Adenocarcinoma of pancreas with NRG1 fusion

BOSTON--( BUSINESS WIRE )-- Foundation Medicine, Inc. today announced a collaboration to develop Foundation Medicine’s RNA platform as a companion diagnostic for Merus N.V.’s (Nasdaq: MRUS) bispecific antibody zenocutuzumab (Zeno) to treat patients with neuregulin 1 fusion (NRG1+) cancer. Zeno is a Biclonics® that utilizes the Merus Dock & Block® mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 fusions (NRG1+ cancer). Through its unique mechanism of binding to HER2 and potently blocking the interaction of HER3 with its ligand NRG1, Zeno has the potential to be particularly effective against NRG1+ cancer. In preclinical studies, Zeno potently inhibits HER2/HER3 heterodimer formation thereby inhibiting oncogenic signaling pathways, leading to inhibition of tumor cell proliferation and blocking tumor cell survival. In May the U.S. Food and Drug Administration (FDA) accepted under priority review a Biologics License Application for Zeno in patients with NRG1+ non-small cell lung (NSCLC) and NRG1+ pancreatic (PDAC) cancer. The FDA has also granted Breakthrough Therapy Designation (BTD) to Zeno for the treatment of patients with advanced unresectable or metastatic NRG1+ pancreatic cancer following progression with prior systemic therapy or who have no satisfactory alternative treatment options. Additionally, the FDA has granted BTD to Zeno for the treatment of patients with advanced unresectable or metastatic NRG1+ NSCLC, following progression with prior systemic therapy. NRG1 gene fusions are rare and have been identified in patients with different types of solid tumors, including NSCLC, pancreatic cancer, gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. 1 NRG1 fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors (NTRK, RET, ROS1, ALK, and FGFR fusions). 2 While DNA sequencing with optimized targeting can detect fusions, Foundation Medicine’s RNA platform can provide another layer of sophisticated fusion detection in 318 genes through RNA sequencing. It also has expanded capabilities for research use to offer gene expression reporting of over 1,500 genes to support biomarker discovery. Foundation Medicine is the only company with FDA-approved CDx indications for fusion biomarkers using CGP tests, including approved claims using tissue or liquid biopsy for ALK, ROS1, RET, NTRK1/2/3, and FGFR2. 3 “We are excited to partner with Merus on this RNA companion diagnostic opportunity to provide fusion detection through next-generation sequencing,” says Troy Schurr, Chief Biopharma Business Officer at Foundation Medicine. “We anticipate this innovative molecular information will help detect more NRG1 fusions and provide healthcare providers with important information to inform their care decisions for patients.” About Foundation Medicine: Your Essential Partner in Cancer Care Foundation Medicine is a pioneer in molecular profiling for cancer, working to shape the future of clinical care and research. We collaborate with a broad range of partners across the cancer community and strive to set the standard for quality, scientific excellence, and regulatory leadership. Our deep understanding of cancer biology helps physicians make informed treatment decisions for their patients and empowers researchers to develop new medicines. Every day, we are driven to help our partners find answers and take action, enabling more people around the world to benefit from precision cancer care. For more information, please visit us on www.FoundationMedicine.com and follow us on LinkedIn and X . 1 Jonna S, Feldman RA, Swensen J, et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res . 2019;25(16):4966-4972. doi: 10.1158/1078-0432.CCR-19-0160 . 2 Suda K, Mitsudomi T. Emerging oncogenic fusions other than ALK , ROS1 , RET , and NTRK in NSCLC and the role of fusions as resistance mechanisms to targeted therapy. Transl Lung Cancer Res . 2020;9(6):2618-2628. doi:10.21037/tlcr-20-186 3 Data on file, Foundation Medicine, Inc. as of 2024.

Ipsen’s Onivyde is currently the standard of care in metastatic pancreatic ductal adenocarcinoma, which has about a 7% chance of response in second to third line patients who progress after prior treatment. Responses to Merus’ bispecific antibody in pancreatic and lung cancer are creeping higher with every data cut, giving CEO Bill Lundberg, M.D., confidence that the dual American and Dutch biotech may someday be able to give a much-needed lifeline for one of the most difficult cancers out there. When people think of pancreatic cancer, their minds immediately go to Alex Trebek or Ruth Bader Ginsburg, who both died from the disease in 2020. “This is just a really difficult disease. We really wish back then we had a much better therapy for pancreatic cancer,” Lundberg said in an interview with Fierce Biotech on the sidelines of the European Society for Medical Oncology Congress in Madrid. “For these NRG-1 fusion tumors, we think we really have something that's a meaningful step change above what the patients could otherwise receive.” Ipsen’s Onivyde is currently the standard of care, which Lundberg said has about a 7% chance of response in second- to third-line patients with metastatic pancreatic ductal adenocarcinoma (PDAC) that progresses after prior treatment. Patients typically only go a couple of months before their disease progresses, he added. “Once a patient's cancer has progressed on standard therapy … it's a very difficult diagnosis,” Lundberg said. This is where Merus is hoping the bispecific antibody zenocutuzumab (Zeno) can make an impact. The therapy is being developed for neuregulin 1 fusion (NRG1+) cancers, including PDAC and non-small cell lung cancer (NSCLC). At the ESMO Congress, the biotech showed a 37% overall response rate and a 61% clinical benefit rate for NSCLC from 105 evaluable patients as of the July 31 cutoff. In PDAC, where 44 patients were evaluable, the therapy led to a 42% ORR, with one patient achieving a complete response and 13 notching a partial response. Merus also reported a 72% clinical benefit rate and 82% of the patients saw tumor reduction. The response rate compares to Merus’ earlier presentation at the American Society of Clinical Oncology annual conference in June 2022. The ORR was 34% for the entire population, 42% for pancreatic cancer and 35% for lung cancer. On safety, Merus called the profile “extremely well tolerated” but detailed information was not provided. Of the 189 total NRG1+ patients, 6% reported grade 3 to 4 toxicities. Speaking about the higher grade of the toxicities, Lundberg said the only other option in the NRG1+ setting is chemotherapy, which can be even more difficult for patients to tolerate. Chemo comes with known side effects such as mucositis (sore/inflamed mouth), gastrointestinal upset, skin or nail changes and lowered blood counts, among others. “There are some adverse events that are noted but the vast majority of them are only grade 1, grade 2, mild or moderate, and really self-limiting in duration,” Lundberg explained. “It appears to be a much easier drug to take than the chemotherapy that we think doesn't work as well and is harder for patients to take.” After discussions with regulators, Merus is planning to seek approval for Zeno in the first half of next year. The therapy was granted a breakthrough tag from the FDA this summer. On whether the regulatory and, if approved, commercial activity, will be done in-house, Lundberg said Merus can only do so much, meaning that partnering talks are welcome. “We recognize that [we] as a small company can gain maximum effectiveness if we have really productive partnerships,” the CEO said. Merus has a discovery partnership with Eli Lilly’s Loxo oncology unit for up to three CD3-engaging T-cell re-directing bispecific antibody therapies. That deal included an upfront payment of $40 million plus a $20 million equity investment by Lilly. The total deal value could rise to $1.6 billion in milestones. Other partners include Betta and Incyte. The next few months for Merus will be “head down, focused on delivering a high-quality dossier to the FDA,” Lundberg said. But, thanks to a $150 million public offering done earlier this year, the CEO said his company is well funded and ready to go with its next asset, petosemtamab, a bispecific antibody for EGFR x LGR5 cancers. “It's a little bit of an embarrassment of riches and we have to make sure that we fully resource this one,” Lundberg said of petosemtamab. “That's really how we think about prioritization, capital allocation—we really want to make sure we're successful with this.” To read more of Fierce Biotech's coverage of the ESMO Congress, click here. Fierce Pharma's coverage is available here.

- 37% ORR and 14.9 months median DOR in 78 evaluable NRG1+ NSCLC patients - 42% ORR and 9.1 months median DOR in 33 evaluable NRG1+ PDAC patients - Sufficient clinical data expected in 1H24 to support potential BLA submissions UTRECHT, The Netherlands and CAMBRIDGE, Mass., Oct. 23, 2023 (GLOBE NEWSWIRE) -- Merus N.V. (Nasdaq: MRUS) (“Merus”, “the Company”, “we”, or “our”), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics® and Triclonics®), today announced interim clinical data, as of a July 31, 2023 data cutoff date, from the phase 1/2 eNRGy trial and Early Access Program (EAP) of the bispecific antibody zenocutuzumab (Zeno) in patients with neuregulin 1 fusion (NRG1+) cancer presented by Principal Investigator, Dr. Alison Schram* of Memorial Sloan Kettering Cancer Center at the European Society for Medical Oncology (ESMO) Congress 2023. “I’ve been impressed by the consistency of the Zeno clinical data and am convinced Zeno has the potential to be both a first and best in class treatment for NRG1+ cancer,” said Dr. Andrew Joe, Chief Medical Officer at Merus. “I expect we will have the dataset in the first half of 2024 to support potential BLA submissions in both NRG1+ NSCLC and PDAC.” Dr. Schram added, “Currently, there are no approved therapies specifically for the treatment of NRG1+ cancer, resulting in patients being treated with standard of care by tumor type despite data suggesting NRG1+ cancers may respond poorly to chemoimmunotherapy. With Zeno’s durable efficacy and excellent safety profile reported at ESMO, I believe Zeno could be an important, new standard of care for patients with NRG1+ cancer.” The reported data are from the phase 1/2 eNRGy trial and EAP which are assessing the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer. Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC) Observations in the presentation include: As of July 31, 2023 data cutoff date, 105 patients with NRG1+ NSCLC were treated with Zeno. 78 patients with measurable disease were treated by February 13, 2023, allowing for the potential for ≥ 24 week follow-up, and who met the criteria for the primary analysis population. 37.2% (29/78; 95% Cl: 26.5-48.9) overall response rate (ORR) per RECIST v1.1 by investigator assessment61.5% (95% CI: 49.8 - 72.3) clinical benefit rate14.9 months median duration of response (DOR) and 20 of patients were continuing treatment as of the data cutoff Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC)  Observations in the presentation include: As of July 31, 2023 data cutoff date, 44 patients with NRG1+ PDAC were treated with Zeno. 33 patients with measurable disease were treated by February 13, 2023, allowing for the potential for ≥ 24 weeks follow-up, and who met the criteria for the primary analysis population. 42.4% (95% CI, 25.5–60.8) ORR per RECIST v1.1 by investigator assessment; 1 (3%) patient achieved a complete response, and 13 (39%) patients achieved a partial response72.7% (95% CI, 54-87) clinical benefit rate82% experienced tumor reductionOf 21 patients evaluable for CA 19-9 levels, 78% showed a ≥ 50% decrease in CA 19-9 values from baseline9.1 months (95% CI, 5.5–12.0) median DOR; and 6 patients were continuing treatment as of the data cutoff Safety findings from both presentations: Zeno demonstrated a well-tolerated safety profile among the 189 NRG1+ cancer patients who were treated with 750 mg Q2W monotherapy, with only 6% of patients experiencing related grade 3-4 toxicities. The full presentations are available on the Publications page of our website. *Dr. Schram has financial interests related to Merus. About the eNRGy Clinical TrialMerus is currently enrolling patients in the phase 1/2 eNRGy trial to assess the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer. The eNRGy trial consists of three cohorts: NRG1+ pancreatic cancer; NRG1+ non-small cell lung cancer; and NRG1+ cancer. Further details, including current trial sites, can be found at www.ClinicalTrials.gov and Merus’ trial website at www.nrg1.com or by calling 1-833-NRG-1234. About ZenoZeno is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced Biclonics® that utilizes the Merus Dock & Block® mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 gene fusions (NRG1+ cancer). Through its unique mechanism of binding to HER2 and potently blocking the interaction of HER3 with its ligand NRG1 or NRG1-fusion proteins, Zeno has the potential to be particularly effective against NRG1+ cancer. In preclinical studies, Zeno also potently inhibits HER2/HER3 heterodimer formation and tumor growth in models harboring NRG1 fusions. About Merus N.V.Merus is a clinical-stage oncology company developing innovative full-length human bispecific and trispecific antibody therapeutics, referred to as Multiclonics®. Multiclonics® are manufactured using industry standard processes and have been observed in preclinical and clinical studies to have several of the same features of conventional human monoclonal antibodies, such as long half-life and low immunogenicity. For additional information, please visit Merus’ website, http://www.merus.nl and https://twitter.com/MerusNV. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the clinical development of Zeno, future clinical trial progress, enrollment, results, clinical activity and safety profile of Zeno in the on-going eNRGy trial and EAP; the potential for Zeno to be a first in class and best in class for patients with NRG1+ cancer and potential of Zeno to offer an important, potential new standard of care; our expectation that we will have a dataset to support potential BLA submissions in both NRG1+ NSCLC and PDAC in the first half of 2024; and the impact of Zeno’s durable efficacy and excellent safety profile reported at ESMO on any future results, including future regulatory interactions or otherwise. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our need for additional funding, which may not be available and which may require us to restrict our operations or require us to relinquish rights to our technologies or Biclonics®, Triclonics® and multispecific antibody candidates; potential delays in regulatory approval, which would impact our ability to commercialize our product candidates and affect our ability to generate revenue; the lengthy and expensive process of clinical drug development, which has an uncertain outcome; the unpredictable nature of our clinical development efforts for marketable drugs; potential delays in enrollment of patients, and our reliance on third parties to conduct our clinical trials, manufacturing and accompanying activities for clinical drug development and potential approval and the potential for those third parties to not perform satisfactorily, which could affect the receipt of necessary regulatory approvals; impacts of the COVID-19 pandemic and global instability; we may not identify suitable Biclonics® or bispecific antibody candidates under our collaborations or our collaborators may fail to perform adequately under our collaborations; our reliance on third parties to manufacture our product candidates, which may delay, prevent or impair our development and commercialization efforts; protection of our proprietary technology; our patents may be found invalid, unenforceable, circumvented by competitors and our patent applications may be found not to comply with the rules and regulations of patentability; we may fail to prevail in potential lawsuits for infringement of third-party intellectual property; and our registered or unregistered trademarks or trade names may be challenged, infringed, circumvented or declared generic or determined to be infringing on other marks. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the period ended June 30, 2023 filed with the Securities and Exchange Commission, or SEC, on August 7, 2023, and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change, except as required under applicable law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Multiclonics®, Biclonics® and Triclonics® are registered trademarks of Merus N.V.