Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer

Abstract

Background: Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion-positive solid tumors are unclear.

Methods: In this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion-positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall response (complete or partial response) according to investigator assessment. Secondary end points included duration of response, progression-free survival, and safety.

Results: A total of 204 patients with 12 tumor types were enrolled and treated. Among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data-cutoff date, a response occurred in 30% (95% confidence interval [CI], 23 to 37). The median duration of response was 11.1 months (95% CI, 7.4 to 12.9); 19% of responses were ongoing at the data-cutoff date. Responses were observed in multiple tumor types - including in 27 of 93 patients (29%; 95% CI, 20 to 39) with non-small-cell lung cancer (NSCLC) and 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer - and across multiple NRG1 fusion partners. The median progression-free survival was 6.8 months (95% CI, 5.5 to 9.1). Adverse events were primarily grade 1 or 2. The most common adverse events that were considered by the investigator to be related to zenocutuzumab were diarrhea (in 18% of the patients), fatigue (in 12%), and nausea (in 11%). Infusion-related reactions (composite term) were observed in 14% of the patients. One patient discontinued zenocutuzumab owing to a treatment-related adverse event.

Conclusions: Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion-positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events. (Funded by Merus; eNRGy ClinicalTrials.gov number, NCT02912949.).

Figure 1.. Efficacy of Zenocutuzumab in NRG1+ Cancer.

Panel A shows a waterfall plot of the maximum percent change from baseline in target lesion tumor burden (sum of the longest diameters) per investigator assessment. The upper and lower limits of the gray shading indicate 20% growth and 30% shrinkage of target lesions, respectively. Among 158 patients in the primary efficacy set with measurable disease, 10 patients discontinued without a post-baseline target lesion response assessment. Panel B shows a swimmer plot of outcomes, including time to response, duration of exposure, and patient status in 161 patients in the primary efficacy set. Arrows indicate that treatment is ongoing at the data cutoff date. NRG1+ denotes neuregulin 1 fusion-positive, and NSCLC non-small cell lung cancer. A. Maximum Change in Tumor Burden According to Tumor Type B. Response Status and Exposure Duration in Individual Patients Over Time

Figure 1.. Efficacy of Zenocutuzumab in NRG1+ Cancer.

Panel A shows a waterfall plot of the maximum percent change from baseline in target lesion tumor burden (sum of the longest diameters) per investigator assessment. The upper and lower limits of the gray shading indicate 20% growth and 30% shrinkage of target lesions, respectively. Among 158 patients in the primary efficacy set with measurable disease, 10 patients discontinued without a post-baseline target lesion response assessment. Panel B shows a swimmer plot of outcomes, including time to response, duration of exposure, and patient status in 161 patients in the primary efficacy set. Arrows indicate that treatment is ongoing at the data cutoff date. NRG1+ denotes neuregulin 1 fusion-positive, and NSCLC non-small cell lung cancer. A. Maximum Change in Tumor Burden According to Tumor Type B. Response Status and Exposure Duration in Individual Patients Over Time