BIZENGRI Solution for injection Ref.[113877] Active ingredients: Zenocutuzumab

5.1 Infusion-Related Reactions/Hypersensitivity/Anaphylactic Reactions

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.

5.2 Interstitial Lung Disease/Pneumonitis

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)].

5.3 Left Ventricular Dysfunction

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)].

5.4 Embryo-Fetal Toxicity

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)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion-Related Reactions/Hypersensitivity/Anaphylaxis [see Warnings and Precautions (5.1)]
• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
• Left Ventricular Dysfunction [see Warnings and Precautions (5.3)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]

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.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to BIZENGRI as a single agent at 750 mg administered intravenously every 2 weeks until disease progression or unacceptable toxicity in 175 patients with NRG1 gene fusion positive tumors in the eNRGy study. Of these, there were 99 patients with NSCLC, 39 patients with pancreatic adenocarcinoma and 37 patients with other solid tumors [see Clinical Studies (14.1, 14.2)]. Among the 175 patients who received BIZENGRI, the median duration of exposure to BIZENGRI was 5.3 months (range: 0.1 to 36), including 45% of patients exposed for at least 6 months and 15% of patients exposed for at least 1 year. In this pooled safety population, the most common (≥10%) adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRR), dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were increased GGT, decreased hemoglobin, decreased sodium, decreased platelets, increased AST, increased ALT, increased alkaline phosphatase, decreased magnesium, decreased phosphate, increased aPTT and increased bilirubin.

NRG1 Gene Fusion Positive Unresectable or Metastatic NSCLC

eNRGy Study

The safety of BIZENGRI was evaluated in the eNRGy study in 99 patients with unresectable or metastatic NSCLC with NRG1 gene fusions [see Clinical Studies (14.1)]. Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 47% were exposed for 6 months or longer and 17% were exposed for greater than one year.

The median age was 66 years (range: 27 to 88), 54% were 65 years or older; 62% were female; 37% were White, 53% were Asian, 2% were Black or African American; and 1% were Hispanic or Latino.

Serious adverse reactions occurred in 25% of patients who received BIZENGRI. Serious adverse reactions in ≥2% of patients included pneumonia (n=4) dyspnea and fatigue (n=2 each). Serious adverse reactions occurring in one patient each were: abdominal pain, acute kidney injury, ascites, bradycardia, carotid artery stenosis, cellulitis, acute cholecystitis, COVID-19, decreased appetite, dehydration, dizziness, dysphagia, hyponatremia, ileus, lymphadenitis, nausea, gastric obstruction, pericardial effusion, pneumonitis, pulmonary hypertension, sepsis, staphylococcal infection, tumor pain, urinary tract infection, viral infection and vomiting. Fatal adverse reactions occurred in 3 (3%) patients and included respiratory failure (n=2) and cardiac failure (n=1).

Permanent discontinuation of BIZENGRI due to an adverse reaction occurred in 3% of patients. Adverse reactions resulting in permanent discontinuation of BIZENGRI included dyspnea, pneumonitis and sepsis (n=1 each).

Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 29% of patients. Adverse reactions leading to dosage interruptions in ≥2% of patients included dyspnea, COVID-19, arrhythmia, increased ALT, increased AST, and pneumonia.

Table 3 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive unresectable or metastatic NSCLC.

Table 3. Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive NSCLC Who Received BIZENGRI in the eNRGy Study:

¹ Based on NCI CTCAE v4.03 and MedDRA v26.0.
² Includes post-procedural diarrhea.
³ Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain.
⁴ Includes dyspnea exertional.
⁵ Includes productive cough.
⁶ Includes asthenia.
⁷ Includes breast edema, peripheral edema, face edema.
⁸ Includes eczema, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous.
⁹ Includes chills, IRR, nausea, cough, diarrhea, back pain, body temperature increased, dyspnea, face edema, fatigue, non-cardiac chest pain, oropharyngeal discomfort, paresthesia, pyrexia, and vomiting. AEs that were considered IRRs were counted under the composite term ‘IRR’, irrespective of the reported PT.

Clinically relevant adverse reactions in <10% of patients receiving BIZENGRI were stomatitis (7%), vomiting (8%), cardiac failure and pneumonitis (2% each).

Table 4 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive unresectable or metastatic NSCLC.

Table 4. Select Laboratory Abnormalities ≥20% that Worsened from Baseline in Patients with NRG1 Gene Fusion Positive NSCLC Who Received BIZENGRI in the eNRGy Study:

¹ The denominator used to calculate the rate varied from 93 to 96 based on the number of patients with a baseline value and at least one post-treatment value.

NRG1 Gene Fusion Positive Unresectable or Metastatic Pancreatic Adenocarcinoma

eNRGy Study

The safety of BIZENGRI was evaluated in the eNRGy study in 39 patients with unresectable or metastatic pancreatic adenocarcinoma with NRG1 gene fusions [see Clinical Studies (14.2)]. Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 50% were exposed for 6 months or longer and 13% were exposed for greater than one year.

The median age was 51 years (range: 21 to 74), 23% were 65 years or older; 49% were female; 82% were White, 13% were Asian, 2.6% were Black or African American; and 5% were Hispanic or Latino.

Serious adverse reactions occurred in 23% of patients who received BIZENGRI. Serious adverse reactions occurring in one patient each were: anemia, thrombocytopenia, tachycardia, abdominal pain, hemorrhoidal hemorrhage, nausea, cholestatic jaundice, COVID-19, liver abscess, traumatic fracture, blood creatinine increased, back pain, myelodysplastic syndrome, and respiratory disorder. There were 2 fatal adverse reactions, one due to COVID-19 and one due to respiratory failure.

Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 33% of patients. Adverse reactions leading to dosage interruptions in ≥2% of patients included COVID-19, pneumonia, increased AST, neutropenia, abdominal pain, agitation, increased blood alkaline phosphatase, increased blood bilirubin, constipation, increased creatinine, hemorrhage, hyperbilirubinemia, cholestatic jaundice, tachycardia, traumatic fracture, and upper respiratory infection.

Table 5 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma.

Table 5. Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma Who Received BIZENGRI in the eNRGy Study:

¹ Based on NCI CTCAE v4.03 and MedDRA v26.0
² Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain
³ Includes asthenia
⁴ Includes peripheral edema, face edema, localized edema, peripheral swelling
⁵ Includes chills, IRR, nausea, cough, diarrhea, back pain, body temperature increased, dyspnea, face edema, fatigue, non-cardiac chest pain, oropharyngeal discomfort, paresthesia, pyrexia, and vomiting
⁶ Includes epistaxis, hematochezia, hematuria, hemorrhoidal hemorrhage

Clinically relevant adverse reactions in <10% of patients receiving BIZENGRI were decreased appetite (5%), and rash (8%) [including dermatitis acneiform, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous].

Table 6 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma.

Table 6. Select Laboratory Abnormalities ≥20% That Worsened from Baseline in Patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma Who Received BIZENGRI in the eNRGy Study:

¹ The denominator used to calculate the rate varied from 35 to 39, based on the number of patients with a baseline value and at least one post-treatment value.

Risk Summary

Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of BIZENGRI in pregnant women to inform a drug-associated risk.

Animal studies have demonstrated that HER2 and/or HER3 deficiency results in embryo-fetal malformation, including effects on cardiac, vascular and neuronal development, and embryolethality (see Data).

Human IgG1 is known to cross the placenta; therefore, BIZENGRI has the potential to be transmitted from the mother to the developing fetus. Advise patients of the potential risk to a fetus.

There are clinical considerations if BIZENGRI is used in pregnant women, or if a patient becomes pregnant within 2 months after the last dose of BIZENGRI (see Clinical Considerations).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor women who received BIZENGRI during pregnancy or within 2 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

There are no available data on the use of BIZENGRI in pregnant women. In literature reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received HER2-directed antibody alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped.

Animal Data

There were no animal reproductive or developmental toxicity studies conducted with zenocutuzumab-zbco. A literature-based assessment of the effects on reproduction demonstrated that HER2 and HER3 are critically important in embryo-fetal development. HER2 knockout mice or mice expressing catalytically inactive HER2 die at mid-gestation due to cardiac dysfunction. HER2 knockout mice have also shown abnormal sympathetic nervous system development. In HER3-deficient mice, embryolethality occurred on embryonic day 13.5 due to cardiac and vascular defects, as well as abnormalities in other organs (neural crest, pancreas, stomach, and adrenal). In addition, HER3 is shown to be involved in mammary gland ductal morphogenesis in mice. Zenocutuzumab-zbco can cause embryo-fetal toxicity based on its mechanism of action.

Risk Summary

There are no data on the presence of zenocutuzumab-zbco in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG1 is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to BIZENGRI are unknown. Consider the developmental and health benefits of breast feeding along with the mother’s clinical need for BIZENGRI treatment and any potential adverse effects on the breastfed child from BIZENGRI or from the underlying maternal condition. This consideration should also take into account the elimination half-life of zenocutuzumab-zbco and washout period of 2 months.

BIZENGRI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating BIZENGRI [see Use in Specific Populations (8.1)].

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with BIZENGRI and for 2 months after the last dose.

The safety and effectiveness of BIZENGRI have not been established in pediatric patients.

Of the 175 patients with NRG1 gene fusion positive tumors in the eNRGy study treated with BIZENGRI at 750 mg every 2 weeks, 75 patients (43%) were 65 years of age or older and 26 patients (15%) were 75 years of age and older. No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.