Supplementary Material for: Cerebrospinal fluid concentration of the RET-inhibitor pralsetinib: a case report

Introduction
Pralsetinib is used to treat metastatic RET fusion-positive non-small cell lung cancer. Preclinical studies of pralsetinib have shown blood-brain barrier (BBB) penetration and intracranial activity. The intracranial efficacy of pralsetinib in patients with brain metastasis is considered to be greater compared to older multikinase tyrosine kinase inhibitors. However, CSF concentrations of pralsetinib in patients are not well described in literature.

Case presentation
We report a case of a patient with RET fusion-positive NSCLC treated with pralsetinib. Despite of extracranial clinical and radiologic remission, the patient developed progressive brain metastasis during treatment with pralsetinib. We measured the pralsetinib concentration in plasma and in CSF to determine the CSF-to-unbound plasma ratio. The measured pralsetinib concentrations in plasma and CSF were 1951 ng/ml (~57 unbound) and 14 ng/mL, respectively, reflecting a CSF-to-unbound plasma concentration ratio of 0.25. Our findings were compared with data from literature.

Conclusion
We showed that pralsetinib penetrates the CSF well and is expected to be an effective treatment for brain metastasis of RET fusion-positive NSCLC. Lack of intracranial efficacy is more likely to be caused by intrinsic or acquired tumor resistance instead of suboptimal exposure of pralsetinib in the brain.

引言
普拉替尼（pralsetinib）适用于治疗转移性RET融合阳性非小细胞肺癌（non-small cell lung cancer, NSCLC）。既往针对普拉替尼的临床前研究已证实，其可穿透血脑屏障（blood-brain barrier，BBB）并具备颅内抗肿瘤活性。相较于传统多靶点酪氨酸激酶抑制剂，普拉替尼在脑转移患者中的颅内疗效更具优势，但目前文献中对患者体内普拉替尼的脑脊液（cerebrospinal fluid, CSF）浓度报道仍较为有限。

病例报告
我们报告1例接受普拉替尼治疗的RET融合阳性NSCLC患者。尽管患者的颅外病灶实现了临床及影像学缓解，但在普拉替尼治疗期间出现了脑转移进展。我们检测了该患者血浆及脑脊液中的普拉替尼浓度，以计算脑脊液与游离血浆浓度的比值。检测结果显示，患者血浆中普拉替尼总浓度为1951 ng/ml（游离浓度约57 ng/ml），脑脊液中浓度为14 ng/mL，据此得到脑脊液与游离血浆浓度比值为0.25。我们将本次研究结果与已发表的文献数据进行了对比分析。

结论
本研究证实普拉替尼可较好穿透脑脊液屏障，有望成为治疗RET融合阳性NSCLC脑转移的有效手段。患者出现颅内疗效不佳的原因更可能为肿瘤的固有耐药或获得性耐药，而非普拉替尼在脑内的暴露量不足。