Background

Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer.

Methods

We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy.

Results

There were ten males (66.7%), and the median patient’s age was 56 years (range 38–70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6–12). The median follow-up after recurrence was 17.1 months (95% CI 12.3–22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8–7.3) and overall survival of 9.0 months (95% CI 3.9–14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.

Conclusions

While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

中文翻译：

---

奥希替尼联合贝伐单抗在同时存在 EGFR 扩增和 EGFRvIII 突变的胶质母细胞瘤患者中的疗效

背景

EGFR 及其活性突变体 EGFRvIII的扩增  在胶质母细胞瘤 (GB) 中很常见。虽然EGFR和EGFRvIII在发病机制中起关键作用，但使用 EGFR-酪氨酸激酶抑制剂或抗体进行靶向治疗的疗效有限。为了提高有效性的可能性，我们针对患有同时发生EGFR扩增和EGFRvIII突变的复发性 GB 的成年患者，使用针对非小细胞肺癌所述剂量的奥希替尼/贝伐单抗。

方法

我们回顾性探讨了先前描述的与EGFR基因扩增相关的EGFRvIII突变是否可以预测复发时接受治疗的 15 名患者子集对奥希替尼/贝伐单抗组合的反应。在液体活检中使用商业下一代测序面板描述了一组受试者中的阻力模式。

结果

有 10 名男性（66.7%），中位患者年龄为 56 岁（范围 38-70 岁）。初步诊断后，12 名患者接受了部分（26.7%）或全切除（53.3%）。随后，所有病例均接受了 IMRT 和同步辅助替莫唑胺（TMZ；中位周期数 9，范围 6-12）。复发后的中位随访时间为 17.1 个月（95% CI 12.3-22.6）。所有患者均接受奥希替尼/贝伐单抗作为二线干预，中位无进展生存期 (PFS) 为 5.1 个月 (95% CI 2.8–7.3)，总生存期为 9.0 个月 (95% CI 3.9–14.0)。PFS6 为 46.7%，总体反应率为 13.3%。暴露于奥希替尼/贝伐单抗组合后，主要的继发性改变是MET扩增、STAT3、IGF1R、PTEN和PDGFR。

结论

虽然奥希替尼/贝伐单抗组合对大多数同时存在EGFR扩增和EGFRvIII突变的 GB 患者有一定的疗效，但有一个亚组经历了长期有意义的益处。这个简短队列的研究结果证明了在临床试验中继续研究的合理性。暴露于奥希替尼/贝伐单抗后的耐药模式包括已知的EGFR调节机制，这些发现有助于逐步合理地理解和靶向该途径。