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Abstract：
GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors.
Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly.
Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC).
GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers.
This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.
Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly.
Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC).
GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers.
This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.
摘要：
GSK2849330，一种抗HER3单克隆抗体，可阻断癌细胞中的HER3/Neuregulin1（NRG1）信号传导，被设计用于增强的抗体依赖性细胞毒性和补体依赖性细胞毒性。这个阶段I,人类第一，开放标签研究评估了安全性，药代动力学（PK），药效学,GSK2849330在表达HER3的晚期实体瘤患者中的初步活性。
通过免疫组织化学前瞻性选择具有各种肿瘤类型的患者的HER3表达;还筛选了NRG1mRNA表达的子集。在剂量递增阶段，患者每2周接受GSK28493301.4-30mg/kg，或每周3mg/kg或30mg/kg，静脉注射（IV）。在剂量膨胀阶段，患者每周静脉注射30mg/kgGSK2849330.
29例HER3表达癌症患者，其中2人表达NRG1，接受GSK2849330（剂量递增：n=18，剂量扩大：n=11）。GSK2849330耐受性良好。没有观察到剂量限制性毒性。最高剂量,每周30毫克/千克，预计将提供全面的目标参与，被选择用于剂量扩张。治疗引起的不良事件（AE）大多为1级或2级。最常见的不良事件是腹泻（66%），疲劳（62%），食欲下降（31%）。实现了与剂量成正比的血浆暴露，在配对的组织活检中有HER3抑制的证据。29名患者中,只有1个确认部分反应，持续19个月,在CD74-NRG1重排的非小细胞肺癌（NSCLC）患者中发现。
GSK2849330表现出良好的安全性，剂量比例PK，和目标交战的证据，但在表达HER3的癌症中抗肿瘤活性有限。在CD74-NRG1重排的NSCLC患者中观察到的异常反应表明在NRG1融合阳性癌症中的进一步探索。
这项首次人体研究证实GSK2849330具有良好的耐受性。重要的是,在各种表达HER3的晚期肿瘤中，仅通过HER3/NRG1表达进行前瞻性选择不足以鉴定可从这种抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性增强的抗HER3抗体治疗中获益的患者。唯一确认的持久反应是CD74-NRG1重排肺癌患者。这凸显了在正在进行的试验中，前瞻性地跨肿瘤类型筛选NRG1融合体以丰富抗HER3药物的潜在应答者的潜在效用。
通过免疫组织化学前瞻性选择具有各种肿瘤类型的患者的HER3表达;还筛选了NRG1mRNA表达的子集。在剂量递增阶段，患者每2周接受GSK28493301.4-30mg/kg，或每周3mg/kg或30mg/kg，静脉注射（IV）。在剂量膨胀阶段，患者每周静脉注射30mg/kgGSK2849330.
29例HER3表达癌症患者，其中2人表达NRG1，接受GSK2849330（剂量递增：n=18，剂量扩大：n=11）。GSK2849330耐受性良好。没有观察到剂量限制性毒性。最高剂量,每周30毫克/千克，预计将提供全面的目标参与，被选择用于剂量扩张。治疗引起的不良事件（AE）大多为1级或2级。最常见的不良事件是腹泻（66%），疲劳（62%），食欲下降（31%）。实现了与剂量成正比的血浆暴露，在配对的组织活检中有HER3抑制的证据。29名患者中,只有1个确认部分反应，持续19个月,在CD74-NRG1重排的非小细胞肺癌（NSCLC）患者中发现。
GSK2849330表现出良好的安全性，剂量比例PK，和目标交战的证据，但在表达HER3的癌症中抗肿瘤活性有限。在CD74-NRG1重排的NSCLC患者中观察到的异常反应表明在NRG1融合阳性癌症中的进一步探索。
这项首次人体研究证实GSK2849330具有良好的耐受性。重要的是,在各种表达HER3的晚期肿瘤中，仅通过HER3/NRG1表达进行前瞻性选择不足以鉴定可从这种抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性增强的抗HER3抗体治疗中获益的患者。唯一确认的持久反应是CD74-NRG1重排肺癌患者。这凸显了在正在进行的试验中，前瞻性地跨肿瘤类型筛选NRG1融合体以丰富抗HER3药物的潜在应答者的潜在效用。
