Unlocking Rare Cancers: The Breakthrough Bispecific Antibody Targeting NRG1 Fusions

How zenocutuzumab is turning obscure genetic flaws into therapeutic opportunities

A microscopic miscommunication in DNA—a genetic "word" breaking off and attaching to the wrong "sentence." This accidental fusion, involving Neuregulin 1 (NRG1), occurs in less than 1% of all solid tumors but drives aggressive cancers. Now, zenocutuzumab is turning this obscure genetic flaw into a therapeutic opportunity 1 3 5 .

The Culprit: How NRG1 Fusions Hijack Cells

NRG1 fusions are unlike common cancer drivers. Most fusion proteins form receptors that sit on the cell surface, but NRG1 fusions function as rogue ligands—signaling molecules that actively bind to and activate HER3 receptors 1 5 .

NRG1 Fusion Mechanism
  1. HER2-HER3 Dimerization: NRG1 fusion proteins bind HER3, forcing it to pair with HER2 1 5
  2. Pathway Activation: The duo ignites downstream signals (PI3K-AKT and MAPK) 1 6
  3. Tumor Promotion: Fuels cancers like lung adenocarcinoma and pancreatic cancer 3 5
Cancer cell mechanism
Illustration of NRG1 fusion mechanism in cancer cells

Because NRG1 fusions act as ligands, blocking their receptor partners (HER2/HER3) became a therapeutic priority.

The Drug: Zenocutuzumab's "Dock and Block" Tactics

Zenocutuzumab (Bizengri) is a bispecific antibody engineered like a molecular Swiss Army knife:

One Arm

Docks firmly onto HER2

The Other Arm

Latches onto HER3, preventing NRG1 binding 1 5

Result

Halts dimerization and silences growth signals 1 3

The Breakthrough Experiment: Inside the eNRGy Trial

Methodology: A Tumor-Agnostic Approach

The phase II eNRGy trial (NCT02912949) adopted a basket design—grouping patients by molecular marker (NRG1 fusion), not tumor type 2 4 :

Patient Selection
  • 204 patients with advanced, NRG1 fusion-positive solid tumors
  • Major cohorts: NSCLC (58%), pancreatic ductal adenocarcinoma (22%)
  • 91% had prior chemotherapy/immunotherapy failures 1 4
Treatment Protocol
  • Dosing: 750 mg zenocutuzumab via 2-hour IV infusion, every 2 weeks
  • Monitoring: Tumor scans every 8 weeks (RECIST v1.1 criteria) 4

Results: Defying Expectations

Table 1: Overall Efficacy in eNRGy Trial
Metric Result (All Patients) 95% Confidence Interval
Objective Response Rate 30% 23–37%
Median Duration of Response 11.1 months 7.4–12.9 months
Median PFS 6.8 months 5.5–9.1 months
Tumor Regression Rate* 72% N/A
Table 2: Response by Tumor Type
Tumor Type ORR Median PFS
Pancreatic Adenocarcinoma 42% 9.2 months
NSCLC 29% 6.8 months
Other (e.g., breast, cholangiocarcinoma) Activity seen, but limited samples 1 3 4
Striking Outcomes
  • Pancreatic cancer patients showed the highest response (42%), with PFS nearing 10 months 1 3
  • Responses occurred across diverse NRG1 partners (CD74, SLC3A2, ATP1B1) 1 5
  • Safety: Most side effects were mild (diarrhea: 18%; fatigue: 12%) 3 4

Analysis: Why These Results Matter

Tumor Agnostic Potential

Unlike tissue-specific therapies, zenocutuzumab worked across cancers sharing the NRG1 driver 4 5

Overcoming Resistance

91% of participants had prior therapy failures, yet zenocutuzumab induced responses 1

The Scientist's Toolkit: Key Research Reagents

Table 3: Essential Tools for NRG1 Fusion Research
Reagent/Technology Function Role in eNRGy
RNA-Based Sequencing Detects functional NRG1 fusions (vs. DNA tests) Identified patients; confirmed fusion partners (e.g., CD74-NRG1) 1 5
RECIST v1.1 Criteria Standardizes tumor response measurement Primary endpoint assessment (ORR) 4
Bispecific Antibodies Dual-targeting molecules (HER2/HER3) Zenocutuzumab's "dock and block" core technology 1 6
Cell Line/Xenograft Models NRG1 fusion-positive tumor models Preclinical validation of zenocutuzumab 1 3

The Future: Challenges and Horizons

Zenocutuzumab earned accelerated FDA approval for NSCLC and pancreatic cancer in 2025—a first for NRG1-targeted therapy 1 3 . But hurdles remain:

Expanding Eligibility

Current approval is tumor-type restricted, yet activity exists in breast, biliary, and other cancers 5

Combination Strategies

Pairing zenocutuzumab with PI3K or ERBB inhibitors could boost efficacy 1 5

Diagnostic Innovation

NRG1 fusions evade detection by standard DNA tests. Liquid biopsies may improve identification 1 5

The Big Picture

This trial exemplifies precision oncology's evolution—from organ-defined cancers to molecularly targeted treatments. As one researcher noted, "NRG1 fusions transform from obscurity to opportunity" 5 .

"In rare cancers, molecular profiling isn't just helpful—it's lifesaving." – eNRGy Trial Investigator 3

References