On February 5, 2025 Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported that the New England Journal of Medicine (NEJM) published results of the registrational phase 2 eNRGy trial for Bizengri (zenocutuzumab), the first and only treatment indicated for adults with pancreatic adenocarcinoma or non–small cell lung cancer (NSCLC) that are advanced unresectable or metastatic and harbor a neuregulin 1 (NRG1) gene fusion who have disease progression on or after prior systemic therapy (Press release, Merus, FEB 5, 2025, View Source [SID1234650061]).

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"This manuscript provides comprehensive data on the safety and efficacy of Bizengri and demonstrates the meaningful results observed in the eNRGy trial," said Bill Lundberg, M.D., President, Chief Executive Officer of Merus. "We continue to make significant progress across our clinical pipeline of important and new cancer therapeutic candidates, all from our own Biclonics antibody technologies."

NRG1 fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors (TRK, RET, ROS1, ALK, and FGFR fusions). This is the first reported prospective clinical trial targeting cancers with this rare genomic alteration, a population enriched for cancer types with limited effective treatment options.1, 2, 3

The publication reviews the results of 204 patients with 12 tumor types enrolled and treated on the eNRGy study, concluding "Zenocutuzumab demonstrated durable efficacy in patients with advanced NRG1+ cancer, notably NSCLC and pancreatic adenocarcinoma, with a favorable safety profile."

"This medicine fills an important need among patients with NRG1 fusion pancreatic adenocarcinoma and lung cancer who have not previously had targeted treatment options," said Alison Schram M.D., an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, a principal investigator for the eNRGy trial, and lead author on the NEJM manuscript.

In December, Merus announced it had entered into an agreement with Partner Therapeutics, Inc. (PTx), a private, fully-integrated biotechnology company with a focus in hematology and oncology, in which Merus has exclusively licensed to PTx the right to commercialize zenocutuzumab (Zeno, tradename Bizengri) for the treatment of NRG1 fusion-positive (NRG1+) cancer in the United States (U.S.).

Indications:

BIZENGRI (zenocutuzumab-zbco) is indicated for adults with pancreatic adenocarcinoma or non–small cell lung cancer (NSCLC) that are advanced unresectable or metastatic and harbor a neuregulin 1 (NRG1) gene fusion who have disease progression on or after prior systemic therapy. These indications are approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

BOXED 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.

WARNINGS AND PRECAUTIONS

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.

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. 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. Immediately stop the infusion and permanently discontinue BIZENGRI for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis reactions.

Interstitial Lung Disease/Pneumonitis

BIZENGRI can cause serious and life-threatening interstitial lung disease (ILD)/pneumonitis. In the eNRGy study, 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.

Left Ventricular Dysfunction

BIZENGRI can cause left ventricular dysfunction.

Left ventricular ejection fraction (LVEF) decrease has been observed 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, 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 which is confirmed, or in patients with symptomatic congestive heart failure (CHF), permanently discontinue BIZENGRI.

Embryo-Fetal Toxicity

Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman. No animal reproduction studies were conducted with BIZENGRI. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In animal models, 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.

ADVERSE REACTIONS

NRG1 Gene Fusion Positive Unresectable or Metastatic Pancreatic Adenocarcinoma

Serious adverse reactions occurred in 23% of patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma who received BIZENGRI.

There were 2 fatal adverse reactions, one due to COVID-19 and one due to respiratory failure.

In patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma who received BIZENGRI the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased alanine aminotransferase (51%), diarrhea (36%), increased aspartate aminotransferase (31%), increased bilirubin (31%), decreased phosphate (31%), increased alkaline phosphatase (28%), decreased sodium (28%) musculoskeletal pain (28%), decreased albumin (26%), decreased potassium (26%), decreased platelets (26%), decreased magnesium (24%), increased gamma-glutamyl transpeptidase (23%), decreased hemoglobin (23%), vomiting (23%), nausea (23%), decreased leukocytes (21%), and fatigue (21%).

NRG1 Gene Fusion Positive Unresectable or Metastatic NSCLC

Serious adverse reactions occurred in 25% of patients with NRG1 Gene Fusion Positive NSCLC who received BIZENGRI. Serious adverse reactions in ≥ 2% of patients included pneumonia (n=4) dyspnea and fatigue (n=2 each). 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).

In patients with NRG1 Gene Fusion Positive NSCLC who received BIZENGRI, the most common (>20%) Adverse Reactions, including laboratory abnormalities, were decreased hemoglobin (35%), increased alanine aminotransferase (30%), decreased magnesium (28%), increased alkaline phosphatase (27%), decreased phosphate (26%) diarrhea (25%), musculoskeletal pain (23%), increased gamma-glutamyl transpeptidase (23%), increased aspartate aminotransferase (22%), and decreased potassium (21%).

Please see full Prescribing Information, including Boxed WARNING, at BIZENGRI.com/pi.

About BIZENGRI
BIZENGRI 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. BIZENGRI decreased cell proliferation and signaling through the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway. In addition, BIZENGRI mediates antibody-dependent cellular cytotoxicity. BIZENGRI showed antitumor activity in mouse models of NRG1+ lung and pancreatic cancers.4

About the eNRGy Trial
The eNRGy trial (Clinicaltrials.gov NCT02912949) is a multicenter, open-label clinical trial that includes patients with advanced unresectable or metastatic NRG1+ pancreatic adenocarcinoma or NRG1+ NSCLC who have disease progression on or after prior systemic therapy. There were 30 patients in the NRG1+ pancreatic adenocarcinoma group and 64 patients in the NRG1+ NSCLC group. The main outcome measures were ORR and DOR, as determined by BICR according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.4

In the NRG1+ pancreatic adenocarcinoma group, the median age was 49 years (range, 21-72 years); 43% were female; 87% were White, 7% were Asian, and 3.3% were Black or African American. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and all patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range, 0-5); 97% had prior systemic therapy with prior chemotherapy.4

In the NRG1+ NSCLC group, the median age was 64 years (range, 32-86 years); 64% were female, 33% were White, 56% were Asian, and 3.4% were Black or African American. ECOG performance status was 0 or 1 in 97% of patients or 2 in 3% of patients, and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range, 1-6).