Meru Reports Proof of Concept for Its Bispecific Antibody in NRG1 Fusion Cancers

By Rajaneesh K.Gopinath, Ph.D.

At the AACR-NCI-EORTC International Conference held at Boston, preliminary data
were reported from a Phase I trial, that tested MCLA-128 in treating rare NRG1 gene
fusion harboring cancers.

The Human epidermal growth factor receptor (HER) proteins, regulates the proliferation and survival of epithelial cells in response to extracellular ligand binding. However, the heterodimerization of HER2 & HER3 also induces tumorigenesis and drives tumor expansion. Through an unbiased combinatorial screening, Merus NV, a Netherlands based clinical-stage company had earlier identified a bispecific IgG1 that inhibited HER3 signaling via HER2-guided ligand blockade. This later developed into MCLA-128 (Zenocutuzumab) which began to get evaluated in a number of clinical trials involving cancer patients with solid tumors.

However, last June the company decided to focus on patients with rare NRG1 gene fusions instead. NRG1 is a potentially actionable oncogenic driver that is present in some solid tumors. At the AACR-NCI-EORTC International Conference yesterday, the data from a phase I trial conducted at Memorial Sloan Kettering Cancer Center was presented. The study has found MCLA-128 to show radiological and clinical responses in NRG1-positive patients. The research team selected 3 patients, 2 with metastatic pancreatic ductal adenocarcinoma (PDAC) and one with metastatic non-small cell lung cancer (NSCLC), from a group of 29 who were positive for NRG1 fusions and administered them with 750 mg of MCLA-128 intravenously every other week. It was found that the bispecific antibody demonstrated significant tumor shrinkage in all three of them. The two PDAC patients, exhibited shrinkages of 54% and 25% in tumor diameter while the NSCLC patient showed 33% shrinkage.

“Treating these three patients with MCLA-128 was a rational decision based on our understanding of biology, and our data provide important proof-of-concept demonstrating the promise of targeting NRG1 fusions with this novel approach,” said Alison Schram, MD, a medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, in an official statement to the press.

“Initial data from these three patients suggests that it is important to look for NRG1 fusions in tumors, particularly in KRAS-negative pancreatic cancer and invasive mucinous adenocarcinoma of the lung [a type of lung cancer], and when identified, patients should consider treatment in a clinical trial targeting this alteration,” Schram said. Based on these data, a phase II trial of MCLA-128 is actively accruing and treating patients with NRG1fusion-positive tumors (NCT02912949)” she added.

Bispecific antibodies are designed to bind to two separate antigens or two epitopes of an antigen in a bid to enhance T cell activation and subsequent killing of tumor cells. By blocking the dual binding sites of HER3, Zenocutuzumab prevents HER2-HER3 heterodimerization and HER3 activation by NRG1. At the moment, Amgen’s Blinatumomab and Chugai’s, Emicizumab are the only two FDA-approved bispecific antibodies. Although these results are encouraging, Meru will be hoping that these preliminary successes continue to translate into late stage clinical trial wins for Zenocutuzumab.

References
1. https://www.ncbi.nlm.nih.gov/pubmed/31175342
2. https://www.ncbi.nlm.nih.gov/pubmed/29763625
3. https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1346

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Author

Rajaneesh K. Gopinath