Allarity Therapeutics, Hørsholm, Denmark.
Allarity Therapeutics, Boston, MA, United States of America.
PLoS One. 2023 Aug 30;18(8):e0290681. doi: 10.1371/journal.pone.0290681. eCollection 2023.
Dovitinib is a receptor tyrosine kinase inhibitor of VEGFR1-3, PDGFR, FGFR1/3, c-KIT, FLT3 and topoisomerase 1 and 2. The drug response predictor (DRP) biomarker algorithm or DRP-Dovitinib is being developed as a companion diagnostic to dovitinib and was applied retrospectively.
Archival tumor samples were obtained from consenting patients in a phase 3 trial comparing dovitinib to sorafenib in renal cell carcinoma patients and the DRP-Dovitinib was applied. The biomarker algorithm combines the expression of 58 messenger RNAs relevant to the in vitro sensitivity or resistance to dovitinib, including genes associated with FGFR, PDGF, VEGF, PI3K/Akt/mTOR and topoisomerase pathways as well as ABC drug transport, and provides a likelihood score between 0-100%.
The DRP-Dovitinib divided the dovitinib treated RCC patients into two groups, sensitive (n = 49, DRP score >50%) or resistant (n = 86, DRP score ≤ 50%) to dovitinib. The DRP sensitive population was compared to the unselected sorafenib arm (n = 286). Median progression-free survival (PFS) was 3.8 months in the DRP sensitive dovitinib arm and 3.6 months in the sorafenib arm (hazard ratio 0.71, 95% CI 0.51-1.01). Median overall survival (OS) was 15.0 months in the DRP sensitive dovitinib arm and 11.2 months in the sorafenib arm (hazard ratio 0.69, 95% CI 0.48-0.99). The observed clinical benefit increased with increasing DRP score. At a cutoff of 67% the median OS was 20.6 months and the median PFS was 5.7 months in the dovitinib arm. The results were confirmed in five smaller phase II trials of dovitinib which showed a similar trend.
The DRP-Dovitinib shows promise as a potential biomarker for identifying advanced RCC patients most likely to experience clinical benefit from dovitinib treatment, subject to confirmation in an independent prospective trial of dovitinib in RCC patients.
多韦替尼是一种受体酪氨酸激酶抑制剂，可抑制 VEGFR1-3、PDGFR、FGFR1/3、c-KIT、FLT3 和拓扑异构酶 1 和 2。药物反应预测器（DRP）生物标志物算法或 DRP-多韦替尼正在作为多韦替尼的伴随诊断方法进行开发，并已被回顾性应用。
从同意参加比较多韦替尼与索拉非尼治疗肾细胞癌患者的 3 期试验的患者中获得存档的肿瘤样本，并应用 DRP-Dovitinib。该生物标志物算法结合了 58 种与多韦替尼体外敏感性或耐药性相关的信使 RNA 的表达，包括与 FGFR、PDGF、VEGF、PI3K/Akt/mTOR 和拓扑异构酶途径以及 ABC 药物转运相关的基因，并提供 0-100%的可能性评分。
DRP-Dovitinib 将多韦替尼治疗的 RCC 患者分为两组，对多韦替尼敏感（n=49，DRP 评分>50%）或耐药（n=86，DRP 评分≤50%）。将 DRP 敏感人群与未选择的索拉非尼组（n=286）进行比较。DRP 敏感的多韦替尼组中位无进展生存期（PFS）为 3.8 个月，索拉非尼组为 3.6 个月（风险比 0.71，95%CI 0.51-1.01）。DRP 敏感的多韦替尼组中位总生存期（OS）为 15.0 个月，索拉非尼组为 11.2 个月（风险比 0.69，95%CI 0.48-0.99）。随着 DRP 评分的增加，观察到的临床获益增加。在 67%的截定点，多韦替尼组的中位 OS 为 20.6 个月，中位 PFS 为 5.7 个月。在五项较小的多韦替尼二期试验中也得到了类似的结果，证实了这一结果。
DRP-Dovitinib 有望成为一种潜在的生物标志物，用于识别最有可能从多韦替尼治疗中获益的晚期 RCC 患者，但需要在多韦替尼治疗 RCC 患者的独立前瞻性试验中得到证实。
