New Bispecific Shrinks NRG1 Fusion-Positive Lung, Pancreatic Tumors

Zenocutuzumab (Bizengri), a bispecific antibody against HER2 and HER3, showed efficacy in patients with advanced NRG1 fusion-positive cancers, particularly non-small cell lung cancer (NSCLC) and pancreatic cancer, according to results from a phase II study.

Among 158 evaluable patients with 10 tumor types, 30% had an overall response, with responses observed in 29% of those with NSCLC and 42% of those with pancreatic cancer, reported Alison M. Schram, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in the New England Journal of Medicine.

The median duration of response was 11.1 months, and 19% of responses were ongoing at the data cutoff date.

Median progression-free survival (PFS) was 6.8 months both in the primary efficacy population and among patients with NSCLC, and was 9.2 months among patients with pancreatic cancer.

Based on the efficacy demonstrated here, the FDA granted accelerated approval to zenocutuzumab for NRG1 fusion-positive pancreatic adenocarcinoma and NSCLC late last year.

NRG1 fusions are rare — occurring in less than 1% of solid tumors. Prior to this approval, there was no approved targeted therapy for NRG1 fusion-positive cancers, Schram told MedPage Today, adding that patients “are in significant need of better therapies.”

“Zenocutuzumab works in several ways,” she said. “One way is that it blocks the neuregulin from binding to HER3. Another is that it blocks the dimerization of HER2 and HER3 by not allowing them to come into contact with each other. And the third way in which it works is [by] antibody-dependent cellular cytotoxicity, which means that once zenocutuzumab binds to the cell, the immune system is then able to recognize it as a potentially foreign cell and … helps to clear the cancer.”

“Importantly, this study is the first prospective trial to validate NRG1 fusion as a targetable oncogenic driver in cancer. It is also the first to validate an oncogenic ligand as a target,” she noted. “Gene fusions are usually the receptor that is abnormal, but this is a novel genetic target in that it is the ligand that is abnormal, so this is a unique mechanism of oncogenesis and a new way to target these cancers.”

Prior to zenocutuzumab’s approval, patients were treated with standard of care for their disease, but outcomes have been mixed. A retrospective analysis involving 110 patients with NSCLC found that those with NRG1 fusion-positive disease had a particularly poor prognosis, with a low likelihood of response to platinum-based chemotherapy (13%) and single-agent immunotherapy (20%, with a PFS of 3.6 months).

Previous results from this study showed that zenocutuzumab induced fast and major radiologic tumor regression and biomarker responses in heavily pretreated patients with metastatic NRG1-positive pancreatic cancer, with an overall response rate of 42%.

Other tumor types with objective responses to zenocutuzumab in the current study were cholangiocarcinoma (n=2), and breast, gastric, and ovarian cancers (one patient each).

“In cholangiocarcinoma, there is a clear signal of efficacy,” Schram said. “The other diseases, we need to treat more patients with HER2- and/or HER3-targeted therapy to truly understand whether this targeted therapy approach is similarly applicable to other cancer types.”

Schram noted that since an NRG1 fusion is a rare genetic alteration, it poses challenges for conducting clinical trials.

“[With] the increased awareness of NRG1 fusions, I hope [this] will fuel increased testing,” she said. “For example, DNA-based sequencing is now becoming more common in patients with solid tumors. RNA sequencing is more sensitive at detecting these NRG1 fusions, and other fusions as well. My hope is with increased uptake of RNA-based sequencing, we’ll be able to find more of these patients and ultimately study these questions in more rare patient populations, including the other diseases that harbor NRG1 fusions.”

For this study, the researchers enrolled 204 patients with 12 tumor types who received zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The current analysis included 158 patients with 10 tumor types who had measurable disease and were enrolled at least 24 weeks before data cutoff.

The median age of the patients in the primary efficacy population was 62 years, and 60% were women. Of the 94 patients with NSCLC, 87% had received previous systemic therapy, with 77% having received systemic therapy for metastatic disease. Almost all of the 36 patients with pancreatic cancer had received previous systemic therapy, and 92% had received systemic therapy for metastatic disease.

The most common adverse events considered to be related to zenocutuzumab included diarrhea (18% of patients), fatigue (12%), and nausea (11%). Infusion-related reactions were observed in 14% of patients.

The most common grade 3 or 4 treatment-related adverse events were diarrhea and anemia, occurring in three patients each. One patient discontinued zenocutuzumab due to a treatment-related adverse event.

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