Depatuxizumab mafodotin 治疗 EGFR 扩增型新诊断胶质母细胞瘤的 III 期随机临床试验。
Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.
机构信息
Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
Herbert Irving Comprehensive Cancer Center, New York, New York, USA.
出版信息
Neuro Oncol. 2023 Feb 14;25(2):339-350. doi: 10.1093/neuonc/noac173.
BACKGROUND
Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs.
METHODS
In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing.
RESULTS
There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue.
CONCLUSIONS
Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.
背景
约 50%的新诊断胶质母细胞瘤（GBM）存在表皮生长因子受体基因扩增（EGFR-amp）。临床前和早期临床数据表明，抗体药物偶联物 depatuxizumab mafodotin（depatux-m）在 EGFR-amp GBM 中具有疗效，该药物由与微管抑制剂毒素连接的单克隆抗体组成，该抗体可与激活的 EGFR（过表达野生型和 EGFRvIII-突变型）结合。
方法
在这项 III 期试验中，经中心确认的 EGFR-amp 新诊断 GBM 成年患者按 1:1 随机分配接受放疗、替莫唑胺和 depatux-m/安慰剂治疗。角膜上皮病采用方案规定的预防和支持措施联合治疗。通过对数秩检验，该试验有 85%的效能检测到总生存期（OS）的风险比（HR）≤0.75（单侧 2.5%显著性水平为传统的双侧 p≤0.05）。
结果
共有 639 名随机患者（中位年龄 60 岁，范围 22-84 岁；62%为男性）。预设的中期分析发现，depatux-m 与安慰剂相比，OS 没有改善（中位 18.9 与 18.7 个月，HR 1.02，95%CI 0.82-1.26，单侧 p=0.63）。depatux-m 组的无进展生存期长于安慰剂组（中位 8.0 与 6.3 个月；HR 0.84，95%CI 0.70-1.01，p=0.029），尤其是在 EGFRvIII-突变型（中位 8.3 与 5.9 个月，HR 0.72，95%CI 0.56-0.93，单侧 p=0.002）或 MGMT 未甲基化（HR 0.77，95%CI 0.61-0.97；单侧 p=0.012）肿瘤患者中。角膜上皮病发生在 94%的 depatux-m 治疗患者中（61%为 3-4 级），导致 12%的患者停药。
结论
中期分析显示，depatux-m 治疗 EGFR-amp 新诊断 GBM 并未带来 OS 获益。未发现新的重要安全风险。
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