The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, UK.
BGOG and Catholic University of Leuven, Leuven Cancer Institute, Leuven, Belgium.
Lancet Oncol. 2019 Mar;20(3):383-393. doi: 10.1016/S1470-2045(18)30859-3. Epub 2019 Feb 8.
Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor.
InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing.
Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2-22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.
Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.
Genmab A/S.
Tisotumab vedotin 是一种针对组织因子的首创人源化抗体 - 药物偶联物，组织因子在多种实体瘤中表达，并与不良临床结局相关。我们旨在评估 tisotumab vedotin 在已知表达组织因子的局部晚期或转移性（或两者兼有）实体瘤混合人群中的安全性、耐受性、药代动力学特征和抗肿瘤活性。
InnovaTV 201 是一项在美国和欧洲 21 个中心进行的 1-2 期、开放标签、剂量递增和剂量扩展研究。患者（年龄≥18 岁）患有复发性、晚期或转移性卵巢癌、宫颈癌、子宫内膜癌、膀胱癌、前列腺癌、食道癌、头颈部鳞状细胞癌或非小细胞肺癌；东部合作肿瘤学组（ECOG）表现状态为 0-1；并且在接受现有标准治疗后复发或不符合标准治疗条件。纳入标准不要求特定的组织因子表达水平。在剂量递增阶段，患者接受 tisotumab vedotin 治疗，剂量为 0.3 至 2.2 mg/kg，每 3 周静脉注射一次，采用传统的 3+3 设计。在剂量扩展阶段，患者接受推荐的 2 期剂量治疗。主要终点是不良事件（包括严重不良事件、输注相关事件、治疗相关事件和 3 级或更高级别的不良事件，以及研究药物相关不良事件）的发生率，在所有接受至少一剂 tisotumab vedotin 治疗的患者（全分析人群）中进行分析。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02001623，目前已关闭招募新患者，正在进行随访。
在 2013 年 12 月 9 日至 2015 年 5 月 18 日期间，共有 27 名符合条件的患者入组剂量递增阶段。在 2.2 mg/kg 剂量组中观察到剂量限制性毒性，包括 3 级 2 型糖尿病、黏膜炎和中性粒细胞减少性发热；因此，确定 2.0 mg/kg 的 tisotumab vedotin 每 3 周静脉注射一次为推荐的 2 期剂量。在 2015 年 10 月 8 日至 2018 年 4 月 26 日期间，共有 147 名符合条件的患者入组剂量扩展阶段。任何级别最常见（≥20%的患者）的治疗后出现的不良事件是鼻出血（147 例患者中有 102 例[69%]）、疲劳（82 例[56%]）、恶心（77 例[52%]）、脱发（64 例[44%]）、结膜炎（63 例[43%]）、食欲减退（53 例[36%]）、便秘（52 例[35%]）、腹泻（44 例[30%]）、呕吐（42 例[29%]）、周围神经病变（33 例[22%]）、干眼症（32 例[22%]）和腹痛（30 例[20%]）。3 级或更高级别的不良事件最常见的是疲劳（147 例患者中有 14 例[10%]）、贫血（8 例[5%]）、腹痛（6 例[4%]）、低钾血症（6 例[4%]）、结膜炎（5 例[3%]）、低钠血症（5 例[3%]）和呕吐（5 例[3%]）。147 例患者中有 67 例（46%）发生了治疗后出现的严重不良事件。147 例患者中有 39 例（27%）发生了与研究药物相关的治疗后出现的严重不良事件。147 例患者中有 17 例（12%）发生了输注相关反应。在所有肿瘤类型中，确认的客观缓解比例为 15.6%（95%CI 10.2-22.5；147 例患者中有 23 例）。所有研究阶段共发生 9 例死亡（3 例在剂量递增阶段，6 例在剂量扩展阶段）；仅 1 例剂量扩展阶段的肺炎病例被认为可能与研究治疗有关。
Tisotumab vedotin 的安全性特征可控，在既往治疗过的多种实体瘤患者中具有令人鼓舞的初步抗肿瘤活性。在实体瘤中继续评估 tisotumab vedotin 是合理的。
Genmab A/S。
