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WARNING
EMBRYO-FETAL TOXICITY
Embryo-Fetal Toxicity: Exposure to BIZENGRI during pregnancy can cause embryo-fetal harm. Advise patients of this risk and the need for effective contraception [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Zenocutuzumab-zbco is a low-fucose humanized full-length immunoglobulin G1 (IgG1) bispecific HER2-and HER3-directed antibody. It has a molecular weight of approximately 146 kDa and is produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
BIZENGRI is a sterile, clear to slightly opalescent, colorless to slightly yellow, preservative-free injection for intravenous infusion in single-dose vials. The pH is 6.0. Each BIZENGRI vial contains 375 mg/18.75 mL zenocutuzumab-zbco at a concentration of 20 mg/mL. Each vial also contains the following inactive ingredients: histidine (34.9 mg), L-histidine hydrochloride monohydrate (51.1 mg), polysorbate 20 (3.7 mg), trehalose (1412 mg), and water for injection.
Included as part of the PRECAUTIONS section.
BIZENGRI can cause serious and life-threatening infusion-related reactions (IRRs), hypersensitivity and anaphylactic reactions. Signs and symptoms of IRR may include chills, nausea, fever, and cough.
In the eNRGy study, 13% of patients experienced IRRs, all were Grade 1 or 2; 91% occurred during the first infusion. The median time to onset was 63 minutes (range: 13 minutes to 240 minutes) from the start of infusion.
Administer BIZENGRI in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications. Monitor patients closely for signs and symptoms of infusion reactions during infusion and for at least 1 hour following completion of first BIZENGRI infusion and as clinically indicated. Prior to the first BIZENGRI infusion, premedicate with a corticosteroid, an H1 antihistamine and acetaminophen to reduce the risk of IRRs [see Dosage and Administration (2.4)]. Corticosteroid premedication can be used as necessary for subsequent BIZENGRI infusions.
Interrupt BIZENGRI infusion in patients with ≤ Grade 3 IRRs and administer symptomatic treatment as needed. Resume infusion at a reduced rate after resolution of symptoms [see Dosage and Administration (2.5)]. Immediately stop the infusion and permanently discontinue BIZENGRI for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis reactions.
BIZENGRI can cause serious and life-threatening interstitial lung disease (ILD)/pneumonitis.
In the eNRGy study [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2 (1.1%) patients treated with BIZENGRI. Grade 2 ILD/pneumonitis (Grade 2) resulting in permanent discontinuation of BIZENGRI occurred in 1 (0.6%) patient.
Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold BIZENGRI in patients with suspected ILD/pneumonitis and administer corticosteroids as clinically indicated. Permanently discontinue BIZENGRI if ILD/pneumonitis ≥ Grade 2 is confirmed [see Dosage and Administration (2.5)].
BIZENGRI can cause left ventricular dysfunction.
Left ventricular ejection fraction (LVEF) decrease occurred with anti-HER2 therapies, including BIZENGRI. Treatment with BIZENGRI has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.
In the eNRGy study [see Adverse Reactions (6.1)], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40%-50%; 10 - 19% drop from baseline)] occurred in 2% of evaluable patients. Cardiac failure without LVEF decrease occurred in 1.7% of patients including 1 (0.6%) fatal event.
Before initiating BIZENGRI, evaluate LVEF and monitor at regular intervals during treatment as clinically indicated. For LVEF of less than 45% or less than 50% with absolute decrease from baseline of 10% or greater is confirmed, permanently discontinue BIZENGRI. Permanently discontinue BIZENGRI in patients with symptomatic congestive heart failure (CHF) [see Dosage and Administration (2.5)].
Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Animal studies have demonstrated that inhibition of HER2 and/or HER3 results in impaired embryo-fetal development, including effects on cardiac, vascular and neuronal development, and embryolethality. Advise patients of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of BIZENGRI. Advise females of reproductive potential to use effective contraception during treatment with BIZENGRI and for 2 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
No studies have been performed to assess the carcinogenic or mutagenic potential of zenocutuzumab-zbco.
Animal fertility studies have not been conducted with zenocutuzumab-zbco.
Zenocutuzumab-zbco is a bispecific antibody that binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumor cells, inhibiting HER2:HER3 dimerization and preventing NRG1 binding to HER3. Zenocutuzumab-zbco decreased cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. In addition, zenocutuzumab-zbco mediates antibodydependent cellular cytotoxicity (ADCC). Zenocutuzumab-zbco showed antitumor activity in mouse models of NRG1 fusion-positive lung and pancreatic cancers.
The exposure-response relationship and time-course of pharmacodynamic response for zenocutuzumab-zbco have not been fully characterized.
Zenocutuzumab-zbco pharmacokinetic parameters are expressed as mean unless otherwise specified. Zenocutuzumab-zbco exposure increases proportionally over a dose range from 480 mg (0.6 times the approved recommended dosage) to 900 mg (1.2 times the approved recommended dosage). The median time to steady state of zenocutuzumab-zbco concentrations is 8 weeks and the median accumulation ratio is 1.6-fold at the approved recommended dosage.
Zenocutuzumab-zbco volume of distribution is 6 L (CV 18%).
The steady state zenocutuzumab-zbco half-life is 8 days (SD ±1.3 days) with a clearance of 22 mL/h (CV 37%).
MetabolismZenocutuzumab-zbco is expected to be metabolized into small peptides by catabolic pathways.
No clinically significant differences in the pharmacokinetics of zenocutuzumab-zbco were observed based on age (22 to 88 years), sex, race [White or Asian], body weight (38 to 126 kg), albumin level (20 to 49 g/L), mild or moderate renal impairment (creatinine clearance (CLcr) 30 to 89 mL/min), and mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN).
The pharmacokinetics of zenocutuzumab-zbco in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to 3 times ULN with any AST) or severe renal impairment (CLcr < 30 mL/min) is unknown.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of the incidence of anti-drug antibodies in the studies below with the incidence of anti-drug antibodies in other studies, including those of BIZENGRI or of other zenocutuzumab products.
In patients who received BIZENGRI at the approved recommended dosage for up to 30 months, 7 of 153 (4.6%) patients developed anti-zenocutuzumab antibodies. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and efficacy of zenocutuzumab is unknown.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advise patients that BIZENGRI can cause serious and life-threatening infusion-related reactions (IRRs). Advise patients to alert their healthcare provider immediately for any signs or symptoms of IRRs during and following the infusion [see Warnings and Precautions (5.1)].
Inform patients that BIZENGRI can cause serious and life threatening ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.2)].
Inform patients that BIZENGRI can cause serious and life threatening left ventricular dysfunction. Advise patients to immediately contact their healthcare provider for new or worsening cardiovascular symptoms [see Warnings and Precautions (5.3)].
Advise women not to breastfeed during treatment with BIZENGRI and for 2 months after the last dose [see Use in Specific Populations (8.2)].
