FDA Extends PDUFA Date for Zenocutuzumab in NRG1+ NSCLC and Pancreatic Cancer

FDA

The FDA has extended the target action date under the Prescription Drug User Fee Act (PDUFA) for the biologics license application (BLA) seeking the approval of zenocutuzumab (MCLA-128) in the treatment of patients with NRG1-positive non–small cell lung cancer (NSCLC) and pancreatic cancer.¹

The regulatory agency previously granted priority review to the BLA in May 2024.² However, additional time was required to review information submitted to the FDA in response to a chemistry manufacturing and controls request.¹ No additional clinical data were requested by the FDA, according to an announcement from Merus NV, the developer of zenocutuzumab.

The new PDUFA target action date is February 4, 2025.

The BLA is supported by data from the phase 1/2 eNRGy trial (NCT02912949), which demonstrated that patients with NSCLC harboring NRG1 fusions (n = 79) achieved an objective response rate (ORR) of 37.2% (95% CI, 26.5%-48.9%) per investigator assessment by RECIST 1.1 criteria.³ The clinical benefit rate was 61.5% (95% CI, 49.8%-72.3%).

Patients with NSCLC experienced a median time to response of 1.8 months (range, 1.5-13.0), and the median duration of response (DOR) was 14.9 months (95% CI, 7.4-20.4). The 6- and 12-month DOR rates were 81% (95% CI, 60%-92%) and 57% (95% CI, 34%-75%), respectively.

In patients with pancreatic ductal adenocarcinoma (PDAC; n = 33), zenocutuzumab produced an investigator-assessed ORR of 42.4% (95% CI, 25.5%-60.8%) per RECIST 1.1 criteria.⁴ One patient (3%) achieved a complete response, and the remainder of responders (39%) had partial responses. The stable disease rate was 45%, and the clinical benefit rate was 72.7% (95% CI, 54%-87%).

The investigator-assessed median DOR was 9.1 months (95% CI, 5.5-12.0) per RECIST 1.1 criteria, and the 6-month DOR rate was 71% (95% CI, 41%-88%).

Zenocutuzumab in a novel bispecific antibody that binds to the extracellular domains of HER2 and HER3.³ NRG1 is a ligand that binds to HER3 to promote HER2 and HER3 heterodimerization and oncogenesis, which leads to tumor growth.

The global, multicenter eNRGy trial enrolled patients at least 18 years of age with locally advanced, unresectable, or metastatic solid tumors—including NSCLC and PDAC—harboring NRG1 fusions who were previously treated with or unable to receive standard-of-care therapy.³ Patients were also required to have an ECOG performance status of 0 to 2.

Eligible participants received 750 mg of intravenous zenocutuzumab once every 2 weeks until disease progression. Tumor assessments were conducted every 8 weeks.

Investigator-assessed ORR per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included DOR, central-assessed ORR, and safety.

Safety data for patients with NRG1-positive solid tumors (n = 189) who received zenocutuzumab at 750 mg once every 2 weeks showed that treatment-emergent adverse effects (TEAEs) did not lead to treatment discontinuation in any patients, and no grade 5 treatment-related TEAEs were reported.

Any-grade TEAEs of any cause occurred in 88% of patients, and 35% of patients had grade 3 or 4 TEAEs. The most common TEAEs of any cause included diarrhea (any-grade, 28%; grade 3/4, 2%), infusion-related reactions (28%; 2%), fatigue (12%; 0%), nausea (16%; 2%), vomiting (11%; 1%), anemia (15%; 4%), constipation (13%; 0%), increased alanine aminotransferase levels (10%; 3%), increased aspartate aminotransferase levels (7%; 3%), decreased appetite (8%; 1%), abdominal pain (11%; 2%), dyspnea (13%; 3%), increased gamma-glutamyl transferase levels (6%; 3%), decreased platelet counts (2%; 1%), hyperuricemia (2%; 1%), bacteremia (1%; 1%), and hypertransaminasemia (1%; 1%).

References

1. Merus receives FDA extension of PDUFA for zenocutuzumab. News release. Merus NV. November 5, 2024. Accessed November 5, 2024. https://ir.merus.nl/news-releases/news-release-details/merus-receives-fda-extension-pdufa-zenocutuzumab
2. Merus announces US FDA acceptance and priority review of biologics license application for zeno for the treatment of NRG1+ NSCLC and PDAC. News release. Merus NV. May 6, 2024. Accessed November 5, 2024. https://ir.merus.nl/news-releases/news-release-details/merus-announces-us-fda-acceptance-and-priority-review-biologics
3. Schram A, Goto K, Kim D-W, et al. Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S756-S757. doi:10.1016/j.annonc.2023.09.2349
4. Schram A, Macarulla T, Cleary J, et al. 1618P Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC). Ann Oncol. 2023;34(suppl 2):S895-S896. doi:10.1016/j.annonc.2023.09.2567