美国纪念斯隆-凯特琳癌症中心Alison M. Schram团队研究了泽妥珠单抗治疗NRG1融合阳性肿瘤的疗效。2025年2月6日出版的《新英格兰医学杂志》发表了这项成果。

神经调节蛋白1（NRG1）融合是多种实体瘤中发现的复发性致癌驱动因素。NRG1与人表皮生长因子受体3（HER3）结合，导致与HER2的异二聚体化，并激活下游生长和增殖途径。针对HER2和HER3的双特异性抗体泽妥珠单抗在NRG1融合阳性实体瘤患者中的疗效和安全性尚不清楚。

在这项注册的2期临床研究中，研究组分配患有任何肿瘤类型的晚期NRG1融合阳性癌症的患者每2周静脉注射750 mg的泽妥珠单抗。根据研究者的评估，主要终点是总体缓解（完全或部分缓解）。次要终点包括反应持续时间、无进展生存期和安全性。

研究组共招募并治疗了204名12种肿瘤类型的患者。在158名患有可测量疾病且在数据截止日期前至少24周登记的患者中，30%的患者有缓解（95%置信区间[CI]，23至37）。中位缓解持续时间为11.1个月（95%CI，7.4至12.9）；19%的随访在数据截止日期仍在进行中。在多种肿瘤类型中观察到缓解，包括93例非小细胞肺癌（NSCLC）患者中的27例（29%；95%CI，20-39）、36例胰腺癌患者中的15例（42%，95%CI，25-59），并跨越多个NRG1融合伴侣。

中位无进展生存期为6.8个月（95%CI，5.5至9.1）。不良事件主要为1级或2级。研究者认为与泽妥珠单抗相关的最常见不良事件是腹泻（18%的患者）、疲劳（12%）和恶心（11%）。14%的患者出现了输液相关反应。一名患者因治疗相关不良事件而停药。

研究结果表明，泽妥珠单抗在晚期NRG1融合阳性癌症患者中显示出疗效，尤其是NSCLC和癌症，主要为轻度不良事件。

附：英文原文

Title: Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer

Author: Alison M. Schram, Koichi Goto, Dong-Wan Kim, Teresa Macarulla, Antoine Hollebecque, Eileen M. O’Reilly, Sai-Hong Ignatius Ou, Jordi Rodon, Sun Young Rha, Kazumi Nishino, Michal Duruisseaux, Joon Oh Park, Cindy Neuzillet, Stephen V. Liu, Benjamin A. Weinberg, James M. Cleary, Emiliano Calvo, Kumiko Umemoto, Misako Nagasaka, Christoph Springfeld, Tanios Bekaii-Saab, Grainne M. O’Kane, Frans Opdam, Kim A. Reiss, Andrew K. Joe, Ernesto Wasserman, Viktoriya Stalbovskaya, Jim Ford, Shola Adeyemi, Lokesh Jain, Shekeab Jauhari, Alexander Drilon

Issue&Volume: 2025-02-06

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.

DOI: NJ202502063920609

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2405008