Hyaluronidase

1 INDICATIONS AND USAGE PHESGO is a combination of pertuzumab and trastuzumab, HER2/neu receptor antagonists, and hyaluronidase, an endoglycosidase, indicated for: Use in combination with chemotherapy as: neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. ( 1.1 ) adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence ( 1.1 ) Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. ( 1.2 ) 1.1 Early Breast Cancer (EBC) PHESGO is indicated for use in combination with chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer [see Dosage and Administration (2.2) and Clinical Studies (14.2) ] . the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.2) ] . Select patients for therapy based on an FDA-authorized companion diagnostic test [see Dosage and Administration (2.1) ]. 1.2 Metastatic Breast Cancer (MBC) PHESGO is indicated for use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease [see Dosage and Administration (2.2) and Clinical Studies (14.1) ] . Select patients for therapy based on an FDA-authorized companion diagnostic test [see Dosage and Administration (2.1) ].

12.1 Mechanism of Action Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling pathway in human tumor cells that overexpress HER2. Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in PHESGO acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into the systemic circulation when given in the subcutis of Göttingen Minipigs.

2 DOSAGE AND ADMINISTRATION For subcutaneous use in the thigh only. ( 2.2 ) PHESGO has different dosage and administration instructions than intravenous pertuzumab and trastuzumab products. ( 2.2 ) Do not administer intravenously. ( 2.2 ) Perform HER2 testing using FDA-authorized tests by laboratories with demonstrated proficiency. ( 1 , 2.1 ) The initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes. ( 2.2 ) Neoadjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion preoperatively for 3 to 6 cycles. ( 2.2 ) Adjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion postoperatively for a total of 1 year (up to 18 cycles). ( 2.2 ) MBC: administer PHESGO by subcutaneous injection and docetaxel by intravenous infusion every 3 weeks. ( 2.2 ) 2.1 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14) ] . Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-authorized tests specific for breast cancer by laboratories with demonstrated proficiency. Information on the FDA-authorized tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.2 Important Dosage and Administration Information PHESGO is for subcutaneous use only in the thigh. Do not administer intravenously. PHESGO has different dosage and administration instructions than intravenous pertuzumab, intravenous trastuzumab, and subcutaneous trastuzumab when administered alone. Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan. PHESGO must always be administered by a healthcare professional. In patients receiving an anthracycline-based regimen for early breast cancer, administer PHESGO following completion of the anthracycline. In patients receiving PHESGO for early breast cancer with docetaxel or paclitaxel, administer docetaxel or paclitaxel after PHESGO. In patients receiving PHESGO for metastatic breast cancer with docetaxel, administer docetaxel after PHESGO. Observe patients for a minimum of 30 minutes after initial dose of PHESGO and 15 minutes after each maintenance dose of PHESGO for signs or hypersensitivity symptoms or administration-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use [see Warnings and Precautions (5.5) ]. 2.3 Recommended Doses and Schedules The recommended dosage and administration schedule for PHESGO are shown in Table 1 . Table 1: Recommended Dosage and Administration Schedule Dose Strength Administration Instructions Initial dose 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase in 15 mL Administer subcutaneously over approximately 8 minutes (1,200 mg, 600 mg, and 30,000 units/15 mL) Maintenance dose (administer every 3 weeks) 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase in 10 mL (600 mg, 600 mg, and 20,000 units/10 mL) Administer subcutaneously over approximately 5 minutes every 3 weeks No dose adjustments for PHESGO are required for patient body weight or for concomitant chemotherapy regimen. Patients currently receiving intravenous pertuzumab and trastuzumab can transition to PHESGO. In patients receivi

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cardiomyopathy [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Pulmonary Toxicity [see Warnings and Precautions (5.3) ] Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.4) ] Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.5) ] Neoadjuvant and Adjuvant Treatment of Breast Cancer The most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia. ( 6.1 ) Metastatic Breast Cancer (based on intravenous pertuzumab ) The most common adverse reactions (> 30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Neoadjuvant and Adjuvant Treatment of Breast Cancer The safety of PHESGO was evaluated in an open-label, multicenter, randomized trial (FeDeriCa) conducted in 500 patients with HER2 overexpressing early breast cancer [see Clinical Studies (14.2) ] . Patients were randomized to receive either PHESGO (1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL) followed every 3 weeks by a maintenance dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL or the recommended dosages for intravenous pertuzumab and intravenous trastuzumab. Patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Following surgery, patients continued therapy with PHESGO alone or intravenous pertuzumab and trastuzumab (intravenous or subcutaneously administered) as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles. The median duration of treatment for PHESGO was 24 weeks (range: 0-42 weeks). Serious adverse reactions occurred in 16% of patients who received PHESGO. Serious adverse reactions in > 1% of patients included febrile neutropenia (4%), neutropenic sepsis (1%), and neutrophil count decreased (1%). One fatal adverse reaction occurred in 1/248 (0.4%) of patients, which was due to acute myocardial infarction, and occurred prior to the start of HER2 targeted treatment with PHESGO. Adverse reactions resulting in permanent discontinuation of any study drug occurred in 8% of patients on the PHESGO arm. Adverse reactions which resulted in permanent discontinuation of PHESGO were ejection fraction decreased (1.2%), cardiac failure (0.8%), and pneumonitis/pulmonary fibrosis (0.8%). Dosage interruptions due to an adverse reaction occurred in 40% of patients who received PHESGO. Adverse reactions which required dosage interruption in > 1% of patients who received PHESGO included neutropenia (8%), neutrophil count decreased (4%), and diarrhea (7%). Table 3 summarizes the adverse reactions in FeDeriCa. Table 3: Adverse Reactions (≥5%) in Patients Who Received PHESGO in FeDeriCa Adverse Reactions PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Skin and subcutaneous tissue disorders Alopecia 77 0 71 0.4 Dry skin 15 0.4 13 0 Rash 16 0.4 21 0 Nail discoloration 9 0 6 0 Erythema 9 0 5 0 Dermatitis 7 0 6 0 Nail disorder 7 0 7 0.4 Palmar-plantar erythrodysaesthesia syndrome 6 0.8 5 0.4 Gastrointestinal disorders Nausea 60 2 61 1.6 Diarrhea 60 7 57 4.8

5 WARNINGS AND PRECAUTIONS Exacerbation of Chemotherapy-Induced Neutropenia. ( 5.4 ) Hypersensitivity and Administration-Related Reactions (ARRs): Monitor patients for systemic hypersensitivity reactions. Permanently discontinue PHESGO in patients who experience anaphylaxis or severe hypersensitivity reactions. ( 5.5 ) 5.1 Cardiomyopathy PHESGO can cause hypertension, arrhythmias, left ventricular cardiac dysfunction, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ]. PHESGO can cause asymptomatic decline in LVEF. An increased incidence of LVEF decline has been observed in patients treated with intravenous pertuzumab, intravenous trastuzumab, and docetaxel. A 4-6 fold increase in the incidence of symptomatic myocardial dysfunction has been reported among patients receiving trastuzumab, with the highest absolute incidence occurring when trastuzumab was administered with an anthracycline. Patients who receive anthracycline after stopping PHESGO may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.2) ]. Cardiac Monitoring Prior to initiation of PHESGO, conduct a thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. During treatment with PHESGO, assess LVEF at regular intervals [see Dosage and Administration (2.4) ]. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO. Following completion of PHESGO, continue to monitor for cardiomyopathy and assess LVEF measurements every 6 months for at least 2 years as a component of adjuvant therapy. PHESGO In the FeDeriCa trial, the percentage of patients with at least one cardiac disorder was 22% in the PHESGO arm. The most frequent cardiac adverse reaction in the PHESGO arm was ejection fraction decreased. The incidence of cardiac failure (NYHA Class III/IV) with a LVEF decline ≥ 10% and a drop to less than 50% was 0.8% in the PHESGO arm. Confirmed asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF ≥ 10% and a drop to less than 50% was 1.2% in the PHESGO arm [see Adverse Reactions (6.1) ] . PHESGO and/or intravenous pertuzumab and trastuzumab have not been studied in patients with a pretreatment LVEF value of < 55% (EBC) or <50% (MBC); a prior history of CHF, conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m 2 of doxorubicin or its equivalent. 5.2 Embryo-Fetal Toxicity PHESGO can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of intravenous trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In an animal reproduction study, administration of intravenous pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on C max . Verify the pregnancy status of females of reproductive potential prior to the initiation of PHESGO. Advise pregnant women and females of reproductive potential that exposure to PHESGO during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PHESGO [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.3) ]. 5.3 Pulmonary Toxicity PHESGO can cause serious and fatal pulmonary toxicity. These adverse reactions have been reported with intravenous trastuzumab. Pulmonary toxi

4 CONTRAINDICATIONS PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients. PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients. ( 4 )