specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.1
As with all therapeutic proteins, there is a potential for immunogenicity with pertuzumab.1 In the CLEOPATRA study, anti-pertuzumab antibodies were detected in 13 of 389 patients (3%) receiving pertuzumab in combination with trastuzumab and docetaxel and in 25 of 372 patients (7%) receiving placebo in combination with trastuzumab and docetaxel.1 Anaphylactic or hypersensitivity reactions related to the presence of anti-pertuzumab antibodies were not observed in these patients.1
During the neoadjuvant period of the BERENICE study, anti-pertuzumab antibodies were detected in 1 of 383 pertuzumab-treated patients (0.3%).1 Anaphylactic or hypersensitivity reactions were not observed in this patient.1
The presence of pertuzumab in the serum sample may interfere with assays used to measure antibodies to the drug.1 In addition, the assay may be detecting antibodies to trastuzumab.1 Therefore, data may not accurately reflect the true incidence of anti-pertuzumab antibody formation.1
Tumor lysis syndrome has occurred in patients receiving pertuzumab during postmarketing experience.1 The risk may be increased in patients with high tumor burden (e.g., bulky metastases).1 Manifestations of tumor lysis syndrome may include hyperuricemia, hyperphosphatemia, and acute renal failure.1 The manufacturer states that additional monitoring and/or treatment should be considered as clinically indicated.1
In a subset of 20 patients enrolled in the CLEOPATRA study, no large (i.e., more than 20 msec) increases in the corrected QT (QTc) interval were observed in patients receiving pertuzumab in combination with trastuzumab and docetaxel.1 However, smaller increases (i.e., less than 10 msec) in QTc interval cannot be excluded because of study limitations.1
Pertuzumab may cause fetal harm if administered to a pregnant female based on its mechanism of action and animal data.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
If pertuzumab is used during pregnancy or if the patient becomes pregnant while receiving the drug or within 7 months following the last dose of pertuzumab, the patient should be apprised of the potential fetal hazard and the patient and clinician should immediately report pertuzumab exposure to the manufacturer (888-835-2555).1
It is not known whether pertuzumab is distributed into milk; however, human immunoglobulin G (IgG) is distributed into milk, but does not distribute to neonatal and infant circulation in substantial amounts.1 (See Description.) The benefit of pertuzumab therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk to the infant from exposure to the drug or from the underlying maternal condition.1 Clinicians should take into account the long elimination half-life of pertuzumab and the 7-month wash-out period following therapy with the anti-HER2 antibody trastuzumab.1
Safety and efficacy of pertuzumab have not been established in children younger than 18 years of age.1, 2
In the CLEOPATRA, NeoSphere, TRYPHAENA, BERENICE, and APHINITY studies, the incidence of the most common grade 3 or 4 adverse effects (i.e., neutropenia, febrile neutropenia, diarrhea) were similar in patients 65 years of age and older and patients 75 years of age or older.1 Grade 3 or 4 anemia also occurred frequently in both age groups.1 Adverse effects that occurred at an incidence that is at least 5% higher in patients 65 years of age or older than that reported in younger adults included decreased appetite, anemia, decreased weight, asthenia, dysgeusia, peripheral neuropathy, and hypomagnesemia.1 No overall differences in efficacy were observed between geriatric and younger patients; however, the number of patients 75 years of age or older was insufficient to determine whether they respond differently from younger adults.1 In a population pharmacokinetic analysis, no substantial differences in pharmacokinetics were observed between geriatric and younger adults.1
The pharmacokinetics of pertuzumab have not been studied in patients with hepatic impairment.1
In a population pharmacokinetic analysis, systemic exposure to pertuzumab was similar between patients with mild (creatinine clearance of 60-90 mL/minute) or moderate (creatinine clearance of 30-60 mL/minute) renal impairment and those with normal renal function.1 Pharmacokinetic data in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) are limited.1 (See Dosage and Administration: Special Populations.)
Adverse effects occurring in more than 30% of patients receiving pertuzumab in combination with trastuzumab and docetaxel for the treatment of metastatic breast cancer include diarrhea,1, 2 alopecia,1, 2 neutropenia,1, 2 nausea,1, 2 fatigue,1, 2 rash,1, 2 and peripheral neuropathy.1 Adverse effects occurring in more than 30% of patients receiving pertuzumab in combination with trastuzumab and docetaxel for neoadjuvant treatment of breast cancer include alopecia, diarrhea, nausea, and neutropenia.1, 20
Adverse effects occurring in more than 30% of patients receiving pertuzumab in combination with trastuzumab and docetaxel for 3 cycles following combination therapy with fluorouracil, epirubicin, and cyclophosphamide for 3 cycles for the neoadjuvant treatment of breast cancer include fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia.1, 21 Asthenia, constipation, mucosal inflammation, myalgia, anemia, fatigue, alopecia, diarrhea, nausea, and vomiting were reported in patients receiving pertuzumab in combination with trastuzumab and docetaxel for 4 cycles following combination therapy with fluorouracil, epirubicin, and cyclophosphamide for 4 cycles in the neoadjuvant setting.1, 23
Adverse effects occurring in more than 30% of patients receiving pertuzumab in combination with docetaxel, carboplatin, and trastuzumab for the neoadjuvant treatment of breast cancer include fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia.1, 21 Adverse effects occurring in more than 30% of patient receiving pertuzumab in combination with trastuzumab and paclitaxel following dose-dense doxorubicin and cyclophosphamide for the neoadjuvant treatment of breast cancer include nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy, and headache.1, 23
Adverse effects occurring in more than 30% of patient receiving pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of breast cancer include diarrhea, nausea, alopecia, fatigue, peripheral neuropathy and vomiting.1, 24 In the APHINITY study, the incidence of diarrhea was higher in patients receiving pertuzumab and trastuzumab in combination with a non-anthracycline-based chemotherapy regimen (85%) compared with pertuzumab and trastuzumab in combination with an anthracycline-based chemotherapy regimen (67%).1, 22, 24, 30 The incidence of diarrhea was 18% when pertuzumab and trastuzumab were administered without chemotherapy compared with 9% in placebo recipients.1, 22, 24 In the APHINITY study, the median duration of diarrhea was 8 days; however, the duration of diarrhea was prolonged in patients experiencing grade 3 or higher diarrhea with a median duration of 20 days.1, 22, 30 Diarrhea requiring hospitalization occurred in more pertuzumab-treated patients compared with placebo-treated patients (2.4 versus 0.7%).1, 22
In the CLEOPATRA, NeoSphere, TRYPHAENA, BERENICE, and APHINITY studies, diarrhea was among the most common adverse effects reported during pertuzumab therapy.1, 2, 20, 21, 22, 23, 24, 29 In the CLEOPATRA, NeoSphere, TRYPHAENA, and APHINITY studies, diarrhea, generally occurring during the first pertuzumab-containing cycle, was grade 1 or 2 in most patients.29 In these studies, loperamide was the most frequently prescribed medication for the management of diarrhea.29, 30 Interruption or discontinuance of therapy due to diarrhea was uncommon.29, 30 The incidence of diarrhea is higher when pertuzumab and trastuzumab are administered with chemotherapy.1, 22, 29, 30
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel, paclitaxel, or carboplatin.1
Pertuzumab, a recombinant humanized anti-human epidermal growth factor receptor type 2 (anti-HER2/ERBB2) monoclonal antibody, is an antineoplastic agent.1, 2, 8, 13, 16 The drug is an IgG1 kappa immunoglobulin produced by recombinant DNA technology in mammalian cell (Chinese hamster ovary) culture.1, 8 Pertuzumab also is referred to as a HER2/neu receptor antagonist.1
Pertuzumab binds specifically to the extracellular dimerization domain (subdomain II) of the HER2 protein, blocking heterodimerization of HER2 with other ligand-bound members of the HER/ERBB family (i.e., epidermal growth factor receptor [HER1/EGFR/ERBB1], HER3/ERBB3, HER4/ERBB4).1, 2, 3, 13 Blockade of HER2 heterodimerization (particularly with HER3) by pertuzumab results in inhibition of ligand-activated intracellular signaling through 2 major signal pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt), potentially causing cell growth arrest and apoptosis, respectively.1, 2, 3, 8, 13, 17 Similar to trastuzumab, pertuzumab also mediates antibody-dependent cell-mediated cytotoxicity (ADCC).1, 13, 16
Pertuzumab binds to a different HER2 domain than trastuzumab and exhibits complementary mechanisms of action with trastuzumab; the combined use of these agents, therefore, may result in more comprehensive inhibition of HER2 signaling.2, 7, 13, 17 Pertuzumab alone inhibits proliferation of human tumor cells, while the combination of pertuzumab and trastuzumab has been shown to substantially augment antitumor activity in HER2-overexpressing xenograft models.1
The pharmacokinetics of pertuzumab are linear over a dose range of 2-25 mg/kg.1 Following administration of an initial dose of 840 mg followed by a maintenance dosage of 420 mg every 3 weeks thereafter, steady-state concentrations of pertuzumab were reached after the first maintenance dose.1 The median half-life of pertuzumab is 18 days.1
The pharmacokinetics of pertuzumab do not appear to be affected by age, sex, ethnicity (Japanese versus non-Japanese), or disease status (neoadjuvant or adjuvant early-stage versus metastatic setting).1, 12, 27 Baseline serum albumin concentration and lean body weight had a minor influence on pharmacokinetic parameters; therefore, the manufacturer states that dosage adjustment based on body weight or baseline albumin concentration is not necessary.1
Risk of left ventricular dysfunction.1 Advise patients to contact a health care professional immediately if new-onset or worsening shortness of breath, cough, swelling of the ankles and/or legs, swelling of the face, palpitations, weight gain exceeding 5 pounds in 24 hours, dizziness, or loss of consciousness occurs.1
Risk of fetal harm (e.g., embryo-fetal death, birth defects).1 Necessity of advising women of childbearing potential to use effective contraceptive methods during and for 7 months after discontinuance of pertuzumab.1 Encourage women who have been exposed to pertuzumab during pregnancy to report exposure to the manufacturer.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Risk of infusion or hypersensitivity reactions.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Pertuzumab can only be obtained through select specialty distributors.3 Contact manufacturer for additional information.4
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 13, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech, Inc. Perjeta® (pertuzumab) injection for intravenous use prescribing information. South San Francisco, CA; 2021 Feb.
2. Baselga J, Cortés J, Kim SB et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med . 2012; 366:109-19. [PubMed 22149875]
3. Genentech Inc. South San Francisco, CA: Personal communication.
4. Genentech Inc. Genentech Access Solutions®- Perjeta® (pertuzumab). South San Francisco, CA. Accessed 2021 May 10. [Web]
5. Jacobs TW, Gown AM, Yaziji H et al. Comparison of fluorescense in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol . 1999; 17:1974-82. [PubMed 10561247]
6. Lenihan D, Suter T, Brammer M et al. Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol . 2012; 23:791-800. [PubMed 21665955]
7. Anon. Pertuzumab (Perjecta) for HER2-positive metastatic breast cancer. Med Lett Drugs Ther . 2012; 54:59-60. [PubMed 22825690]
8. Agus DB, Gordon MS, Taylor C et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol . 2005; 23:2534-43. [PubMed 15699478]
9. Portera CC, Walshe JM, Rosing DR et al. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res . 2008; 14:2710-6. [PubMedCentral][PubMed 18451236]
12. Yamamoto N, Yamada Y, Fujiwara Y et al. Phase I and pharmacokinetic study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese patients with solid tumors. Jpn J Clin Oncol . 2009; 39:260-6. [PubMedCentral][PubMed 19261664]
13. Capelan M, Pugliano L, De Azambuja E et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol . 2012; :.
16. Franklin MC, Carey KD, Vajdos FF et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell . 2004; 5:317-28. [PubMed 15093539]
17. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res . 2004; 64:2343-6. [PubMed 15059883]
18. Hoffmann-La Roche Inc. Perjeta® (pertuzumab) injection material safety data sheet. Nutley, NJ; 2012 May.
19. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
20. Gianni L, Pienkowski T, Im YH, et al. 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. Lancet Oncol. 2012;13(1):25-32.
21. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284.
22. Center for Drug Evaluation and Research. Pertuzumab (Multi-disciplinary Review and Evaluation): BLA 125409-S113. Food and Drug Administration website. [Web]/drugsatfda_docs/nda/2017/125409Orig1s113.pdf. Published December 20, 2017. Accessed 1 May 2021.
23. Swain SM, Ewer MS, Viale G, et al. 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. Ann Oncol. 2018;29(3):646-653.
24. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017;377(2):122-131.
25. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.
26. Schneeweiss A, Chia S, Hickish T, et al. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018;89:27-35.
27. Kirschbrown WP, Kågedal M, Wang B, et al. Pharmacokinetic and exploratory exposure-response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study. Cancer Chemother Pharmacol. 2019;83(6):1147-1158.
28. Genentech, Inc. Phesgo® (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection for subcutaneous use prescribing information. South San Francisco, CA; 2020 Jun.
29. Swain SM, Schneeweiss A, Gianni L, et al. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017;28(4):761-768.
30. Bines J, Procter M, Restuccia E, et al. Incidence and Management of Diarrhea With Adjuvant Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. Clin Breast Cancer. 2020;20(2):174-181 e173.
31. Food and Drug Administration. Pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval guidance for industry. Silver Spring, MD; 2020 Jul. From FDA website. [Web]