NEW YORK – NRG1 gene fusions, rare alterations found most commonly in lung and pancreatic cancers, have attracted the attention of several drugmakers as a new indication for precision oncology therapeutics worthy of pursuit.
Startup Elevation Oncology and drug developer Merus both announced this month they were advancing cancer drugs targeting NRG1 fusions.
Elevation Oncology, which recently emerged from stealth with $32.5 million in Series A funding, is partnering with Strata Oncology to identify and enroll solid tumor patients with NRG1 fusions in the newly initiated Phase II CRESTONE clinical trial evaluating seribantumab.
Similarly, Merus is partnering with Caris Life Sciences to identify pancreatic cancer patients with NRG1 fusions who may be eligible to enroll in its ongoing Phase I/II eNRGy trial evaluating the safety and antitumor activity of zenocutuzumab, which was granted orphan drug designation by the US Food and Drug Administration last week.
NRG1 fusions have been identified in more than 10 different types of cancers. They show up in up to 0.2 percent of solid tumors and are particularly enriched within a subtype of lung cancer called invasive mucinous adenocarcinoma and a subtype of pancreatic cancer called pancreatic ductal adenocarcinoma. Between 0.3 percent and 3 percent of lung cancers are characterized by these fusions and between 0.5 percent and 1.5 percent of pancreatic ductal adenocarcinomas have them.
NRG1 is a ligand for the HER3 receptor. Normally, the NRG1 protein regulates cell signaling and growth. However, when portions of the NRG1 gene fuse with certain other genes, this results in an aberrant protein product. In cancer cells, these fusion proteins extensively bind to the HER3 receptor and stimulate uncontrolled cell growth.
"Patients who have these [types of] cancers have a cancer that is driven uniquely and specifically by this NRG1 gene fusion," said Merus CEO Bill Lundberg.
Elevation Oncology Founder and Chief Business Officer Shawn Leland agreed, further pointing out that NRG1 fusions and other known oncogenic drivers, such as KRAS, appear to be mutually exclusive, meaning that testing for these alterations would identify a subset of patients that aren't captured by the genetic alterations commonly tested for in cancer care.
Elevation redirects a HER3 antibody
The idea of drugging NRG1 fusions first came to Leland during a case presentation at the 2018 European Society for Medical Oncology's annual meeting. In this presentation, Alexander Drilon from Memorial Sloan Kettering Cancer Center, who is now part of Elevation's scientific advisory committee, discussed a patient with an NRG1 fusion who was treated in a Phase I clinical trial with GSK's investigational HER3 monoclonal antibody GSK2849330. The treatment resulted in a 90 percent tumor reduction and a 19-month duration of response. In fact, the response to GSK2849330 was longer than this patient's combined response to all four prior lines of treatment.
"There are plenty of companies out there that have HER3 monoclonal antibodies that they viewed as failed assets," Leland said. "I felt there was this opportunity to go out and approach companies that had these programs and see if they could be in-licensed and repurposed for this genetically-defined patient population."
In July 2019, Elevation closed a $32.5 million Series A funding round that was led by Aisling Capital and included additional investors Vertex Ventures, Qiming Ventures, BVF Partners, and Driehaus Capital Management. That same day, Elevation inked an agreement with Merrimack Pharmaceuticals for its anti-HER3 antibody assets, MM-121 (seribantumab) and MM-111, for an upfront cash payment of $3.5 million. Under the deal, Merrimack is also eligible to receive up to $54.5 million in development, regulatory approval, and commercial-based milestone payments.
Prior to 2019, seribantumab was being studied in a global, open-label, biomarker-selected, Phase II randomized SHERLOC clinical trial in combination with docetaxel, versus docetaxel alone, in patients with heregulin-positive non-small cell lung cancer. Heregulin, or HRG, is also a ligand for the HER3 receptor and another growth factor involved in cell proliferation and survival. When disrupted, it has been implicated in cancer. The trial was terminated in October 2018 because the investigators determined that the addition of seribantumb to docetaxel did not improve progression-free survival over docetaxel alone in the biomarker-selected patient population.
Subsequently, Leland saw the ESMO presentation that offered another avenue for personalizing HER3-directed monoclonal antibodies.
"It's very clear that the biology [associated with NRG1 gene fusions] was driven through HER3. It seemed like NRG1 was very amendable to target inhibition. Seribantumab had the ability to block ligand-dependent activation of HER3," said Leland. "We were also looking for a product that had the ability to block HER3-HER2 dimerization and seribantumab had the ability to do that … it was the optimal product to be able to block signaling for cancer growth in patients with NRG1 gene fusions."
For Elevation, seribantumab was an ideal lead candidate to push into a Phase II study, as it already had a recommended Phase II dose, a robust safety database, and pre-existing intellectual property. Leland said that the vast majority of the Series A funds the company raised will go towards the development of seribantumab.
After Elevation launched in 2019, it was able to quickly generate preclinical in vivo proof-of-concept data and data from a patient-derived xenograft model, which has been submitted for presentation at a medical conference in the second half of 2020. Elevation also met with the FDA at the end of 2019, which allowed for the initiation of the Phase II trial that may result in registrational data for seribantumab.
The development program presents an attractive opportunity for the startup since the NRG1 fusion-positive patient population is an identifiable subset with an unmet need. Also, the vast majority of next-generation sequencing tests can identify these fusions. And according to a study using data from a global registry of cancer patients presented at the 2019 American Society of Clinical Oncology annual meeting by Michael Duruisseaux from the Hospices Civils de Lyon in France, patients with NRG1 gene fusions fare poorly when treated with chemotherapy or chemo-immunotherapy.
The overall response rate among these patients is anywhere from 0 percent to 11 percent with standard-of-care chemotherapy or chemo-immunotherapy, Leland noted. And while some NRG1 fusion-positive patients treated with the HER2 inhibitor afatinib have responded, the responses were not durable.
"We felt there was this ability to address an unmet medical need by delivering a precision oncology asset completely tailored to diagnostic testing results for patients with NRG1 gene fusions," Leland said.
Elevation purchased MM-111 as a potential backup program in NRG1 fusion-positive cancers. MM-111, a HER2/HER3 bispecific antibody, was previously studied in a Phase I trial for HER2-amplified breast cancer and a Phase II trial for HER2-positive gastrointestinal cancers that was terminated due to lack of efficacy.
The Phase II CRESTONE study the company just kicked off will investigate seribantumab as a monotherapy. However, Elevation is conducting preclinical research to identify potential combination approaches.
In addition to Strata Oncology, Elevation is partnering with diagnostic companies Caris Life Sciences, Tempus, and Ashion Analytics to identify patients with NRG1 fusion-driven tumors. The partnerships with the four diagnostics companies will also enable Elevation to expand clinical trial access to patients and to activate a local study site where a patient is identified within 14 days or less.
Merus pivots to NRG1 gene fusions
Merus initially had broader development plans for its zenocutuzumab as a treatment for patients who are HER2-positive or had HER3-mediated resistance to a HER2 agent. Last year, Merus decided to home in on NRG1 fusion-positive cancers and revised one of the ongoing Phase II trials into the eNRGy trial. The company added three specific cohorts of patients. The first cohort will enroll patients with NRG1 fusion-positive lung cancer, the second cohort will enroll NRG1 fusion-positive pancreatic cancer, and the third cohort is for all other types of cancers with NRG1 fusions.
Preliminary data from the eNRGy trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics last year found that three NRG1 fusion-positive patients — two with pancreatic ductal adenocarcinoma and one with non-small cell lung cancer — treated with zenocutuzumab saw their tumors shrink.
Lundberg attributes the promising early activity seen with zenocutuzumab to the unique properties of the drug.
Most often, HER3 receptors have no intrinsic tyrosine kinase activity and must partner with molecules in the HER family (commonly HER2) in order to activate oncogenic signaling. Because zenocutuzumab can target both HER3 and HER2, it not only disrupts the NRG1 fusion protein from binding to the HER3 protein, but it also disrupts the interaction between HER2 and HER3.
"We keep the ligand from binding HER3, [and] we keep HER3 from binding on to HER2. Even in situations where there are ligand-independent growth mechanisms, we block the function of HER3 as well," explained Lundberg.
Additionally, Merus engineered zenocutuzumab to be able to outcompete the NRG1 fusion protein for the binding site on the HER3 receptor. Lundberg said that he believed having a bispecific antibody that docks onto the HER2 receptor and blocks the HER3 receptor from interacting with the NRG1 fusion protein will allow the drug to be more potent.
Merus has completed Phase I programs for the drug in breast, gastric, and other cancers. In these trials, investigators have observed evidence of tumor shrinkage or a delay in time to progression in line with other HER2, HER3 targeting molecules.
On the safety side, Merus has accrued data on more than 100 patients treated with zenocutuzumab at its recommended Phase II dose. Lundberg noted that the antibody appears to be well tolerated, with most of the adverse events being grade 1 or grade 2.
Other drugs targeting the HER family of proteins, such as antibodies against EGFR and antibodies against HER2, have been associated with toxicities, such as skin rash, gut problems, or cardiac safety signals, but these have not been observed with zenocutuzumab.
In order to identify patients in this rare, molecularly-defined population, Merus has an early-access program for zenocutuzumab for NRG1 fusion-positive patients with any type of cancer in place, in addition to a partnership with Caris to find and enroll NRG1 fusion-positive pancreatic patients into the clinical trial.
"If there's a patient who is either unwilling or unable to get to a clinical trial site, we can have drugs brought to their local hospital and have an early-access program set up at that hospital so that they can participate by receiving the drug," said Lundberg. "We're robustly capturing essentially all the same data that we would in a clinical trial setting."
Although Elevation and Merus are potential competitors, they recognized that multiple treatment options for rare indications will ultimately benefit patients. Elevation's Leland said the promising activity of Merus' drug is "positive" and encouraging, as it "provides further evidence and data that precision oncology assets targeting HER3 have this likelihood of being beneficial in patients with NRG1 gene fusions."
Leland reflected that even in a rare, genetically defined patient population, there is room for more than one clinically beneficial drug on the market.
"We can look and see this for NTRK, where larotrectinib and entrectinib have been approved. And also with RET fusions where Lilly [and] Loxo have a program targeting RET fusions, and so does Blueprint," he said. "Any potential advantages we have over Merus or vice versa, we'll see those things play out over the coming years."