FDA Grants Breakthrough Therapy Designation to Zenocutuzumab for NRG1+ Pancreatic Cancer

The FDA has granted breakthrough therapy designation to zenocutuzumab (MCLA-128) for use as a potential therapeutic option in patients with advanced unresectable or metastatic NRG1 fusion–positive pancreatic cancer after disease progression on previous systemic therapy or who have no satisfactory alternative options available.¹

Zenocutuzumab is a common light chain bispecific Biclonics antibody that has strong antibody-dependent cellular cytotoxicity activity.² By docking on HER2 and blocking the interaction between NRG1 and HER3, the agent prevents HER2/HER3 heterodimerization. Previously, the agent has demonstrated strong inhibition of cell growth and molecular signaling at up to 0.01 µM.

The designation is supported by findings from an early access program for the drug (NCT04100694) and the phase 1/2 eNRGy trial (NCT02912949).¹

Data presented at the 2022 ASCO Annual Meeting showed that at a median follow-up of 6.3 months, zenocutuzumab induced an objective response rate (ORR) of 34% (95% CI, 24%-46%) by investigator assessment and RECIST v1.1 criteria in patients with previously treated advanced NRG1-positive cancers (n = 79).² 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 breakthrough therapy designation, 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 of Merus NV, stated in a press release.¹

The global, open-label, multicenter, phase 1/2 trial enrolled patients with locally advanced, unresectable or metastatic solid tumors harboring NRG1 fusions. To be eligible, patients needed to be aged 18 years or older, received prior treatment with or have been unable to receive standard therapy, and an ECOG performance status of 0 to 2.²

Patients were given zenocutuzumab at 750 mg intravenously every 2 weeks until disease progression. Tumor assessments were done every 8 weeks. Patients then entered a follow-up period of up to 2 years.

In addition to investigator-assessed ORR serving as the primary end point of the trial, secondary end points included DOR, ORR by central review, safety, pharmacokinetics, and antidrug antibodies.

As of the data cutoff date of April 12, 2022, a total of 83 patients comprised the primary analysis population. Twenty-seven patients were excluded due to less than 6 months of follow-up (n = 21), a baseline scan happening more than 5 weeks before their first dose (n = 1). Other genetic drivers like KRAS (n = 2), previous treatment with an anti-HER3 inhibitor (n = 3), aand an ECOG performance status of 3 (n = 1).

The median age of patients was 59 years (range, 22-84) and more than half of patients were female (59%) and White (57%). The majority of patients had metastatic (99%) and measurable (95%) disease. Primary tumors included non–small cell lung cancer (NSCLC; 57%), pancreatic ductal adenocarcinoma (PDAC; 23%), breast cancer (8%), cholangiocarcinoma (4%), colorectal cancer (4%), or other (5%).

Patients had received a median of 2 prior lines of therapy (range, 0-8) and 11% previously received afatinib (Gilotrif). Twenty-four percent of patients were still receiving treatment at the time of data cutoff. Most of those who discontinued treatment did so because of progressive disease (73%). Patients were exposed to zenocutuzumab for a median of 6.3 months (range, 1-21).

In all patients (n = 83), 77% had their NRG1 fusion detected by RNA sequencing, 22% by DNA sequencing, and 1% through nanostring technology. There were 26 distinct fusion partners identified, the most common of which being CD74 (31%), SLC3A2 (16%), and ATP1B1 (13%).

Additional data showed that zenocutuzumab induced an investigator-assessed ORR of 42% (95% CI, 20%-67%) in those with PDAC and of 35% (95% CI, 21%-50%) in those with NSCLC. In all patients, the 6-month DOR rate was 76% and the 12-month DOR rate was 27%.

Of 79 evaluable patients, 70% of patients experienced tumor reduction with treatment from baseline.

Among all patients who received zenocutuzumab at the recommended phase 2 dose across indications on the phase 1/2 trial—not just those with NRG1 fusions, 92% of patients reported at least 1 all-grade AE, 36% had grade 3 or 4 toxicity, and 3% had a grade 5 effect.

All-grade treatment-related AEs (TRAEs) were observed in 61% of patients, 5% experienced grade 3 or 4 TRAEs, and 0.5% experienced a grade 5 TRAE. The most common all-grade TRAEs experienced with zenocutuzumab were diarrhea (21%), asthenia/fatigue (12%), infusion-related reactions (15%), and nausea (10%).

Less than 1 percent of patients discontinued treatment due to AEs.

Previously, in July 2020, the FDA granted an orphan drug designation to zenocutuzumab for use in patients with pancreatic cancer.¹ In January 2021, the agent received fast track status from the regulatory agency for use in patients with NRG1-positive metastatic solid tumors that have progressed on standard treatment.

Merus shared plans to present a clinical update on the agent in NRG1-positive cancers at an upcoming medical conference.

References

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 June 30, 2023. https://ir.merus.nl/news-releases/news-release-details/zenocutuzumab-zeno-granted-breakthrough-therapy-designation-us
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