Zenocutuzumab Receives FDA BTD in Advanced NRG1+ Pancreatic Cancer

The FDA has granted breakthrough therapy designation (BTD) to zenocutuzumab (MCLA-128) as a treatment for patients with advanced unresectable or metastatic NRG1 fusion–positive pancreatic cancer that has progressed following prior systemic therapy or for which there are no suitable alternative treatment options, according to a press release from Merus.¹

Supporting data for the BTD came from the ongoing phase 1/2 eNRGy trial (NCT02912949) as well as an Early Access Program (NCT04100694) that are both evaluating single agent zenocutuzumab among those with NRG1-positive cancers. After a median follow-up of 6.3 months in the eNRGy trial, the investigator-assessed objective response rate (ORR) was 34% (95% CI, 24%-46%) among all evaluable patients (n = 79), according to an update from the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.² Additionally, the median time to response was 1.8 months, and the median duration of response (DOR) was 9.1 months (95% CI, 7.4-not reached).

“We believe the compelling clinical data for [zenocutuzumab] in [NRG1-positive] cancer, and [BTD], provide the opportunity to further engage with the FDA to expedite the review of a potential [biologics license application] submission,” Bill Lundberg, MD, president and chief executive officer at Merus, said in the press release.

Investigators of the international, open-label, multi-center phase 1/2 eNRGy trial are assessing zenocutuzumab in NRG1-positive canceracross 3 patient cohorts, including those with pancreatic adenocarcinoma, non–small cell lung cancer (NSCLC), and other solid tumors. Each patient received 750 mg of the agent every 2 weeks until disease progression, and investigators performed tumor assessments every 8 weeks.

The trial’s primary end points are ORR per investigator assessment and DOR based on RECIST v1.1 criteria. Secondary end points include the maximum plasma concentration and volume of distribution of zenocutuzumab, clinical benefit rate, time to response, and safety and tolerability.

Patients 18 years and older with at least 1 measurable lesion per RECIST v1.1 criteria and an ECOG performance status of 0 to 2 were eligible to enroll on the trial. Additional eligibility criteria included having an estimated life expectancy of at least 12 weeks, receipt of prior standard therapy appropriate for their tumor type and stage of disease, and any toxicities due to previous anti-cancer treatment resolved.

In the eNRGy trial, 61% of patients experienced any-grade treatment-related adverse effects (TRAEs), including grade 3/4 TRAEs in 5%. The most common any-grade TRAEs included diarrhea (21%), asthenia/fatigue (12%), infusion-related reactions (15%), and nausea (10%). Additionally, less than 1% of patients discontinued treatment due to toxicity.

The developers of zenocutuzumab plan to evaluate the agent in combination with androgen deprivation therapy agents such as enzalutamide (Xtandi) or abiraterone (Zytiga) among patients with castration-resistant prostate cancer and expect to have a readout of initial data in the second half of 2023. Moreover, investigators are assessing zenocutuzumab plus afatinib (Gilotrif) as a treatment for those with NRG1-positive NSCLC.

The FDA previously granted fast track designation to zenocutuzumab for treating metastatic NRG1-positive tumors in January 2021.³ The agent also received an orphan drug designation from the regulatory agency in July 2020.

References

1. Zenocutuzumab (Zeno) granted breakthrough therapy designation by the U.S. Food & Drug Administration for the treatment of NRG1+ pancreatic cancer. News release. Merus N.V. June 29, 2023. Accessed July 5, 2023. https://shorturl.at/iGRX2
2. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105
3. Merus granted FDA fast track designation of zenocutuzumab for the treatment of patients with neuregulin 1 fusion cancers. News release. Merus N.V. January 7, 2021. Accessed July 5, 2023. https://shorturl.at/vUWZ1