Zenocutuzumab Wins FDA Breakthrough Therapy Designation for Advanced NRG1+ NSCLC

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 non–small cell lung cancer (NSCLC) following progression with prior systemic therapy.¹

The designation is supported by data from the ongoing phase 1/2 eNRGy trial (NCT02912949) and early access program (NCT04100694). Pooled findings from the trial and the early access program presented at the 2022 ASCO Annual Meeting showed that among all patients with NRG1-positive tumors (n = 79), zenocutuzumab elicited an overall response rate (ORR) of 34% (95% CI, 24%-46%), and tumor reduction was observed in 70% of patients. Specifically, in patients with NSCLC (n = 46), the ORR was 35% (95% CI, 21%-50%) with the agent.²

On June 30, 2023, the FDA also granted breakthrough therapy designation to zenocutuzumab 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.3 That decision was also supported by findings from eNRGy and the early access program, which showed that patients with pancreatic ductal adenocarcinoma (n = 19) experienced an ORR of 42% (95% CI, 20%-67%).²

“We are thrilled to receive the second breakthrough therapy designation for zenocutuzumab, this time in NRG1-positive lung cancer,” Bill Lundberg, MD, president and chief executive officer of Merus, stated in a news release.¹ “We believe this further acknowledges zenocutuzumab’s clinically meaningful, durable response for patients with NRG1-positive cancer, and we aim to bring this potential first and best in class targeted agent for NRG1-positive cancer to market with support from a potential commercial partner.”

Zenocutuzumab is a common light chain bispecific antibody designed to dock on HER2 and block the interaction between NRG1 and HER3 to disallow the heterodimerization of HER2 and HER3.

The global, multicenter eNRGy trial and early access program are enrolling patients at least 18 years of age with locally advanced, unresectable or metastatic solid tumors harboring NRG1 fusions who were previously treated or unable to receive standard therapy. An ECOG performance of 0 to 2 is also required.²

Patients are being treated with 750 mg of intravenous zenocutuzumab once every 2 weeks until disease progression, with tumor assessments occurring every 8 weeks.

Investigator-assessed ORR per RECIST v1.1 criteria serves as the primary end point of eNRGy. Secondary end points include duration of response (DOR), ORR per central review, safety, pharmacokinetics, and analysis of antidrug antibodies.

Additional data from the overall population showed that the median duration of exposure to zenocutuzumab was 6.3 months (range, 1-21), and 20 of 83 patients remained on treatment at the April 12, 2022, data cutoff.

The median time to response was 1.8 months. At a median follow-up of 6.3 months, the median DOR was 9.1 months (95% CI, 7.4-not reached). The 6- and 12-month DOR rates were 76% and 27%, respectively.

Pooled safety data for 208 patients treated with recommended phase 2 dose of single-agent zenocutuzumab showed that any-grade adverse effects (AEs) occurred in 92% of patients. Thirty-six percent of patients experienced grade 3/4 AEs, and 3% of patients had a grade 5 AE.

Treatment-related AEs (TRAEs) of any grade were reported in 61% of patients, including 5% who had grade 3/4 TRAEs. Notably, 0.5% of patients had a grade 5 TRAE, and this was an infusion-related reaction.

The most common TRAEs included diarrhea (any grade, 21%; grade 3/4, 0.5%), asthenia/fatigue (12%; 0.5%), nausea (10%; 0.5%), anemia (1%; 0%), infusion-related reaction (15%; 1%), dyspnea (2%; 0.5%), vomiting (4%; 0%), abdominal pain (2%; 0.5%) constipation (2%; 0%), and decreased appetite (4%; 0%). No clinical cardiotoxicity was reported, and less then 1% of patients discontinued treatment due to toxicities.

A clinical update for zenocutuzumab is expected to be provided at an upcoming medical conference in 2023.¹

References

1. Zenocutuzumab (zeno) granted second breakthrough therapy designation by the US Food & Drug Administration. News release. Merus NV. July 5, 2023. Accessed July 7, 2023. https://ir.merus.nl/news-releases/news-release-details/zenocutuzumab-zeno-granted-second-breakthrough-therapy
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. 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 7, 2023. https://ir.merus.nl/news-releases/news-release-details/zenocutuzumab-zeno-granted-breakthrough-therapy-designation-us