胃肠道间质瘤 PDGFRA D842V 突变患者中阿伐普替尼与其他酪氨酸激酶抑制剂的临床疗效比较：临床试验和真实世界数据的回顾性分析。
Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data.
机构信息
Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA.
Division of Hematology and Medical Oncology, Portland VA Health Care System and Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA.
出版信息
BMC Cancer. 2021 Mar 19;21(1):291. doi: 10.1186/s12885-021-08013-1.
BACKGROUND
Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST).
METHODS
This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression.
RESULTS
Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002.
CONCLUSIONS
In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST.
TRIAL REGISTRATION
The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .
背景
阿伐普利尼是一种强效的 KIT 和血小板衍生生长因子受体 A（PDGFRA）酪氨酸激酶抑制剂，在 PDGFRA D842V 突变胃肠间质瘤（GIST）患者中显示出前所未有的临床疗效。
方法
本回顾性分析比较了 NAVIGATOR 期 1 试验（NCT02508532）中接受阿伐普利尼治疗的患者的疗效与回顾性自然史研究（Study 1002）中接受不可切除/转移性 PDGFRA D842V 突变 GIST 一线治疗的其他酪氨酸激酶抑制剂（TKI）治疗的患者的疗效。主要终点是从参考治疗开始的总生存期（OS）（NAVIGATOR 患者为阿伐普利尼，Study 1002 患者为不可切除/转移性 GIST 的一线 TKI）；次要终点是无进展生存期（PFS）。通过 Cox 回归比较调整后的 Kaplan-Meier 生存曲线。
结果
56 例（NAVIGATOR）和 19 例（Study 1002）PDGFRA D842V 突变 GIST 患者接受了评估；在 NAVIGATOR 中，56 例患者中有一部分患者接受了 300mg（推荐的 2 期剂量）或 400mg（最大耐受剂量）起始剂量的阿伐普利尼治疗（n=38），对这些患者进行了单独分析。通过研究组之间的倾向评分对患者特征进行了不平衡调整。经逆概率治疗权重调整的 OS 分析显示，接受任何剂量阿伐普利尼治疗的 NAVIGATOR 患者的中位 OS 未达到，而 Study 1002 患者的中位 OS 为 12.6 个月；6/48 个月时的 OS 率在 NAVIGATOR 中为 100%/63%，在 Study 1002 中为 56%/17%（P=0.0001）。在 300/400mg 亚组中，6/36 个月时的调整 OS 率在 Study 1002 中分别为 100%/73%和 68%/20%（P=0.0016）。调整后的中位 PFS 在 NAVIGATOR 中为 29.5 个月，在 Study 1002 中为 3.4 个月。
结论
在这项间接的回顾性分析中，与其他 TKI 相比，阿伐普利尼在不可切除/转移性 PDGFRA D842V 突变 GIST 患者中显示出更持久的生存获益。
试验注册
NAVIGATOR 试验于 2015 年 7 月在 ClinicalTrials.gov 上注册，标识符：NCT02508532。
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