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Overview of PHESGO clinical trials

FeDeriCa trial design
PHranceSCa trial design

FeDeriCa trial design1-3

FeDeriCa evaluated the pharmacokinetics (PK), efficacy, and safety of PHESGO vs IV PERJETA® (pertuzumab) + trastuzumab

Phase III, randomized, open-label trial designed to demonstrate non-inferiority of PHESGO compared to IV PERJETA and trastuzumab.

Trial design for the PHESGO FeDeriCa study

Treatment cycles with PHESGO or IV PERJETA + trastuzumab were received every 3 weeks. Patients received adjuvant radiotherapy and endocrine therapy as per investigator’s discretion.

Primary endpoint: Non-inferiority of the Cycle 7 (i.e., pre-dose Cycle 8) pertuzumab serum Ctrough. 

Secondary endpoints: Non-inferiority of the Cycle 7 (i.e., pre-dose Cycle 8) trastuzumab Ctrough, efficacy (pCR),‡ and safety.

Stratification factors: Hormone receptor status; clinical stage at presentation (Stage II-IIIA or IIIB-IIIC); type of chemotherapy.

Select patient baseline characteristics3

  PHESGO (n=248) IV PERJETA + trastuzumab (n=252)
Median age, years (range) 52 (25-81) 49 (27-76)
Median weight at baseline, lbs (range) 143.3 (89.3-299.8) 145.5 (88.2-277.8)
Race, n (%)    
American Indian or Alaska Native 10 (4.0) 10 (4.0)
Asian 51 (20.6) 54 (21.4)
Black or African American 3 (1.2)  3 (1.2)
Native Hawaiian or Other Pacific Islander 0 0
White 165 (66.5) 164 (65.1)
Multiple 3 (1.2) 2 (0.8)
Unknown 16 (6.5) 19 (7.5)
Clinical stage at presentation, n (%)    
II-IIIA 198 (79.8) 201 (79.8)
IIIB-IIIC 50 (20.2) 51 (20.2)
Hormone receptor status, n (%)    
ER- and PgR-negative 96 (38.7) 97 (38.5)
ER- or PgR-positive 151 (60.9) 155 (61.5)
Unknown§ 1 (0.4) 0
Nodal status, n (%)    
Node-negative 101 (40.7) 109 (43.3)
Node-positive 147 (59.3) 141 (56.0)
Unknown|| 0 2 (0.8)
Type of chemotherapy, n (%)    
ddAC → paclitaxel 120 (48.4) 120 (47.6)
AC → docetaxel 128 (51.6) 132 (52.4)
  • Clinical stage at presentation, hormone receptor status, and type of chemotherapy were stratification factors3

§Status is considered unknown if either ER or PgR status is unknown.2 
∥Regional lymph nodes could not be assessed (eg, previously removed, or not removed at all).3

*PHESGO dosing: 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase loading dose, followed by 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase maintenance dose. 
†IV PERJETA dosing: 840 mg loading dose, 420 mg for subsequent cycles; IV trastuzumab dosing: 8 mg/kg loading dose, 6 mg/kg for subsequent cycles. In adjuvant period, substitution of IV trastuzumab for subcutaneous trastuzumab (trastuzumab-oysk) was permitted at investigator discretion. Trastuzumab-oysk was given as a fixed dose of 600 mg. 61 patients received trastuzumab-oysk. 
‡pCR=pathological complete response (ypT0/is, ypN0, defined as the absence of invasive neoplastic cells in the breast and in the axillary lymph nodes). 

Chemotherapy regimens: ddAC dosing: doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks; AC dosing: doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks; paclitaxel dosing: 80 mg/m2 weekly; docetaxel dosing: 75 mg/m2 every 3 weeks. Docetaxel dose could be escalated to 100 mg/m2 at subsequent cycles at investigator’s discretion.

AC=doxorubicin + cyclophosphamide; ddAC=dose-dense doxorubicin-cyclophosphamide; ER=estrogen receptor; PgR=progesterone receptor.

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PHranceSCa trial design1,4,5

PHranceSCa evaluated patient preference of PHESGO vs IV PERJETA + trastuzumab

Phase II, randomized, open-label, crossover trial of patients with HER2+ early breast cancer. The primary objective of the study was to evaluate patient preference for PHESGO.

Trial design for the PHESGO PhransceSCa study

Primary endpoint: Percentage of patients who preferred PHESGO over IV PERJETA + trastuzumab when surveyed after Cycle 6 of adjuvant treatment.

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    • PHESGO Prescribing Information. Genentech, Inc. 2020.

      PHESGO Prescribing Information. Genentech, Inc. 2020.

    • Tan AR, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Poster presentation at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract PD4-07.

      Tan AR, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Poster presentation at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract PD4-07.

    • Data on file. Genentech, Inc.

      Data on file. Genentech, Inc.

    • O’Shaughnessy J, Sousa S, Cruz J, et al. Patient (pt) preference for the pertuzumab–trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) in HER2-positive early breast cancer (EBC): Primary analysis of the open-label, randomised crossover PHranceSCa study. https://medically.roche.com/global/en/asset-viewer.eeb4fcc7-b0b5-43d5-9b9a-8f4445f7424f.qr.html?cid=slpsxx2009onbresmo2020. Accessed September 30, 2020.

      O’Shaughnessy J, Sousa S, Cruz J, et al. Patient (pt) preference for the pertuzumab–trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) in HER2-positive early breast cancer (EBC): Primary analysis of the open-label, randomised crossover PHranceSCa study. https://medically.roche.com/global/en/asset-viewer.eeb4fcc7-b0b5-43d5-9b9a-8f4445f7424f.qr.html?cid=slpsxx2009onbresmo2020. Accessed September 30, 2020.

    • ClinicalTrials.gov. A study to evaluate patient preference and satisfaction of subcutaneous administration of the fixed-dose combination of pertuzumab and trastuzumab in participants with HER2-positive early breast cancer (PHranceSCa). https://clinicaltrials.gov/ct2/show/NCT03674112. Accessed May 7, 2020. 

      ClinicalTrials.gov. A study to evaluate patient preference and satisfaction of subcutaneous administration of the fixed-dose combination of pertuzumab and trastuzumab in participants with HER2-positive early breast cancer (PHranceSCa). https://clinicaltrials.gov/ct2/show/NCT03674112. Accessed May 7, 2020. 

    Important Safety Information & Indications

    Indications

    Early Breast Cancer

    PHESGO® (pertuzumab, trastuzumab, and hyaluronidase-zzxf) 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 (EBC)
    • the adjuvant treatment of adult patients with HER2-positive early breast cancer (EBC) at high risk of recurrence

    Select patients for therapy based on an FDA-approved companion diagnostic test.

    Metastatic Breast Cancer

    PHESGO is indicated for use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

    Select patients for therapy based on an FDA-approved companion diagnostic test.

    BOXED WARNINGS: Cardiomyopathy, Embryo-Fetal Toxicity, and Pulmonary Toxicity

    • PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving PHESGO with anthracycline-containing chemotherapy regimens. Evaluate cardiac function prior to and during treatment with PHESGO. Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function

    • Exposure to PHESGO can result in embryo-fetal death and birth defects, including oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception

    • PHESGO administration can result in serious and fatal pulmonary toxicity. Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Monitor patients until symptoms completely resolve

    Contraindications

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

    Additional Important Safety Information

    Cardiomyopathy

    • PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving PHESGO with anthracycline-containing chemotherapy regimens. An increased incidence of left ventricular ejection fraction (LVEF) decline has been observed in patients treated with intravenous pertuzumab, intravenous trastuzumab, and docetaxel

    • PHESGO can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death

    • PHESGO can also cause asymptomatic decline in LVEF

    • Patients who receive anthracycline after stopping PHESGO may also be at increased risk of cardiac dysfunction

    • Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function

    Cardiac Monitoring

    • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of PHESGO

    • Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan

    • Monitor frequently for decreased left ventricular function during and after PHESGO treatment

    • Monitor more frequently if PHESGO is withheld for significant left ventricular cardiac dysfunction

    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 Cmax

    • 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

    • There is a pregnancy pharmacovigilance program for PHESGO. 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

    Pulmonary Toxicity

    • PHESGO can cause serious and fatal pulmonary toxicity. These adverse reactions have been reported with intravenous trastuzumab

    • Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity

    Exacerbation of Chemotherapy-Induced Neutropenia

    • PHESGO may exacerbate chemotherapy-induced neutropenia. In randomized controlled clinical trials with intravenous trastuzumab, Grade 3-4 neutropenia and febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not

    Hypersensitivity and Administration-Related Reactions

    • Severe administration-related reactions (ARRs), including hypersensitivity, anaphylaxis, and events with fatal outcomes, have been associated with intravenous pertuzumab and trastuzumab. Patients experiencing dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or of a fatal ARR

    • In the FeDeriCa study the incidence of hypersensitivity was 1.2% in the PHESGO arm. ARRs occurred in 21% of patients who received PHESGO. In the PHESGO arm, the most common ARRs were injection site reaction (15%) and injection site pain (2%).

    • Closely monitor patients during and for 30 minutes after the injection of initial dose and during and for 15 minutes following subsequent injections of maintenance dose of PHESGO. If a significant injection-related reaction occurs, slow down or pause the injection and administer appropriate medical therapies. Evaluate and carefully monitor patients until complete resolution of signs and symptoms

    • Permanently discontinue treatment with PHESGO in patients who experience anaphylaxis or severe injection-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. For patients experiencing reversible Grade 1 or 2 hypersensitivity reactions, consider pre-medication with an analgesic, antipyretic, or an antihistamine prior to readministration of PHESGO

    Most Common Adverse Reactions

    Early Breast Cancer

    The most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia.

    Metastatic Breast Cancer (based on IV 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.

    You are encouraged to report side effects to Genentech and the FDA. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

    Please see full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.