Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers
Zenocutuzumab Mechanism of Action: Antibody-dependent cell cytotoxicity; ERBB 2 receptor antagonists; ERBB-3 receptor antagonists; Immunomodulators
Merus’ Zenocutuzumab is a bispecific antibody containing 2 different Fab arms directed against HER2 and HER3. The agent purportedly docks on HER2 and then binds to HER3, blocking its binding site for NRG1. The reported data are from the Phase I/II eNRGy trial and EAP, which are assessing the safety and anti-tumor activity of zenocutuzumab monotherapy in NRG1+ cancer.
As of April 12, 2022, 110 patients were treated with zenocutuzumab. Efficacy was assessed in 79 evaluable patients with the measurable disease having the opportunity for 6 months or more follow-up and who met the criteria for the primary analysis population. 57% of patients had NSCLC, 23% had Pancreatic ductal adenocarcinoma, 8% had Breast cancer. The median age was 59 years; 59% were female. The median number of prior lines of systemic therapy was 2 . Qualifying NRG1 fusions included 26 distinct fusion partners.
Key findings of the results are:
● ORR per RECIST criteria as assessed by the investigator was 34% across multiple tumor types
- PDAC ORR 42% (8/19)
- NSCLC ORR 35% (16/46)
● Tumor shrinkage was observed in 70% of patients.
● The median time to response was 1.8 months, and the median duration of exposure was 6.3 months.
● The median duration of response was 9.1 months, and 20/83 patients were continuing treatment as of the cutoff date.
● Strong safety profile with a low incidence of Grade 3 or higher treatment-related adverse events
“Zenocutuzumab has led to durable responses in previously treated NRG1 fusion-positive cancer, with a median duration of response greater than 9 months and more than 25% of those responding continuing at 12 months. Additionally, Zenocutuzumab has an extremely well-tolerated safety profile. There are currently no approved therapies targeting NRG1 fusion-positive cancer, and Zenocutuzumab offers an important, potential new standard of care.” – Expert Opinion.
“Zenocutuzumab has the potential to be the first drug approved for NRG1 fusion-positive cancers and likely provides a more effective and tolerable option for patients who have progressed on or failed to respond to standard therapy” – Expert Opinion.
CONCLUSION
NRG1 fusions arising from chromosomal rearrangements occur at low frequencies (< 1%) across solid tumors but are enriched in certain cancer types, including KRAS wild-type pancreatic cancer, driver-negative non–small cell lung cancer (NSCLC), and the invasive mucinous adenocarcinoma subtype of lung cancer. Merus currently estimates that 0.5-1.5% of pancreatic cancer and 0.3-3% of lung cancer patients have NRG1 fusions. The head start provided by zenocutuzumab could make a difference in NRG1 fusion tumors.
The FDA has granted Fast-Track designation to zenocutuzumab for NRG1+ cancer and Orphan designation for pancreatic cancer. No targeted therapies are currently approved for tumors harboring NRG1 fusions, but that may soon change based on the results of the pivotal eNRGy study. Given acceptable evidence of anticancer effectiveness across several NRG1 fusion-positive tumor types, the present eNRGy data bolster support for zenocutuzumab, especially when patients had already undergone a median of two prior regimens. Another advantage of zenocutuzumab is its tolerability profile, which is superior to that of regular chemotherapy.
NRG1 fusion cancers are a niche, and there are some Her3-targeting projects with potential in NRG1 fusion cancers. Hummingbird Bioscience’s HMBD-001 recently went into the clinic in HER3-positive solid tumours, including NRG1 fusion-driven cancers. Meanwhile, Aveo Oncology is developing a Her3-targeting antibody radio-conjugate. GSK's GSK2849330 has also shown promise in NRG1 fusion tumours, albeit it is not currently in the company's pipeline. At ASCO 2022, Daiichi Sankyo's patritumab deruxtecan, a Her3-targeting antibody-drug combination, showed promising results in breast and lung malignancies; however, the company does not seems to be focused on NRG1 fusions
Companies- Gilead, Daiichi Sankyo, Merus, Sanofi, AstraZeneca, Eli Lilly, Radius Health, Sermonix Pharmaceuticals, Roche, Veru Pharma, and others.
