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Merus' Investigational Drug Shows Promise in NRG1 Fusion-Positive Cancers


NEW YORK – Zenocutuzumab, a bispecific humanized IgG antibody for the treatment of NRG1 fusion-positive cancers, yielded encouraging results in a Phase I/II trial, raising hopes that it may become a new standard of care for tumors that are currently considered some of the hardest to treat.

At the American Society of Clinical Oncology's virtual annual meeting on Friday, Alison Schram, a Memorial Sloan Kettering oncologist, presented new data on the efficacy and safety of zenocutuzumab, which is being developed by Merus, in advanced pancreatic cancer and other solid tumors harboring NRG1 fusions.

NRG1 is a ligand that binds to HER3, promoting the heterodimerization of HER2 and HER3 and activation of PI3K, AKT, and mTOR signaling. Chromosomal rearrangements involving NRG1 are rare oncogenic drivers in solid tumors and are enriched in KRAS wild-type pancreatic ductal adenocarcinoma, or PDAC, and invasive mucinous adenocarcinoma of the lung.

Numerous NRG1 fusions have already been identified, Schram said, and NRG1 fusion-positive in vitro and in vivo models have been shown to be sensitive to HER2/HER3-directed therapy.

Zenocutuzumab is what Merus calls a common light chain, bispecific humanized IgG1 antibody. It's based on the company's Multiclonics therapeutics platform, which is able to generate a diverse array of antibody binding domains against a variety of targets. These multiple binding domains can be combined to produce novel bispecific and trispecific antibodies, according to Merus.

Zenocutuzumab contains two arms that target the extracellular domains of HER2 and HER3. Specifically, it works by docking onto HER2 and blocking NRG1 interaction with HER3. In NRG1 fusion-positive models, zenocutuzumab induced antibody-dependent cytotoxicity, thereby resulting in potent inhibition of cell growth and molecular signaling, Schram said.

At the meeting, she presented data from a Phase I/II global, open-label clinical trial, dubbed eNRGy, plus an early-access program in which patients with PDAC, non-small cell lung cancer, or NSCLC, and other solid tumors were treated with zenocutuzumab. To be included in the study, patients had to have locally advanced, unresectable, or metastatic solid tumors that were positive for NRG1 fusions and were previously treated or unable to receive standard therapy.

Patients received zenocutuzumab until disease progression and were followed for up to a year. At the time of data cutoff, which was April 13, 61 patients were enrolled in the study, but the primary analysis population included 47 patients — 12 patients had PDAC, 25 had NSCLC, and 10 were enrolled in a cohort for a variety of solid tumors, including breast and colon cancers.

At the time of the data cutoff, treatment was ongoing in a total of 19 patients (40 percent), and median duration on therapy was 5.5 months. Seven (58 percent) of the PDAC patients had ongoing treatment compared to six (24 percent) of the NSCLC patients and six (60 percent) of the patients in the basket cohort.

Nine out of the 12 patients with PDAC (75 percent) had tumor shrinkage with a confirmed partial response rate of 42 percent (five out of the 12). Half of the dozen patients had stable disease. This was in a heavily pretreated population with an average of two previous lines of systemic therapy, Schram noted.

She further added that there was confirmed efficacy with zenocutuzumab treatment regardless of tumor type, as long as an NGR1 fusion was present. The confirmed partial response rate for all the tumor types at the time of data cutoff was 29 percent, with 13 out of the 45 patients showing a response to the drug, and 34 out of the 45 patients, or 76 percent, showing reductions in tumor size.

In addition to showcasing the activity of zenocutuzumab, the eNRGy trial was also the first prospective clinical validation of NRG1 fusions as actionable oncogenic drivers, according to Schram. The study also demonstrated zenocutuzumab's ability to target a genomically altered ligand and was first proof of concept that antibody-based therapy can target a fusion oncoprotein.

"Zenocutuzumab is the first genome-directed therapy for NRG1 fusion-positive cancer, offering a potential new standard of care," she added.

In a presentation to investors on Sunday, Merus' chief medical officer, Andrew Joe, noted that the company believes zenocutuzumab addresses an important unmet medical need, as there are no approved NRG1-directed therapies for cancer. This is especially important for previously treated PDAC, which has a notoriously poor prognosis. Similarly, NRG1-positive lung cancers have adverse prognostic features, lower response rates to standard therapies, and shorter overall survival rates than non-NRG1-positive cancers.

"We believe that the meaningful efficacy and safety data, as well as our program design, may support multiple potential paths to registration," Joe added.

Merus CEO Bill Lundberg noted that the drug has already passed several regulatory milestones including receiving orphan designation from the US Food and Drug Administration for pancreatic cancer and fast-track status for metastatic NRG1 fusion-positive cancers that have progressed on standard-of-care treatments.

The company will provide additional updates by the first half of 2022, including an update on study enrollment, efficacy, durability, and safety, as well as additional insights on Merus' regulatory and registration strategy for the drug.

According to Joe, the eNRGy trial's design may support a path to either a cancer-specific or tissue-agnostic registration, though Merus hasn't yet decided a specific path. Regulatory authorities will want to see consistency in the data either way, he added, and the data right now show the best activity for the drug in the pancreas, lung, breast, and colon, so Merus still has room to go either way.

In addition to zenocutuzumab, Lundberg said the company has several drug candidates in its pipeline based on its common light chain platforms. There's MCLA-158, which targets Lgr5 and EGFR fusions in solid tumors and is currently undergoing investigation in a Phase I trial. MCLA-145 is another pipeline drug targeting CD137 and PD-L1 fusions in solid tumors, which Merus is developing in partnership with Incyte outside the US. MCLA-145 is being studied in an ongoing Phase I trial, and the company is planning to provide a clinical update in the second half of 2021.

Finally, Merus is developing MCLA-129, which targets EGFR and c-MET fusions in solid tumors. This candidate is being developed in partnership with Betta Pharmaceuticals in China, and a Phase I/II trial is currently ongoing.