Zenocutuzumab Effectively Blocks Growth of NRG1 Fusion-Driven Tumors

In NRG1 fusion–positive cell lines, zenocutuzumab (Zeno; MCLA-128) demonstrated blockage of growth and cell death, as well as tumor shrinkage and durable tumor regression in multiple cancers when used in NRG1 fusion–positive patient-derived xenografts, according to a poster presentation given during the virtual AACR Annual Meeting 2021.¹

The antibody-dependent cellular cytotoxicity (ADCC)–enhanced anti-HER2/HER3 bispecific antibody was also found to block HER3 phosphorylation and downstream signaling, induce expression of markers of apoptosis and cell cycle arrest, and inhibit expression of cyclin D1.

“Zenocutuzumab effectively blocks the growth of NRG1 fusion–positive cell lines and xenograft models of tumors arising from the lung, pancreas, and other organs,” lead author Igor Odintsov, MD, research fellow at Memorial Sloan Kettering Cancer Center, and colleagues, wrote in the poster on the data. “In vitro, zenocutuzumab has no significant effect on parental cells and only inhibits viability induced by expression of a NRG1 fusion. In vivo, [the agent] demonstrated significant efficacy at clinically relevant dose levels illustrating potent therapeutic activity.”

Fusions that involve the NRG1 gene occur at low frequency in pancreatic cancer, lung cancer, and other cancers, according to the study authors. NRG1 fusion oncoproteins adhere to HER3, resulting in heterodimerization with HER2 and strong activation of downstream signaling that happens mainly through the PI3K/AKT pathway.

Zenocutuzumab, which is manufactured by Merus, was designed to “dock” on HER2 to appropriately position the antibody and then “block” NRG1 from interacting with HER3; this serves to effectively prevent HER2:HER3 heterodimerization and downstream signaling.

Previously, in January 2021, the FDA granted a fast track designation to zenocutuzumab for the treatment of patients with solid tumors that harbor NRG1 gene fusions and have progressed on standard-of-care therapy.

For the study presented during the meeting, investigators set out to examine the efficacy of zenocutuzumab in preclinical models of NRG1 fusion–positive cancers. To do this, the agent was evaluated in a panel of isogenic and patient-derived cell lines and xenograft (PDX) models of several cancers, including of the lung, breast, and pancreas. Cell lines either expressed an NRG1 fusion endogenously or by lentiviral transfer of cDNAs.

The models were generated from non–small cell lung cancer samples that harbored CD74-NRG1 (ST3204) or SLC3A2-NRG1 (LUAD-0061AS3) fusions, as well as from a high-grade serous ovarian cancer that harbored a CLU-NRG1 fusion (OV-10-0050). Pancreas samples harbored ATP1B1-NRG1 fusion (H6C7-ATP1B1-NRG1) and SLC3A2-NRG1 fusion (H6C7-SLC3A2-NRG1).

When the agent was examined in NRG1 fusion–positive breast cancer, pancreatic cancer, and lung cancer cell lines, investigators noted a reduction of disease growth that was dose dependent. In all of the cell lines that had been evaluated, abrogated phosphorylation of HER3, HER4, AKT, p70S6 kinase, and STAT3 had been observed.

Additionally, phosphorylation of HER2, EGFR, and MEK/ERK was also found to be inhibited with the agent in a cell-specific manner, though with some variation. Notably, treatment with zenocutuzumab did not significantly alter the growth of isogenic control cell lines that did not harbor NRG1 fusions.

Specifically, in the breast cancer and lung cancer cell lines, the bispecific antibody resulted in the downregulation of cyclin D1 level and elicited expression of the negative cell cycle regulators P21 or P27.

Moreover, in the cells that had been exposed to zenocutuzumab, evidence of apoptosis activation, such as cleaved PARP, expression of BIM and PUMA, was also noted.

When the bispecific antibody was administered at doses of 2.5 mg/kg, 8 mg/kg, and 25 mg/kg every week to mice who had LUAD-0061AS3, ST3204, and OV-10-0050 PDX tumors, dose-dependent inhibition of tumor growth was observed. Notably, tumor shrinkage was noted when the highest dose of zenocutuzumab was administered; this dose was equivalent to the 650-mg, twice-weekly dose that has been identified for humans.

Using a chromium release assay and peripheral blood mononuclear cells, investigators found that the agent induced substantial cytotoxicity in MDA-MB-175-VII cells. Notably, a non-ADCC–enhanced, non-specific IgG was not reported to have any effect.

“These results further support the clinical development of zenocutuzumab by Merus as therapy for [patients with] NRG1 fusion–driven cancers,” the study authors concluded in the poster.

To this end, the agent will be evaluated in the multicenter, multinational, dose-escalation, phase 1/2 eNRGy trial (NCT02912949).2 Here, investigators will further evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of the agent in patients with NRG1 fusion–positive solid tumors.

_References:

_{1. Odintsov I, Khodos I, Espinosa-Cotton M, et al. The HER2xHER3 bi-specific antibody Zenocutuzumab is effective at blocking growth of tumors driven by NRG1 gene fusions. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract 956.}

_{2. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion. ClinicalTrials.gov. Updated January 12, 2021. Accessed April 10, 2021. https://clinicaltrials.gov/ct2/show/NCT02912949}