1.1 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Non-Small Cell Lung Cancer

BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

1.2 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma

BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2.1 Patient Selection

Select patients for treatment with BIZENGRI based on the presence of an NRG1 gene fusion in tumor specimens [see Clinical Studies (14.1, 14.2)].

An FDA-approved test for the detection of NRG1 gene fusions is not currently available.

2.2 Recommended Evaluation Before Initiating BIZENGRI

Before initiating BIZENGRI, evaluate left ventricular ejection fraction (LVEF) [see Warnings and Precautions (5.3)].

2.3 Recommended Dosage

• The recommended dosage of BIZENGRI is 750 mg as an intravenous (IV) infusion every 2 weeks until disease progression or unacceptable toxicity [see Dosage and Administration (2.7)].
• Administer premedications before each BIZENGRI infusion as recommended to reduce the risk of infusion-related reactions [see Dosage and Administration (2.4)].

2.4 Recommended Premedications

Prior to each infusion of BIZENGRI, administer premedications to reduce the risk of infusion-related reactions (IRRs) [see Warnings and Precautions (5.1)] (see Table 1).

2.5 Dosage Modifications for Adverse Reactions

No dose reduction is recommended for BIZENGRI. The recommended dosage modifications of BIZENGRI for adverse reactions are provided in Table 2.

2.6 Preparation

Dilute and prepare BIZENGRI for intravenous infusion before administration.

For the initial infusion, prepare BIZENGRI as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.

• Check that the BIZENGRI solution is clear to slightly opalescent, colorless to slightly yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.
• Withdraw and then discard 37.5 mL 0.9% Sodium Chloride Injection from the 250 mL infusion bag. Only use infusion bags made of polyvinylchloride (PVC), polyolefin or polyolefin/polyamide coextruded plastic.
• Withdraw a total of 37.5 mL of BIZENGRI from 2 vials and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.
• Gently invert the bag to mix the solution. Do not shake.
• If not used immediately, store the diluted solution refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light after preparation unless the infusion is initiated within 2 hours of preparation.

2.7 Administration

• If the infusion time exceeds the recommended storage time, the infusion bag must be discarded and a new infusion bag prepared to continue the infusion. Diluted BIZENGRI solution must by administered within:
  • 6 hours from end of preparation of infusion solution stored at room temperature [15°C to 25°C (59°F to 77°F)]
  • 28 hours from end of preparation of infusion solution stored refrigerated [2°C to 8°C (36°F to 46°F)]
• If the diluted BIZENGRI solution has been refrigerated, allow it to reach room temperature (approximately 30 minutes) prior to administration.
• Administer diluted BIZENGRI solution [see Dosage and Administration (2.6)] by intravenous infusion using an infusion set made of either PVC, polyethylene (PE), polyurethane (PUR) or polybutadiene (PB) with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer).
• Do not infuse BIZENGRI concomitantly in the same IV line with other agents.
• Administer BIZENGRI infusion via a peripheral or central line.
• Monitor patients closely for signs and symptoms of infusion-related reactions during BIZENGRI infusion and monitor patients for at least 1 hour following completion of the first BIZENGRI infusion and as clinically indicated [see Warnings and Precautions (5.1)].
• Administer intravenous infusion over 4 hours.

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)].

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.

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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.

12.1 Mechanism of Action

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 antibody-dependent cellular cytotoxicity (ADCC). Zenocutuzumab-zbco showed antitumor activity in mouse models of NRG1 fusion-positive lung and pancreatic cancers.

12.2 Pharmacodynamics

The exposure-response relationship and time-course of pharmacodynamic response for zenocutuzumab-zbco have not been fully characterized.

12.3 Pharmacokinetics

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.

12.6 Immunogenicity

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14.1 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Non-Small Cell Lung Cancer

The efficacy of BIZENGRI was evaluated in the eNRGy study (NCT02912949) a multicenter, open-label, multi-cohort clinical study. The study enrolled adult patients with advanced or metastatic NRG1 fusion-positive NSCLC who had disease progression following standard of care treatment for their disease. Identification of positive NRG1 gene fusion status was prospectively determined based on next generation sequencing (NGS) assays performed at local laboratories or central laboratories. Patients received BIZENGRI as an intravenous infusion, 750 mg every 2 weeks, until unacceptable toxicity or disease progression. Tumor assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Efficacy was evaluated in 64 patients with NRG1 fusion-positive NSCLC previously treated with systemic therapy enrolled in eNRGy.

The trial population characteristics were: median age 63.5 years (range: 32 to 86) with 10% of patients ≥ 65 years of age; 64% female; 56% Asian, 33% White, 3.4% Black or African American, and 11% other races or not reported; none were Hispanic or Latino; baseline ECOG performance status of 0 or 1 (97%) or 2 (3%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 to 6); 95% had prior platinum chemotherapy and 64% had prior anti-PD-1/PD-L1 therapy. A total of 54 patients (84%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 9 (14%) had an NRG1 gene fusion detected by DNA-based NGS.

Efficacy results are summarized in Table 7 and Table 8.

14.2 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma

The efficacy of BIZENGRI was evaluated in the eNRGy study (NCT02912949), a multicenter, open-label, multi-cohort clinical study. The study enrolled 30 adult patients with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma who had disease progression following standard of care treatment. Identification of an NRG1 gene fusion was prospectively determined in local laboratories using next generation sequencing (NGS). Patients received BIZENGRI as an intravenous infusion, 750 mg every 2 weeks, until unacceptable toxicity or disease progression. Tumor assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by a blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The trial population characteristics were: median age 49 years (range: 21 to 72) with 10% of patients ≥ 65 years of age; 43% female; 87% White, 7% Asian, 3.3% Black or African American, and 3.3% other races or not reported; 3.3% were Hispanic or Latino; baseline ECOG performance status of 0 (53%) or 1 (47%) and all patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 0 to 5); 97% had prior systemic therapy with FOLFIRINOX, gemcitabine/taxane-based therapy, or both. A total of 27 patients (90%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 3 (10%) had an NRG1 gene fusion detected by DNA-based NGS.

Efficacy results are summarized in Table 9 and Table 10.

How Supplied

BIZENGRI (zenocutuzumab-zbco) injection is a sterile, clear to slightly opalescent, colorless to slightly yellow, preservative-free solution for intravenous infusion. Each single-dose vial contains 375 mg/18.75 mL (20 mg/mL) BIZENGRI. Two vials (equivalent to 1 dose) are packed in a single carton. (NDC 83077-100-01 for individual vial and NDC 83077-100-02 for a single carton).

Storage and Handling

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

Infusion-Related Reactions/Hypersensitivity/Anaphylaxis

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)].

Interstitial Lung Disease (ILD)/Pneumonitis

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)].

Left Ventricular Dysfunction

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)].

Embryo-Fetal Toxicity

• Inform female patients of the potential risk to a fetus. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
• 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)].

Lactation

Advise women not to breastfeed during treatment with BIZENGRI and for 2 months after the last dose [see Use in Specific Populations (8.2)].

Product of the USA

Manufactured by: Merus N.V. Uppsalalaan 17, Utrecht, The Netherlands

Distributed by: Merus US, Inc. Cambridge, MA 02142

BIZENGRI® is a registered trademark of Merus N.V.

U.S. License Number 2310

©2024 Merus N.V. All rights reserved.

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