FDA Grants Breakthrough Designation to Zenocutuzumab for NRG1+ Pancreatic Cancer


Data from an early access program and the eNRGy trial evaluating zenocutuzumab have led the FDA to grant the agent breakthrough designation for patients with NRG1 fusion-positive pancreatic cancer.

The FDA has a granted breakthrough therapy designation to zenocutuzumab (MCLA-128) for the treatment of patients with advanced unresectable or metastatic NRG1 fusion-positive pancreatic cancer following disease progression on previous systemic therapy or for whom there are no satisfactory alternative options available.1

Findings from an early access program (EAP) assessing the safety and antitumor activity of zenocutuzumab (NCT04100694) and the phase 1/2 eNRGy trial (NCT02912949) support the designation.

According to data previously reported presented from the eNRGy trial, zenocutuzumab led to an objective response rate (ORR) of 34% (95% CI, 24%-46%) by investigator assessment and RECIST v1.1 criteria at a median follow-up of 6.3 months in 79 patients with previously treated advanced NRG1-positive cancers.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). Now as of June 1, 2023, over 175 patients with NRG1-positive cancer have been treated with zenocutuzumab monotherapy.

“We believe the compelling clinical data for zenocutuzumab in NRG1-positive cancer, and breakthrough therapy designation, provide the opportunity to further engage with the FDA to expedite the review of a potential biologics license application submission,” said Bill Lundberg, MD, president and chief executive officer of Merus NV, in a press release.1

Zenocutuzumab is an antibody-dependent cell-mediated cytotoxicity-enhanced Biclonics. The agent binds to HER2 and potently blocks the interaction of HER3 with its ligand NRG1 or NRG1-fusion proteins. Previously, in July 2020, the FDA granted an orphan drug designation to zenocutuzumab for use in patients with pancreatic cancer.1 Then in January 2021, the FDA granted the agent fast track status for the treatment of patients with NRG1-positive metastatic solid tumors that have progressed on standard treatment.

Treatment with zenocutuzumab has to potential to be effective against NRG1+ cancers as it previously demonstrated strong inhibition of cell growth and molecular signaling at up to 0.01 µM.2

In a global, open-label, multicenter, phase 1/2 trial, patients with locally advanced, unresectable, or metastatic solid tumors harbor NRG1 fusions were enrolled if aged 18 years or older. Patients were required to have received prior treatment with or have been unable to receive standard therapy, and must have had an ECOG performance status of 0 to 2.2

Zenocutuzumab was given to patients at a dose of 750 mg intravenously every 2 weeks until disease progression with tumor assessments done every 8 weeks. Patients then entered a follow-up period of up to 2 years.

The primary end point of the trial was investigator-assessed ORR, and secondary end points were DOR, ORR by central review, safety, pharmacokinetics, and antidrug antibodies.

At the data cutoff date of April 12, 2022, 83 patients were enrolled in the primary analysis population. Patients had a median age of 59 years (range, 22-84) and more than half of patients were female (59%), White (57%), and had metastatic (99%) and measurable (95%) disease. A median of 2 prior lines of therapy was received among the patients enrolled (range, 0-8) and 11% previously were treated with afatinib (Gilotrif). Twenty-four percent of patients were still receiving treatment at the time of data cutoff. The most common reason for treatment discontinuation was progressive disease (73%). Patients were exposed to zenocutuzumab for a median of 6.3 months (range, 1-21).

Further, patients enrolled had primary tumors, including non–small cell lung cancer (NSCLC; 57%), pancreatic ductal adenocarcinoma (PDAC; 23%), breast cancer (8%), cholangiocarcinoma (4%), colorectal cancer (4%), or other (5%). A total of 77% of patients had their NRG1 fusion detected by RNA sequencing, 22% by DNA sequencing, and 1% through nanostring technology. Twenty-six distinct fusion partners were identified, with the most common being CD74 (31%), SLC3A2 (16%), and ATP1B1 (13%).

Data also revealed that zenocutuzumab produced an investigator-assessed ORR of 42% (95% CI, 20%-67%) among patients with PDAC and the ORR was 35% (95% CI, 21%-50%) in patients with NSCLC. The 6-month DOR rate among all patients was 76% and the 12-month DOR rate was 27%. Seventy percent of the 79 evaluable patients experienced tumor reduction with treatment from baseline.

Regarding safety, for patients who received zenocutuzumab at the recommended phase 2 dose across indications on the phase 1/2 trial, 92% of patients had at least 1 all-grade AE, 36% had grade 3 or 4 AE, and 3% had a grade 5 AE. A total of 61% of patients experienced all-grade treatment-related AEs (TRAEs), 5% had grade 3 or 4 TRAEs, and 0.5% experienced a grade 5 TRAE. The most common all-grade TRAEs seen with zenocutuzumab included diarrhea (21%), asthenia/fatigue (12%), infusion-related reactions (15%), and nausea (10%). Moreover, less than 1% of patients discontinued treatment with zenocutuzumab due to their AEs.

Merus is expected to provide a clinical update on the agent in NRG1-positive cancers at an upcoming medical conference and is currently also evaluating the combination of zenocutuzumab and afatinib (Gilotrif) in patients with NRG1-positive NSCLC.

  1. Zenocutuzumab (Zeno) granted breakthrough therapy designation by the US Food & Drug Administration for the treatment of NRG1+ pancreatic cancer. News release. Merus NV. June 29, 2023. Accessed July 5, 2023. https://tinyurl.com/2uxeftap
  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
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