FDA Grants Priority Review to Zenocutuzumab BLA for NRG1+ NSCLC and Pancreatic Cancer

The FDA has granted priority review to a biologics license application (BLA) seeking the approval of zenocutuzumab (MCLA-128) for use in the treatment of patients with NRG1-positive non–small cell lung cancer (NSCLC) and pancreatic cancer.¹

The application is partly supported by findings from the phase 1/2 eNRGy trial (NCT02912949), in which the bispecific antibody elicited an investigator-assessed objective response rate (ORR) of 37.2% (95% CI, 26.5%-48.9%) by RECIST 1.1 criteria in patients with NSCLC (n = 79).² In the patients with pancreatic ductal adenocarcinoma (PDAC; n = 33), zenocutuzumab induced an investigator-assessed ORR of 42.4% (95% CI, 25.5%-60.8%) by RECIST 1.1 criteria.³

“FDA acceptance of our first BLA represents an important achievement for Merus and an important potential treatment opportunity for patients with NRG1-positive cancer, a disease with poor prognosis and high unmet need,” Andrew Joe, MD, chief medical officer at Merus NV, stated in a press release.¹ “Zenocutuzumab has the potential to be the first and only targeted therapy for patients with NRG1-positive lung and pancreatic cancer, and may offer a substantial improvement over currently available therapies.”

Zenocutuzumab binds to the HER2 and HER3 extracellular domains.² Preclinical findings have suggested that because the agent blocks the binding of NRG1 to HER3 and the dimerization of HER2 and HER3 it quells tumor cell proliferation and survival. The agent has also been found to mediate antibody-dependent cellular cytotoxicity in vitro.

In the ongoing, global, open-label, phase 1/2 eNRGy study, investigators enrolled patients with NRG1-positive locally advanced unresectable or metastatic solid tumors who previously received or were not able to receive standard treatment. Patients needed to be at least 18 years of age and have an ECOG performance status ranging from 0 to 2.

Study participants were administered zenocutuzumab at 750 mg every 2 weeks until progressive disease. The primary end point of the study is investigator-assessed ORR by RECIST 1.1 criteria, and secondary end points include duration of response (DOR), ORR by central review assessment, and safety.

NSCLC Data Snapshot

Data from the NSCLC primary analysis population were shared during the 2023 ESMO Congress and had a data cutoff date of July 31, 2023.

The median patient age was 64 years (range, 32-88). The majority were female (62%), had an ECOG performance status of 1 (63%), and were Asian (51%). With regard to histology, 84% had adenocarcinoma, 14% had invasive mucinous adenocarcinoma, 1% had squamous cell carcinoma, and 1% had poorly differentiated carcinoma. In this population, the median number of metastatic sites was 2 (range, 0-8).

The median number of prior lines of systemic treatment received was 1, with a range of 0 to 6. Seventy-two percent of patients had received platinum-based chemotherapy, 11% had prior exposure to afatinib (Gilotrif), and 15% were treatment naive.

At the time of data cutoff, 25% of patients were still receiving treatment. Additional efficacy data showed that the clinical benefit rate achieved with the bispecific antibody was 61.5% (95% CI, 49.8%-72.3%). The median time to response (TTR) was 1.8 months (range, 1.5-13.0), and the median DOR was 14.9 months (95% CI, 7.4-20.4). The Kaplan-Meier estimated 6-month DOR rate was 81% (95% CI, 60%-92%) and the 12-month DOR rate was 57% (95% CI, 34%-75%).

PDAC Data Deep Dive

Findings from the PDAC primary analysis population were also shared during the 2023 ESMO Congress and had a data cutoff date of July 31, 2023.

In this population, the median patient age was 49 years (range,21-72). Slightly more than half of patients were male (55%), and most patients were White (85%). Fifty-five percent of patients had an ECOG performance status of 0, 42% had a status of 1, 0% had a status of 2, and 3% had a status of 3. All patients had KRAS wild-type disease. The median number of prior lines of systemic treatment was 2, with a range of 0 to 5. Patients had a median of 2 metastatic sites (range, 1-8), all in the liver and 30% also in the lung.

Additional efficacy findings revealed that the median TTR was 1.8 months (range, 1.6-5.4) and the median DOR with zenocutuzumab was 9.1 months (95% CI, 5.5-12.0) by investigator assessment and RECIST 1.1 criteria. The Kaplan-Meier estimated 6-month DOR rate in this population was 71% (95% CI, 41%-88%).

Safety Insights

Zenocutuzumab was determined to have a tolerable safety profile in the 189 patients with NRG1-positive cancer who received the bispecific antibody as a single agent at 750 mg every 2 weeks. At least one related treatment-emergent adverse effect (TEAE) was experienced by 61% of patients; these effects were grade 3 or 4 in 6% of patients. The most common related TEAEs that occurred in 10% or more of patients included diarrhea (all grade, 17%; grade 3/4, 2%), infusion-related reactions (12%; 0%), fatigue (10%; 0%), nausea (8%; 1%), vomiting (6%; 1%), anemia (4%; 1%), constipation (3%; 0%), increased alanine aminotransferase (3%; 1%), increased aspartate aminotransferase (3%; 1%), reduced appetite (3%; 1%), and abdominal pain (2%; 1%).

Prior Designations Paving the Road to Priority Review

In January 2021, the FDA granted fast track designation to zenocutuzumab for use in patients with metastatic solid tumors harboring NRG1 fusions who have progressed on standard therapies.⁴ In June 2023, the regulatory agency also granted breakthrough therapy designation to the agent for use in patients with advanced unresectable or metastatic NRG1 fusion–positive pancreatic cancer following progressive disease on prior systemic therapy or who have no satisfactory alternative options available.⁵ A month later, the FDA granted a breakthrough therapy designation to zenocutuzumab for use in those with advanced unresectable or metastatic NSCLC harboring NRG1 fusions after disease progression on previous systemic therapy.⁶

References

1. 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 May 7, 2024. https://ir.merus.nl/news-releases/news-release-details/merus-announces-us-fda-acceptance-and-priority-review-biologics
2. Schram A, Goto K, Kim D-W, et al. 1315MO 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
3. 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
4. Merus granted FDA fast track designation of zenocutuzumab for the treatment of patients with Neuregulin 1 Fusion cancers. News release. Merus NV. January 7, 2021. Accessed May 7, 2024. https://ir.merus.nl/news-releases/news-release-details/merus-granted-fda-fast-track-designation-zenocutuzumab-treatment
5. 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 May 7, 2024. https://ir.merus.nl/news-releases/news-release-details/zenocutuzumab-zeno-granted-breakthrough-therapy-designation-us
6. Zenocutuzumab (zeno) granted second breakthrough therapy designation by the US Food & Drug Administration. News release. Merus NV. July 5, 2023. Accessed May 7, 2024. https://ir.merus.nl/news-releases/news-release-details/zenocutuzumab-zeno-granted-second-breakthrough-therapy