Phesgo Drug Information

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 . 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

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

Palmar-plantar erythrodysaesthesia syndrome 6 0.8 5 0.4 Gastrointestinal disorders Nausea 60 2

61

Diarrhea 60 7 57 4.8 Stomatitis 25 0.8 24 0.8 Constipation 22

0 21 0 Vomiting 20 0.8 19

Dyspepsia 14 0 12 0 Hemorrhoids 9 0 4.0 0 Abdominal pain

upper 8 0 6 0 Abdominal pain 9 0.4 6 0 Blood and lymphatic system disorders Anemia 36 1.6 43

Neutropenia 22 14 27 14 Leukopenia 9 2.4 14 2 Febrile neutropenia

7 7 6 6 General disorders and administration site conditions Asthenia 31 0.4 32

Fatigue 29 2 24 2 Mucosal inflammation 15 0.8 20 1.2 Injection

site reaction 15 0 0.8 0 Pyrexia 13 0 16

Edema peripheral 8 0 10 0 Malaise 7 0 6 0.4 Influenza-like

illness 5 0 3.6 0 Nervous system disorders Dysgeusia 17 0 14 0 Peripheral sensory neuropathy 16 0.8 14

Headache 17 0 25 0.8 Neuropathy peripheral 12 0.4 15 2 Paresthesia

10 0.8 8 0 Dizziness 13 0 11 0 Investigations Weight decreased 11 0.8 6

Musculoskeletal and connective tissue disorders Myalgia 25 0.4 19 0.4 Arthralgia 24

0 28

Back pain 10 0 4.8 0 Bone pain 7 0 5 0

Pain in extremity 6 0 8 0 Muscle spasms 6 0 7 0 Musculoskeletal pain 6 0.4 8 0 Respiratory, thoracic and mediastinal disorder Cough 15 0.4 13 0 Epistaxis 12 0 14

Dyspnea 10 1.2 5 0 Rhinorrhea 7 0 4.4 0 Infections and

infestations Upper respiratory tract infection 11 0 8

Nasopharyngitis 9 0 10 0 Paronychia 7 0.4 3.6 0 Urinary tract

infection 7 0.4 5 0 Injury, poisoning and procedural complications Procedural pain 13 0 10 0 Radiation skin injury 19 0.4 19

Infusion related reaction 3.6 0 15 0.8 Metabolism and nutrition disorders Decreased

appetite 17 0.8 19

Hypokalemia 7 1.6 8 0 Psychiatric disorders Insomnia 17 0 13 0.4

Eye disorders Lacrimation increased 5 0.4 6 0 Dry eye 5 0.4 3.2 0 Vascular disorders Hot flush 12 0 13 0 Clinically relevant adverse reactions in <5% of patients who received PHESGO include ejection fraction decreased (3.6%) and pruritus (3.2%). In the FeDeriCa trial, when PHESGO was administered alone, adverse reactions occurred in <10% of patients with the exception of radiation skin injury (20%), arthralgia (19%), diarrhea (17%), injection site reaction (13%), dyspepsia (12%), asthenia (11%), hot flush (11%), and pruritus (10%). Table 4 summarizes the laboratory abnormalities in FeDeriCa. Table 4: Select Laboratory Abnormalities (≥5%) that Worsened from Baseline in Patients Who Received PHESGO in FeDeriCa The denominator used to calculate the rate varied from 163 to 252 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Hematology Hemoglobin (low) 90 2.8 92

Lymphocytes, Absolute (low) 89 37 88 36 Total Leukocyte Count (low) 82

25 78 25 Neutrophils, Total Absolute (low) 68 30 67 33 Platelet (low) 27 0 28

Chemistry Creatinine (high) 84 0 87 0.4 Alanine aminotransferase (high) 58 1.6

68

Albumin (low) 16 0 20 0.4 Potassium (high) 13 1.2 9 0

Sodium (low) 13 0.4 10

Bilirubin (high) 9 0 9 0.4 Glucose (low) 9 0 9 0.4

Sodium (high) 7 0.8 10

Other Clinical Trials Experience

The safety of the addition of intravenous pertuzumab to trastuzumab in combination with chemotherapy has been established in studies conducted in patients with HER2 overexpressing early breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, nausea, fatigue, neutropenia, vomiting, peripheral neuropathy, constipation, anemia, asthenia, mucosal inflammation, myalgia, and thrombocytopenia. Refer to the Prescribing Information for pertuzumab for more information.

The safety of intravenous pertuzumab, trastuzumab and docetaxel has been established in patients with HER2 overexpressing metastatic breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. Refer to the Prescribing Information for pertuzumab for more information.

Postmarketing Experience

The following adverse reactions have been identified with the use of intravenous trastuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Glomerulopathy Immune thrombocytopenia Tumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at a higher risk.

Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

Patients who receive anthracycline after stopping PHESGO may be at increased risk of cardiac dysfunction because of PHESGO's long washout period . If possible, avoid anthracycline-based therapy for up to 7 months after stopping PHESGO. If anthracyclines are used, carefully monitor the patient's cardiac function.

Pregnancy If PHESGO is administered during pregnancy, or if a patient becomes pregnant while receiving PHESGO or within 7 months following the last dose of PHESGO, health care providers and patients should immediately report PHESGO exposure to Genentech at 1-888-835-2555. Risk Summary 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 (see Data ). In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures that were 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on C max (see Data ). Apprise the patient of the potential risks to a fetus. There are clinical considerations if PHESGO is used during pregnancy or within 7 months prior to conception (see Clinical Considerations ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received PHESGO during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

Data Human Data In post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped.

In one case, trastuzumab therapy resumed after amniotic index improved and oligohydramnios recurred. Animal Data PHESGO for subcutaneous injection contains pertuzumab, trastuzumab, and hyaluronidase . Pertuzumab: Pregnant cynomolgus monkeys were treated on Gestational Day (GD) 19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on C max.

Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85%. At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. Trastuzumab: In studies where intravenous trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.

Hyaluronidase: In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is >2,400 and 3,600, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is >400 and 600, based on loading and maintenance doses, respectively, times higher than the human dose.

In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is >1,200 and 1,800, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

Pediatric Use The safety and effectiveness of PHESGO in pediatric patients have not been established.

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.