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A focus on fusions
UTRECHT, The Netherlands—This year’s AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston saw presentations from a variety of companies, including Merus N.V., which shared initial clinical data for MCLA-128 and three patients being treated with the compound in its Early Access Program.
The patients in question all have cancers with NRG1 fusions, two of whom have pancreatic ductal adenocarcinoma (PDAC) and one of whom has non-small cell lung cancer (NSCLC). The patients were treated with MCLA-128 at 750 mg intravenously every other week. Patient assessments, which were conducted at Memorial Sloan Kettering Cancer Center (MSKCC), revealed that all three demonstrated tumor shrinkage, symptomatic improvement and durability up to the most recent evaluation.
MCLA-128 is an antibody-dependent cell-mediated cytotoxicity-enhanced Biclonics that is thought to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors by blocking growth/survival pathways to stop tumor growth and by recruiting and enhancing immune effector cells to destroy tumors.
“These initial data are an important proof of concept demonstrating the promise of targeting NRG1 fusions with MCLA-128,” said Dr. Alison Schram, a medical oncologist in the Early Drug Development Service at MSKCC and investigator for the trial. “It is notable that two of the patients described have pancreatic cancer, a disease with a poor prognosis and limited therapeutic options. MCLA-128’s mechanism of action addresses the specific molecular abnormality in cancers harboring NRG1 fusions by binding to HER2 and blocking the interaction of the NRG1 fusion oncoprotein with HER3, and may make MCLA-128 uniquely suited to target this distinct oncogenic driver.”
One PDAC patient demonstrated a 44-percent reduction in tumor diameter at eight weeks, and a 54-percent reduction at a five-month scan. In addition, symptoms such as fatigue and weight loss improved within weeks of the first dose. The second PDAC patient saw a reduction in tumor diameter of 22 percent at seven weeks, and a 25-percent reduction at the confirmatory five-month scan. Neither patient showed evidence of metabolically active tumor under PET imaging, and both remain on treatment after more than seven months of therapy. Similarly encouraging results were seen from the NSCLC patient: a 33-percent reduction in tumor diameter at eight weeks, and a 41-percent reduction by the time of the five-month scan.
The NRG1 gene encodes for neuregulin, the ligand for HER3. Fusions between NRG1 and other genes are associated with the activation of HER2/HER3 signaling and cancer cell growth. While rare, these fusions are seen in a variety of solid tumor types. Preclinical work has shown that the NRG1 fusion protein’s mechanism for stimulating tumor growth is very susceptible to inhibition by MCLA-128’s dual mechanism of action.
“We currently estimate NRG1 fusions to occur at a rate of between 0.3 to 3 percent in non-small cell lung cancer, approximately 0.5 to 1.5 percent in pancreatic ductal adenocarcinoma, and less than 1 percent in most other solid tumor types,” Dr. Ton Logtenberg, president and CEO of Merus, commented in a conference call.
Thus far, Merus has identified nine patients with NRG1 fusions—three with PDAC and six with NSCLC—who have been enrolled and treated with MCLA-128 in either the Early Access Program or the Phase 1/2 eNRGy trial. The company is also evaluating their compound in a Phase 2 trial of patients with metastatic breast cancer.
“Over the past decade, we’ve seen a paradigm shift in cancer treatment, with an increasing number of effective therapies for the target-specific genetic aberrations in patients’ tumors. Drugs targeting gene fusions have become an area of potential to have substantially improved outcomes for patients with tumors that have these alterations,” Logtenberg reported in a conference call. “While the data is early and our understanding of NRG1 fusions is still limited, they have recently been described in several cancer types and are enriched in certain subpopulations where patients are in desperate need of better therapies ... identifying a new, effective treatment strategy for these patients could make a meaningful impact in their lives.”
“In summary, we are very encouraged by the early responses observed in these several patients with cancers harboring NRG1 fusions treated with MCLA-128,” Logtenberg concluded. “We are focused on our plan to continue to identify and recruit patients that may be amenable to MCLA-128 therapy, and to execute on our recently amended clinical development strategy for the program. We expect to next report on interim NRG1 data at a medical conference by the end of 2020, when we may be able to better characterize the activity of MCLA-128 in a larger set of patients and with more mature data.”