Can Partner Therapeutics’ zenocutuzumab-zbco deliver a first-line breakthrough in NRG1+ lung cancer?

Partner Therapeutics, Inc. has released updated data from its Phase 2 eNRGy trial, reinforcing the potential of zenocutuzumab-zbco (BIZENGRI) as a targeted first-line treatment for NRG1 fusion-positive non-small cell lung cancer (NSCLC). The findings, presented during a high-profile session at the IASLC-ASCO North America Lung Cancer Conference, suggest that early intervention with the HER3-blocking bispecific antibody may deliver longer-lasting tumor control in this difficult-to-treat subset.

In the post hoc analysis unveiled at the conference in Chicago, zenocutuzumab demonstrated a 35 percent overall response rate among treatment-naïve patients with NRG1-positive NSCLC. This was slightly higher than the 31 percent response observed in previously treated patients. However, the duration of response revealed a more striking gap: 17.1 months in the frontline setting compared to just 7.4 months among those who had already received prior systemic therapy.

The clinical benefit rate, defined as achieving partial or complete response or stable disease for at least 24 weeks, was 65 percent in treatment-naïve patients versus 58 percent in those previously treated. Importantly, all treatment-related adverse events were limited to Grade 1 or 2 severity, indicating a favorable safety profile.

Why is zenocutuzumab’s mechanism particularly suited for NRG1 fusion-positive tumors?

Zenocutuzumab-zbco is designed to inhibit HER2/HER3 heterodimerization by blocking neuregulin 1 (NRG1) fusion ligands from interacting with the HER3 receptor. Unlike more common oncogenic gene fusions that create abnormal receptors—such as ALK, ROS1, RET, or FGFR—NRG1 fusions generate chimeric ligands that initiate cancer growth by activating the HER3 signaling pathway. This unique biology requires a differentiated therapeutic approach.

Zenocutuzumab’s bispecific format enables dual engagement of HER2 and HER3, thereby suppressing downstream pro-oncogenic signaling in NRG1-driven cancers. The mechanism is particularly relevant in tumors with NRG1 rearrangements, which are rare but increasingly identified through RNA-based next-generation sequencing. Partner Therapeutics emphasized that comprehensive molecular profiling, especially RNA sequencing of tumor tissue, is essential to identify eligible patients who can benefit from this targeted strategy.

What did the updated eNRGy trial reveal about safety and tolerability?

The updated eNRGy trial data reaffirmed the manageable safety profile of zenocutuzumab in both NSCLC and pancreatic cancer settings. Among the 141 patients evaluated, infusion-related reactions were observed in 13 percent, all of which were Grade 1 or 2 and occurred predominantly during the first infusion. The adverse events did not require hospitalization and were resolved with symptomatic management.

For NRG1 fusion-positive NSCLC patients, the most common treatment-emergent adverse events included decreased hemoglobin levels, increased liver enzymes such as alanine aminotransferase and aspartate aminotransferase, electrolyte disturbances including low magnesium, phosphate, and potassium levels, diarrhea, musculoskeletal pain, and elevated alkaline phosphatase. Serious adverse events occurred in 25 percent of patients, including respiratory failure and cardiac failure, with three fatal cases reported.

In patients with pancreatic adenocarcinoma, adverse events followed a broadly similar pattern. Two deaths were reported, one due to COVID-19 and the other due to respiratory failure. The most frequently observed issues included increased liver enzymes, diarrhea, decreased albumin and electrolytes, and general fatigue. In both populations, treatment discontinuation due to adverse events remained low, affecting only three percent of patients.

Why clinicians see zenocutuzumab as a potential shift in first-line care for patients with rare NRG1-driven lung cancer

Clinical researchers and lung cancer experts expressed cautious optimism about zenocutuzumab’s potential to shift treatment guidelines for NRG1-driven lung cancers. Dr. Stephen Liu from Georgetown University, a key investigator in the eNRGy trial, noted that the durability of response and early efficacy signal offer promise for patients who typically do not benefit from standard chemotherapy regimens. He suggested that targeted intervention in the first-line setting could be a game-changer for a molecularly defined subset often left behind in clinical innovation.

Partner Therapeutics’ Chief Development Officer, Pritesh J. Gandhi, underscored the importance of early inhibition of the NRG1 pathway, echoing the trend seen in other oncogene-addicted tumors. According to Gandhi, the improved outcomes observed in treatment-naïve patients validate the company’s development focus and highlight the critical window of opportunity in first-line treatment.

Danielle Hicks, Chief Patient Officer at GO2 for Lung Cancer, emphasized the emotional and clinical significance of the findings. She said the durability and tolerability profile of zenocutuzumab offers a sense of renewed hope to patients and caregivers, particularly in a rare molecular subtype that has long been underserved by conventional therapies.

What are the regulatory milestones ahead for zenocutuzumab?

Zenocutuzumab received accelerated approval from the U.S. Food and Drug Administration in December 2024 for the treatment of adults with unresectable or metastatic NSCLC and pancreatic cancer harboring NRG1 gene fusions, following disease progression on prior systemic therapy. The approval was based on overall response rate and duration of response metrics from the earlier eNRGy readout.

However, continued approval remains contingent upon verification of clinical benefit in confirmatory studies. With the new data strengthening the rationale for frontline use, Partner Therapeutics is expected to design a pivotal Phase 3 trial to formally evaluate zenocutuzumab as a first-line treatment for NRG1+ NSCLC. Regulatory clarity on the design, endpoints, and potential for breakthrough designation will be closely watched over the coming year.

How could BIZENGRI reshape precision oncology for rare gene fusions?

The broader oncology market has seen a growing focus on rare genetic drivers, especially as sequencing becomes more accessible. The success of TRK inhibitors in NTRK fusion-positive cancers and RET inhibitors in RET-driven tumors has validated the “tumor-agnostic but mutation-specific” approach. Zenocutuzumab may now be joining that club, especially given the multi-indication strategy targeting both lung and pancreatic cancers.

However, the key to commercial scale will lie in diagnostics and awareness. NRG1 fusions are still underdiagnosed due to the complexity of RNA-based detection. Expanding diagnostic infrastructure and embedding testing into clinical workflows will be vital to ensure that eligible patients are not missed. Partner Therapeutics appears to be investing in this area, with plans to collaborate with diagnostic partners and advocacy groups to support broader NRG1 fusion testing.

What does the future look like for Partner Therapeutics and its portfolio?

Partner Therapeutics operates as a fully integrated biotech company with a focused pipeline around cancer and serious diseases. In addition to zenocutuzumab-zbco, the company’s marketed portfolio includes sargramostim under the brands IMREPLYS, LEUKINE, and SARGMALIN, depending on the jurisdiction. These assets reflect a broader strategy of supporting immunomodulation and targeted therapeutics.

Zenocutuzumab represents the firm’s most advanced oncology program and potentially its most significant value driver. Should the Phase 3 confirmatory trials validate the current findings, Partner Therapeutics could establish itself as a leader in HER3-targeted therapy and in the broader rare-oncogene drug space. Industry analysts anticipate increased interest from larger pharmaceutical players seeking to expand their portfolios into niche genetic indications, particularly if real-world uptake and companion diagnostic integration progress smoothly.

What are the key takeaways from the updated eNRGy trial results for zenocutuzumab in NRG1+ lung cancer?

The latest analysis of Partner Therapeutics’ Phase 2 eNRGy trial reinforces the role of zenocutuzumab-zbco as a potential first-line treatment option for patients with NRG1 fusion-positive non-small cell lung cancer. The trial results revealed stronger response durability among treatment-naïve patients and reaffirmed the favorable safety profile observed in earlier studies. Expert perspectives from oncologists and advocacy leaders suggest this may represent a significant shift in treatment for this underserved patient population. With accelerated approval already granted by the U.S. Food and Drug Administration, future regulatory decisions will likely hinge on a successful confirmatory trial. The data also underscore the importance of early molecular testing for rare fusion drivers and signal renewed momentum in targeted lung cancer therapy.

• Zenocutuzumab achieved a 35 percent response rate and 17.1-month median duration of response in untreated NRG1+ NSCLC

• Previously treated patients showed a 31 percent response rate with a shorter 7.4-month median duration

• The clinical benefit rate reached 65 percent in the treatment-naïve group

• All treatment-related adverse events were Grade 1 or 2, with no new safety concerns identified

• Expert commentary emphasized potential for first-line use, especially given poor chemotherapy outcomes in NRG1+ lung cancer

• The therapy’s mechanism targets HER3/HER2 signaling activated by NRG1 chimeric ligands

• Broader clinical adoption will depend on increased use of RNA-based fusion testing

• Partner Therapeutics is expected to advance a Phase 3 trial to confirm the early benefits seen

• FDA approval remains contingent on verification of clinical benefit in confirmatory studies

• Zenocutuzumab could become a cornerstone therapy for HER3-targeted intervention in rare genomic cancers