Lu Kevin, Tse Victoria, Altaie Ghaith, Husain Hatim
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
J Thorac Dis. 2024 Aug 31;16(8):5379-5387. doi: 10.21037/jtd-23-629. Epub 2024 Jun 21.
Acquired mutations within bypass pathways including V600E have been observed in post-osimertinib progression in -mutant non-small cell lung cancer (NSCLC). The combination of dabrafenib and trametinib is currently Food and Drug Administration-approved in V600E-mutant NSCLC. However, the application of osimertinib and dabrafenib and trametinib in the setting of acquired V600E mutation resistance from osimertinib therapy has not been clearly defined. In this case series, we evaluate the efficacy and tolerability of continued osimertinib in combination with dabrafenib and trametinib in V600E acquired -mutant NSCLC.
We retrospectively reviewed our clinical patient cohort at the University of California San Diego and patients from published case studies. Individuals who had metastatic -mutant lung adenocarcinoma treated with osimertinib at any line whom subsequently developed an acquired V600E mutation confirmed by next-generation sequencing were included for analysis. All patients had subsequent dabrafenib and trametinib in combination with osimertinib after detection of the novel V600E mutation post-osimertinib therapy. We identified three cases from our practice and nine cases from literature review. In our study cohort (n=12), we observed a median progression-free survival of 7 months on triplet therapy (osimertinib, dabrafenib, and trametinib) post progression on osimertinib, median overall survival of 46.2 months, and 60% partial response on first scan after treatment initiation. Dose reductions were required in 5/12 patients due to adverse events and treatment discontinuation in 2/12 patients. The most common adverse events were pyrexia and rash, and two cases of pneumonitis were observed (grade 1 & unreported grade).
We concluded that the addition of combination dabrafenib and trametinib can be tolerable and effective in patients with acquired V600E mutation post progression on osimertinib. This study supports molecular profiling at osimertinib progression and provides additional information on the appropriate sequencing of targeted therapies in the EGFR tyrosine kinase inhibitor resistance setting.
在携带EGFR突变的非小细胞肺癌（NSCLC）患者中，接受奥希替尼治疗后疾病进展时，已观察到包括V600E在内的旁路途径中出现获得性突变。达拉非尼和曲美替尼联合用药目前已获美国食品药品监督管理局批准用于治疗携带V600E突变的NSCLC。然而，奥希替尼与达拉非尼及曲美替尼联合应用于治疗奥希替尼治疗后出现的V600E获得性耐药情况，尚未有明确定义。在本病例系列中，我们评估了继续使用奥希替尼联合达拉非尼及曲美替尼治疗携带V600E获得性突变的NSCLC的疗效和耐受性。
我们回顾性分析了加利福尼亚大学圣地亚哥分校的临床患者队列以及已发表病例研究中的患者。纳入分析的患者为经任何一线奥希替尼治疗的转移性EGFR突变肺腺癌患者，且通过下一代测序确认随后出现了获得性V600E突变。所有患者在奥希替尼治疗后检测到新的V600E突变后，均接受了达拉非尼和曲美替尼联合奥希替尼治疗。我们从自身临床实践中识别出3例病例，并通过文献回顾识别出9例病例。在我们的研究队列（n = 12）中，我们观察到三联疗法（奥希替尼、达拉非尼和曲美替尼）治疗后，患者在奥希替尼治疗进展后的中位无进展生存期为7个月，中位总生存期为46.2个月，治疗开始后首次扫描时的部分缓解率为60%。12例患者中有5例因不良事件需要减量，2例患者停药。最常见的不良事件为发热和皮疹，观察到2例肺炎（1级及未报告分级）。
我们得出结论，对于奥希替尼治疗进展后出现获得性V600E突变的患者，加用达拉非尼和曲美替尼联合治疗可耐受且有效。本研究支持在奥希替尼治疗进展时进行分子谱分析，并提供了关于EGFR酪氨酸激酶抑制剂耐药情况下靶向治疗适当序贯的更多信息。
