A Pathway to Immunotherapeutic Targeting of Multiple Cancer Types

Neuroregulin 1 (NRG1) is an epidermal growth factor that is pathogenically altered in about 1% of solid tumors via fusion with one of many partner genes, resulting in a chimeric protein that drives oncogenesis via the HER2/HER3 pathway. Investigators conducted an industry-sponsored, multicenter, phase 2 trial of zenocutuzumab (Zeno), a bispecific anti-HER2 and anti-HER3 monoclonal antibody, in patients with advanced or metastatic cancer and an NRG1 gene fusion as detected by next-generation DNA or RNA sequencing. Eligible patients had either received prior standard therapy, which could include prior anti-HER2 antibodies or inhibitors, or were not candidates for standard therapy. Zeno infusions were administered intravenously once every 2 weeks until progression, death, or unacceptable toxicity.

Ten different tumor types were represented in the primary efficacy population (n=158). Overall, 47 patients (30%) had a treatment response, including one complete response. Response rates were 29% among the 93 patients with non–small-cell lung cancer (NSCLC) and 42% among the 36 patients with pancreatic cancer; median durations of response were 12.7 and 7.4 months, respectively. Responses also occurred in cholangiocarcinoma as well as breast, ovarian, and gastric cancers and were observed across NRG1 fusion partners. Of the 204 patients treated with Zeno, only one discontinued because of toxicity (grade 2 pneumonitis). Grade 3 or 4 toxicities occurred infrequently; 14% of patients had grade 1 or 2 infusion reactions.