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Partnership to Find Patients With NRG1 Fusions for Zenocutuzumab Trial in Pancreatic Cancer

Publication
Article
Evidence-Based OncologyAugust 2020
Volume 26
Issue 7
Pages: SP203

An agreement will tap Caris Life Sciences' next-generation sequencing technology to identify patients for Merus’ phase 1/2 eNRGy trial.

A recent collaboration between a Netherlands-based biotech and a well-known US diagnostics company highlights the journey of cancer care today: The bispecific antibody zenocutuzumab, previously studied more broadly in solid tumors, is now being focused in the specific patients in whom it seems to work wonders. These patients have neuregulin 1 (NRG1) fusions, a rare but powerful oncogene driver that makes cancer particularly aggressively and deadly when it is present.1

Gene fusions occur when 2 previously independent genes connect, producing increased amounts of abnormal protein that trigger and fuel tumor growth. There are many types of NRG1 fusions, involving different genes, and they are a culprit in many cancers with poor survival rates, such as lung cancers among patients who never smoked and pancreatic cancer.

Zenocutuzumab targets both HER2 and HER3 and blocks the interaction of the NRG1 fusion protein with its receptor HER3; it has shown success in treating cancers fueled by NRG1 gene fusions.2 In fact, Merus, the maker of zenocutuzumab, was studying the drug’s effectiveness in breast cancer when it shifted gears to focus on patients with this rare cancer driver.

That’s where Merus’ collaborator, Caris Life Sciences, comes in: Although the strategy of matching the therapy with patients whose cancer is driven by NRG1 fusions appears to be a winner, the companies say these fusions are rare, occurring in only 0.3% to 3.0% of non–small cell lung cancer (NSCLC), 0.5% to 1.5% of pancreatic ductal cancer, and less than 1.0 % of other tumor types, based on available literature.1 Thus, it takes effort to find patients eligible for a trial.

The agreement will tap Caris’ next-generation sequencing technology to identify patients eligible for Merus’ phase 1/2 eNRGy trial and its Early Access Program.

David Spetzler, PhD, MBA, MS, president and chief scientific officer of Caris Life Sciences, said in an interview with Evidence-Based Oncology™ that when a patient receives molecular profiling, “We perform whole exome sequencing and whole transcriptome sequencing. We’re assessing every single gene in their DNA and every single gene in their RNA.” He explained that for NRG1 fusions, it is best to look at the RNA, so this is a standard part of testing.

“We’re able to identify those patients who have NRG1 fusions and assess the expression level of them as well,” he said. “So, not only can we see that the fusion event has occurred, but we can also get a sense of the magnitude of how big it is within that particular tumor type.”

The focus will be on pancreatic cancer, for which Merus received an orphan drug designation from the FDA on July 29, 2020.3 Caris will perform whole exome sequencing of DNA and whole transcriptome sequencing of RNA for certain cancer patients, and make those who potentially meet the criteria aware of the trial.

Results for Zenocutuzumab

FDA’s action followed results from a proof-of-concept study presented in October 2019 at the American Association of Cancer Research/National Cancer Institute/European Platform of Cancer Research International Conference on Molecular Targets and Cancer Therapeutics. At that meeting, investigators presented results from 3 patients with NRG1 gene fusions: 2 with pancreatic cancer and 1 with NSCLC.4 The patients were not part of a clinical trial, but rather an expanded access program at Memorial Sloan Kettering.5

The patients with pancreatic cancer were a 52-year-old male who achieved a partial response and a 34-year-old male achieved who achieved stable disease; both were treated for at least 7 months. A 54-year-old male treated for NSCLC achieved partial response after being treated for at least 4.5 months. Among the 117 patients treated in the entire study, most adverse events (AEs) were grade 1 or 2, less than 5% had a grade 3 AE, and none had a grade 4 event.4

“Receiving orphan drug designation for zenocutuzumab is another important milestone for our lead program, and it validates the significant unmet need in patients with pancreatic cancer,” Bill Lundberg, MD, president, CEO, and principal financial officer of Merus, said in a statement. “We are pleased with the progress we are making in our ongoing global clinical trial and believe that zenocutuzumab has the potential to play a significant role in shifting the treatment paradigm for NRG1 fusion cancers from conventional chemotherapy to a personalized medicine approach.”3

The Importance—and Future—of Testing

This shift in gears highlights the evolution of cancer treatment: The focus increasingly is not solely on tumor type but also on the biomarkers that the tumors or blood cancers present, and then on finding therapies that will target the genetic markers driving the cancer. In a review article on developing precision and personalized medicine strategies, authors from Rutgers University wrote in 2018 that this may make cancer treatment more complex, but it has many advantages, from sparing patients the AEs of medicines that won’t work to lowering costs.6

Using testing to define the clinical trial population is hugely beneficial, the Rutgers team wrote. “By focusing on smaller populations, clinical trial size will shrink, substantially reducing the costs. In addition, the population admitted to the trial is more likely to respond to the therapy, reducing the risk associated with failed clinical trials,” the authors wrote in Technology.6

To that end, can the Caris technology identify patients who might be good candidates for 1 treatable target of a bispecific antibody, but not the other?

“There’s a lot behind that question,” Spetzler said, “but it’s a very complex answer. Whether a patient would be eligible for the drug is really up to the pharma company in terms of defining their inclusion and exclusion criteria.”

Generally, Spetzler said, testing technology is also moving toward “a much more rigorous approach” that defines the best biological pathway, not just the genes involved.

“There’s growing evidence that we should be moving away from gene-specific associations more toward pathway-associated associations, and so the more complex signatures really can start to untangle some of the inherent complexity of these molecular systems,” he said. “I actually believe that is the future of molecular diagnostics: We’re going to move away from these univariate assessments of disease toward very complex signatures.

“Nobody’s really doing it yet, but it’s coming for sure.”

Author Information

Mary Caffrey is the associate editorial director for Managed Markets, MJH Life Sciences.

References

1. Merus and Caris Life Sciences announce collaboration to detect NRG1 fusions in cancer patients. News release. Merus; July 13, 2020. Accessed July 14, 2020. https://www.globenewswire.com/newsrelease/2020/07/13/2061475/0/en/Merus-and-Caris-Life-Sciences-Announce-Collaboration-to-Detect-NRG1-Fusions-in-Cancer-Patients.html

2. Mishra R, Patel H, Alanazi S, et al. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12(1):355. doi:10.4081/oncol.2018.355

3. Merus announces FDA orphan drug designation of zenocutuzumab for the treatment of pancreatic cancer. News release. Merus; July 27, 2020. Accessed July 29, 2020. https://www.globenewswire.com/

news-release/2020/07/27/2067850/0/en/Merus-announces-FDA-Orphan-Drug-Designation-of-Zenocutuzumab-for-the-Treatment-of-Pancreatic-Cancer.html

4. Ternyila D. FDA grants orphan drug designation to zenocutuzumab as treatment of pancreatic cancer. Targeted Oncology. Published July 29, 2020. Accessed July 29, 2020. https://www.targetedonc.com/view/fda-grants-orphan-drug-designation-to-zenocutuzumab-as-treatment-of-pancreatic-cancer

5. Plieth J. Triple meeting—targeted focus validates Merus’ change of tack. Evaluate Vantage. Published October 27, 2019. Accessed July 29, 2020. https://www.evaluate.com/vantage/articles/events/conferences/triple-meeting-targeted-focus-validates-meruss-change-tack

6. Krzyszczyk P, Acevedo A, Davidoff EJ, et al. The growing role of precision and personalized medicine for cancer treatment. Technology (Singap World Sci). 2018;6(3-4):79-100. doi:10.1142/S2339547818300020

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