Zenocutuzumab: An Effective Option Beyond Progression in NRG1+ NSCLC?

NRG1 fusions are a clinically meaningful oncogenic driver to target in non–small cell lung cancer (NSCLC) with zenocutuzumab-zbco (Bizengri), even in the event of initial disease progression, according to Zhaohui Liao Arter, MD.

In a conversation with CancerNetwork^®, Arter detailed findings from an updated analysis of the phase 2 eNRGy trial (NCT02912949) assessing zenocutuzumab among patients with NSCLC harboring NRG1 fusions. Data presented at the 2026 IASCLC Targeted Therapies of Cancer Meeting showed “encouraging” responses and clinical benefits in a cohort of patients who experienced initial disease progression on the agent.^1,2

Arter, an assistant professor of Medicine in the Division of Hematology and Oncology and a thoracic oncologist at the University of California, Irvine School of Medicine, discussed how the latest analysis may affirm the FDA’s accelerated approval of zenocutuzumab in this NRG1 fusion–positive population based on earlier data from the eNRGy trial.³ She also spoke to how the agent’s safety profile supports extended durations of therapy, with some patients continuing treatment for over 3 years.

CancerNetwork: What was the rationale for assessing zenocutuzumab beyond progression among patients with NRG1 fusion–positive NSCLC in the phase 2 eNRGy trial?

Arter: The rationale came down to the unique clinical situation these patients [have]. NRG1 fusion–positive NSCLC is very rare. We're talking about less than 1% [of NSCLC cases], and these patients have historically had very limited treatment options.... The outcomes with the standard therapies are frankly disappointing. Platinum-based chemotherapy achieves only about a 13% response rate, and single-agent immunotherapy gets around 20% with a median progression-free survival [PFS] of just 3.6 months. We are dealing with patients who don't have very good alternatives.

The other piece that we learned from other targeted therapies in lung cancer, such as EGFR [tyrosine kinase inhibitors (TKIs)], is that continuing treatment beyond RECIST-defined progression can provide meaningful clinical benefit, especially in patients with oligoprogression or asymptomatic disease. The NCCN guidelines already incorporate this approach for EGFR- and ALK-positive disease. When we did this analysis, we were asking, "Can we apply that same principle here? If a patient is tolerating zenocutuzumab well [and] has asymptomatic oligoprogression, or isolated sites that can be managed with local therapy, either radiation or surgical resection, why would we stop a drug that's still providing systemic disease control?" Also, the favorable safety profile of zenocutuzumab supports this approach.

What did efficacy findings show among 27 patients who received at least 3 doses of zenocutuzumab after radiographic progression? Which patients experienced the most pronounced benefits?

The findings were encouraging among the 27 patients who continued treatment beyond progression. We saw an overall response rate of 52% prior to progression, with a clinical benefit rate of 67%. The median duration of response was 7.4 months. Importantly, the median total exposure to zenocutuzumab was 9.9 months, with 3.1 months of that coming after progression. What's particularly striking is that 8 patients—that was 30% of the cohort—remained on zenocutuzumab for more than 6 months beyond progression. As of the data cutoff, 4 patients remained on treatment, and we have 1 patient who's been on treatment for over 23 months beyond progression [who] is still ongoing as of December 2025.

In terms of who benefited most, the case studies illustrated that the patients who did the best tended to have oligoprogressive disease. Basically, 81% of patients had 3 or fewer lesions and 2 or fewer sites. Most of them were asymptomatic or minimally symptomatic, maintained a good performance status, and had disease amenable to local therapy. For example, [patient] 2 was a 75-year-old woman who achieved a partial response and has been on treatment for over 3 years, with more than 2.3 years beyond progression; [treatment] is still ongoing. Her rationale for continuation was minimum disease, and she was asymptomatic. That's exactly the kind of patients where this approach makes sense. We also saw that 22% of patients received a local therapy—Gamma Knife, radiotherapy, or surgical resection—as an adjunct to continued systemic zenocutuzumab. This multimodality approach allowed us to address isolated sites of the progression while maintaining systemic disease control.

Did the updated analysis reveal anything new regarding the safety and tolerability of zenocutuzumab in this patient population?

The short answer is no. What's reassuring is that the safety profile remained excellent, even with extended treatment duration. In this beyond progression cohort, 78% of patients experienced treatment-related adverse events [TRAEs]. However, the vast majority were low grade. The most common TRAEs were diarrhea at 33% and paronychia at 11%, both grade 1 or 2. We had only 1 patient with a grade 3 or higher TRAE in the entire cohort, which was grade 3 anemia.

But here's the key finding: No patients discontinued treatment due to AEs. When you consider that some of these patients have been on treatment for over 3 years, that's very remarkable. It tells us that extended treatment does not lead to cumulative toxicity. This is consistent with what we saw in the primary eNRGy analysis, where the most common TRAEs were diarrhea and fatigue, all grade 1 or 2.⁴ Only 1 patient in the entire patient safety population [of more than 200] discontinued due to a drug-related toxicity. Basically, the updated analysis reinforced that zenocutuzumab has a favorable safety profile that supports the rationale for treatment beyond progression. Patients can continue therapy without accumulating significant toxicity, which is crucial when we are asking them to stay on treatment for extended periods.

How might these updated findings affirm the FDA accelerated approval of zenocutuzumab for adults with unresectable or metastatic NSCLC harboring an NRG1 gene fusion?

These findings strengthen the case for this FDA decision in several important ways. First, they demonstrate durable clinical benefit beyond what we saw in the primary analysis, which was published in the New England Journal of Medicine.⁴ The fact that patients can continue to derive benefit even after RECIST-defined progression, with some patients remaining on treatment for over 3 years, speaks to the meaningful impact this drug has. Second, the safety data are critical for accelerated approval, which requires a favorable benefit-risk assessment. The fact that we saw no discontinuation due to AEs in this beyond-progression cohort, even with the standard treatment duration, confirms that the safety profile supports prolonged therapy. Finally, this addresses a true unmet medical need. As we know, prior to zenocutuzumab, there was no approved targeted therapy for NRG1 fusion-positive cancer, so these patients had essentially been offered [a new option] by the precision medicine revolution. Now, they have an option that's specially designed for the molecular alteration.

These findings can certainly support the accelerated approval pathway and provide additional evidence that will be important for the confirmatory studies needed for the full approval.

What do you hope others take away from this conversation?

There are several key messages I would like colleagues to take away. First, NRG1 fusions are actionable targets. Even though they are rare—less than 1% [of patients]—they represent a clinically meaningful oncogenic driver that we should be looking for. If you are treating a patient with the driver in NSCLC—especially invasive, mucinous adenocarcinoma—or KRAS wild-type pancreatic cancer, consider RNA-based next-generation sequencing to look for an NRG1 fusion.

Second, progressive disease does not always mean treatment failure. This analysis challenges the conventional paradigm that RECIST-defined progression mandates stopping therapy. In select patients, such as in this case and this analysis, especially for those with oligoprogression, asymptomatic disease, and who maintained performance status, continuing zenocutuzumab can provide meaningful clinical benefit.

Third, the safety profile supports extended treatment, with no discontinuation due to adverse events, even in patients treated for over 3 years. We can feel confident offering prolonged therapy to patients who are benefiting.

Fourth, multidisciplinary care matters. The integration of local therapy, such as Gamma Knife, radiotherapy, and surgical resection, with the continued systemic therapy requires tumor board discussion. This isn’t a one-size-fits-all approach. It does require individualized decision-making.

Finally, there’s a hope for [managing] rare molecular subtypes. For a long time, patients with NRG1 fusions had no targeted options. This work demonstrates that even for rare alterations, precision medicine can deliver meaningful clinical benefit. It is a reminder of why comprehensive genomic profiling matters and why we should continue investing in understanding and targeting real drivers.

References

1. Arter ZL, Schram AM, Rha SY, et al. Continued treatment beyond progression with zenocutuzumab, a HER2/HER3 bispecific antibody, in patients with NRG1+ NSCLC: analysis from the ongoing phase 2 eNRGy trial. Presented at the International Association for the Study of Lung Cancer (IASLC) 2026 Targeted Therapies of Lung Cancer Meeting; Huntington Beach, CA; February 20, 2026.
2. Zenocutuzumab treatment beyond progression demonstrates continued benefit in patients with NRG1+ non-small cell lung cancer: new results from the eNRGy trial. News release. Partner Therapeutics Inc. February 20, 2026. Accessed March 3, 2026. https://tinyurl.com/3tzz5vma
3. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. December 4, 2024. Accessed December 4, 2024. https://shorturl.at/E3HBS
4. Schram AM, Goto K, Kim DW, et al. Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. N Engl J Med. 2025;392(6):566-576. doi:10.1056/NEJMoa2405008