|
Turning Point Therapeutics更新了RET TKI TPX-0046的初步结果 
https://ir./static-files/9c6efb12-ac81-4cde-beac-e73c1772aaad 回顾 RET激酶结构上通过E734、R912和D771“栓住”一段富含甘氨酸的loop（GRL）闭合后呈顺式抑制构象，像BLU-667和LOXO-292这两个小分子的设计都是结合抑制状态的RET，整个分子在tethered pocket里呈现延伸状态，相反TPTX-0046采取了更紧凑的大环结构，另外结合的是活化状态的RET，也不结合Solvent-front 区域，所以不管是结构还是机理都区别于BLU-667和LOXO-292，可以克服两者引起的耐药 
激酶抑制谱：TPTX-0046对RET和SRC家族（红色）有着强效的抑制
体外活性对比：对野生型RET及Y806N的抑制与BLU-667、LOXO-292相当，对溶剂前沿区G810S/R突变抑制更强，但是对看门突变 V804M的抑制更弱
体内模型： A-B：在野生型的KIF5B-RET融合的CDX模型中TPTX-0046对肿瘤生长的抑制呈现出剂量依赖，另外RET磷酸化的抑制（PD）与游离药物浓度（PK）也体现出相关性 C：在携带溶剂前沿区G810R突变的CDX模型中，TPTX-0046强于已有的两款药物，这个与之前体外的数据一致 D-F：不管是人髓样甲状腺癌细胞（TT细胞）来源的模型还是PDX模型，TPTX-0046同样也呈现出剂量依赖的肿瘤抑制
所以
SWORD-1是评估TPTX-46用于携带RET融合或突变的晚期实体瘤的Ph1/2，对先前治疗不做限制，允许纳入接受过RET治疗的患者及无症状的脑转移，其中Ph1剂量递增部分采取3+3设计：确定了RP2D后进入Ph2，会入组未RET TKI naive或经治的RET融合 NSCLC、RET突变MTC及携带RET融合或突变的其他类型实体瘤
入组21例患者，包括10例NSCLC和11例MTC，14例可评估疗效期中TKI naive和经治的分别5例和9例
患者基线：90% ECOG PS 1分，67%的患者属≥3L治疗，76%的患者接受过RET TKI期中10%接受过BLU-667+Loxo-292的治疗 
安全性非常好，绝大部分都是Gr1-2 最常见的TEAE是头晕，因TEAE引起的剂量下调和终止分别19%和10% MTD未达到，30mg QD的DL有1例DLT
没有≥Gr3 的肝毒性，也没有治疗相关的高血压、出血、QT延长及ILD 目前DoT近8周
初步疗效：1）TKI naive的5例患者中，2例30mgQD的患者确认PR；2）TKI经治的9例患者中2例SD，肿瘤缩小17-27%仍在组等下一次影像检查
9例TKI经治的患者中，获得SD的2例患者先前均只接受过1轮TKI
在可评估的14患者中，仍有50%在组，TKI Naive及经治的患者DoT范围分别8.9-51+ wks和5.1 to 41.3+wks
病例分析
下一步
TPX-0046 Initial Clinical Data
Twenty-one patients enrolled in the study including 10 with non-small cell lung cancer (NSCLC) and 11 with medullary thyroid carcinoma (MTC) who were treated from December 2019 to the data cut-off date of March 10, 2021. Patients included those with RET-altered TKI-naïve NSCLC (n=3; all previously treated with platinum-based chemotherapy and immunotherapy) and MTC (n=2), and TKI-pretreated NSCLC (n=7) and MTC (n=9). All 16 TKI-pretreated patients were previously treated with a selective RET TKI and 9 patients (56%) were treated with more than 1 prior TKI. Ninety-one percent of patients (19/21) had a baseline ECOG performance score of 1, and nearly half (10/21) received 3 or more prior therapies. Preliminary efficacy data by investigator assessment was available for 14 evaluable patients with baseline measurable disease and at least one post-baseline assessment per RECIST v1.1, including TKI-naïve NSCLC (n=3) and MTC (n=2), and TKI-pretreated NSCLC (n=4) and MTC (n=5). As of the March 10, 2021 data cut-off date: Preliminary Safety and Pharmacokinetic Results A total of 21 patients with RET-altered NSCLC or MTC were treated with TPX-0046 across multiple doses and schedules from 10mg once daily (QD) to 30mg QD TPX-0046 was generally well tolerated, with the most frequent treatment emergent adverse event (TEAE) being Grade 1 or 2 dizziness The maximum tolerated dose had not been determined, with 1 dose-limiting toxicity of treatment-related Grade 2 gait disturbance at 30 mg QD TEAEs reported in greater than 20 percent of patients were dizziness (43%); fatigue (38%); alkaline phosphatase increase, constipation, decreased appetite, dry mouth, hyperphosphataemia, lipase increase (29% each); and alanine aminotransferase increase, dehydration, and muscular weakness (24% each) There were infrequent dose reductions or drug discontinuations due to TEAEs The majority of treatment related adverse events (TRAEs) were Grade 1 or 2 and there were no Grade 4 or 5 TRAEs There were no treatment related Grade 3 or greater ALT/AST elevations, any grade of hypertension, hemorrhagic events or QT prolongation, and no interstitial lung disease or pneumonitis Preliminary pharmacokinetic data indicates exposure increases in a dose dependent manner
Preliminary Efficacy Results Of 5 RET TKI-naïve patients, 4 showed tumor regressions of -42%, -37%, -23%, and -3%, including 2 patients dosed at 30 mg QD who achieved confirmed partial responses with duration of responses of 5.6 and 5.8+ months, respectively. Three of the 4 patients with regressions remained on treatment awaiting their next scan Of 9 TKI-pretreated patients, 3 patients (2 treated with only 1 prior selective RET TKI) achieved tumor regressions of -44%, -27% and -17%. All 3 patients remained on treatment awaiting their next scan Of the 14 evaluable patients, 7 (50%) remained on treatment with duration of treatment ranging from 5.1 to 51+ weeks
|
