Zenocutuzumab Shows Superior Efficacy in Treatment-Naïve NRG1+ NSCLC Patients
Key Insights
New post hoc analysis of the Phase 2 eNRGy trial demonstrates zenocutuzumab-zbco achieved a 35% overall response rate in treatment-naïve NRG1 (search)+ NSCLC patients compared to 31% in previously treated patients.
Treatment-naïve patients experienced significantly longer median duration of response at 17.1 months versus 7.4 months in previously treated patients, with all treatment-related adverse events being grade 1 or 2.
The clinical benefit rate reached 65% in treatment-naïve patients compared to 58% in previously treated patients, supporting early intervention with targeted therapy for this rare molecular subset.
Partner Therapeutics announced new data from a post hoc analysis of the Phase 2 eNRGy trial evaluating zenocutuzumab-zbco in patients with treatment-naïve non-small cell lung cancer harboring a neuregulin 1 gene fusion. The results, presented at the IASLC-ASCO North America Conference on Lung Cancer in Chicago, demonstrate superior efficacy outcomes when the bispecific antibody is used as first-line therapy.
Enhanced Efficacy in Treatment-Naïve Patients
The analysis evaluated 20 treatment-naïve and 121 previously treated NRG1 (search)+ NSCLC patients. Zenocutuzumab demonstrated an overall response rate of 35% in treatment-naïve patients compared to 31% in previously treated patients. More notably, the median duration of response was substantially longer in treatment-naïve patients at 17.1 months versus 7.4 months in previously treated patients.
The clinical benefit rate, defined as partial/complete response or stable disease for ≥24 weeks, was 65% in treatment-naïve patients and 58% in previously treated patients. All treatment-related adverse events were grade 1 or 2, maintaining the favorable safety profile observed in prior studies.
Clinical Significance for Rare Molecular Subset
"These data underscore the potential of zenocutuzumab as a first-line option for patients with NRG1 (search)-positive NSCLC, a patient population that typically responds poorly to standard first-line therapy," said Stephen Liu, MD, of Georgetown University. "Early and durable responses, coupled with a favorable safety profile are encouraging and highlight the importance of targeted therapy in this rare molecular subset."
Pritesh J. Gandhi, Chief Development Officer at Partner Therapeutics, emphasized the importance of early intervention: "Consistent with other therapies targeting key oncogenic drivers, early intervention can lead to better outcomes — and we see the same with zenocutuzumab. These findings strengthen our conviction that early targeted inhibition of the NRG1 (search) pathway with zenocutuzumab has the potential to meaningfully improve outcomes for patients with NRG1+ NSCLC."
Mechanism of Action and Regulatory Status
NRG1 (search) fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors. The chimeric ligands bind to HER3 (search), triggering HER2 (search)/HER3 heterodimerization and activating downstream signaling pathways that cause cancer cells to grow and proliferate. Zenocutuzumab-zbco is a bispecific antibody that blocks HER2/HER3 dimerization and NRG1 fusion interactions with HER3, resulting in the suppression of these pathways.
In December 2024, zenocutuzumab-zbco received U.S. Food and Drug Administration accelerated approval for the treatment of adults with advanced unresectable or metastatic NSCLC and pancreatic adenocarcinoma harboring a NRG1 (search) gene fusion with disease progression on or after prior systemic therapy. The indications were approved under accelerated approval based on overall response rate and duration of response.
Safety Profile
The eNRGy study demonstrated a manageable safety profile. In patients with NRG1 (search) gene fusion positive NSCLC, serious adverse reactions occurred in 25% of patients. The most common adverse reactions included decreased hemoglobin (35%), increased alanine aminotransferase (30%), decreased magnesium (28%), and increased alkaline phosphatase (27%). Fatal adverse reactions occurred in 3% of patients and included respiratory failure and cardiac failure.
Infusion-related reactions occurred in 13% of patients, all grade 1 or 2, with 91% occurring during the first infusion. Interstitial lung disease/pneumonitis occurred in 1.1% of patients, and left ventricular ejection fraction decrease occurred in 2% of evaluable patients.
Patient Advocacy Perspective
Danielle Hicks, Chief Patient Officer of GO2 for Lung Cancer (search), highlighted the significance for patients: "For patients and families facing NRG1 (search)+ lung cancer, these results mark meaningful progress. The durable responses and manageable safety profile of zenocutuzumab offer renewed hope and reinforce the need for continued innovation in biomarker-driven lung cancer care."
The findings support the use of comprehensive molecular testing, notably tissue-based RNA next generation sequencing, to identify rare and actionable gene fusions like NRG1 (search) in NSCLC patients.