1 Fédération d'Endocrinologie, Hospices Civils de Lyon, Université Claude Bernard Lyon 1 , Lyon, France .
2 Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Université Lyon 1 , Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France .
Thyroid. 2018 Sep;28(9):1174-1179. doi: 10.1089/thy.2017.0663.
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is frequent in advanced follicular (FTC) and poorly differentiated thyroid (PDTC) carcinomas and has been implicated in oncogenesis and tumor progression. This study investigated the efficacy and safety of buparlisib, a pan-PI3K inhibitor in radioiodine refractory FTC and PDTC.
The primary endpoint of this open-label, multicenter, phase 2 pilot study was progression-free survival (PFS) at 6 months. The sample size was determined considering that a PFS ≤50% at 6 months would denote an absence of benefits (null hypothesis). Secondary endpoints were objective response rate, PFS at 12 months, overall survival at 6 and 12 months, and safety based on the frequency and severity of adverse events (AEs).
Forty-three patients (19M/24 F; median age: 67 years) with metastatic, radioiodine refractory, progressive disease received buparlisib, 100 mg, daily. Histology was PDTC in 25 (58%), FTC in 17 (40%), and Hürthle cell carcinoma in 1 (2%). RAS mutation was found in 44% (12/27) and activation of the PI3K pathway in 35% (8/23) of tested tumors. The probability of PFS was 41.7% [95% confidence interval (CI) 7.7-55.5] at 6 months and 20.9% [CI 0-35.7] at 12 months, lower than the 50% expected PFS. At 6 months, 25.6% patients had stable disease, 48.8% were progressive and 25.6% had stopped treatment due to AE. The response to therapy was not influenced by age, sex, histology, or genetic alterations. The overall survivals at 6 and 12 months were 85.9% [CI 76-97] and 78.7 % [CI 67-92], respectively. The mean tumor growth rate decreased from 3.78 mm/month [CI 2.61-4.95] before treatment to 0.8 mm/month [CI -0.2-1.88] during treatment (p < 0.02). Severe grade 3-4 AEs occurred in 27 patients (63%), including hepatitis (25%), hyperglycemia (21%), mood disorders (12%), and skin toxicity (12%), with favorable outcome after temporary or permanent treatment discontinuation or dose reduction.
Buparlisib did not result in significant efficacy in advanced FTC and PDTC. However, the decrease in tumor growth rate may suggest incomplete inhibition of oncogenic pathways and/or escape mechanisms. This should lead to evaluate combined therapy associating inhibitors of both the PI3K and mitogen-activated protein kinase pathways.
磷酸肌醇 3-激酶（PI3K）通路的失调在晚期滤泡性（FTC）和低分化甲状腺癌（PDTC）中很常见，并且与肿瘤发生和肿瘤进展有关。本研究调查了泛 PI3K 抑制剂 buparlisib 在放射性碘难治性 FTC 和 PDTC 中的疗效和安全性。
本开放标签、多中心、2 期试验的主要终点为 6 个月时的无进展生存期（PFS）。考虑到 6 个月时 PFS≤50%表示无益处（零假设），因此确定了样本量。次要终点是客观缓解率、12 个月时的 PFS、6 个月和 12 个月时的总生存率以及根据不良事件（AE）的频率和严重程度评估的安全性。
43 名（19 名男性/24 名女性；中位年龄：67 岁）患有转移性、放射性碘难治性、进行性疾病的患者接受了每日 100mg 的 buparlisib 治疗。组织学为 PDTC 25 例（58%）、FTC 17 例（40%）、Hürthle 细胞癌 1 例（2%）。在 27 例可检测肿瘤中发现 RAS 突变 44%（12/27），PI3K 通路激活 35%（8/23）。6 个月时 PFS 的概率为 41.7%[95%置信区间（CI）7.7-55.5]，12 个月时为 20.9%[CI 0-35.7]，低于预期的 50%PFS。6 个月时，25.6%的患者疾病稳定，48.8%的患者进展，25.6%的患者因 AE 停止治疗。治疗反应不受年龄、性别、组织学或遗传改变的影响。6 个月和 12 个月时的总生存率分别为 85.9%[CI 76-97]和 78.7%[CI 67-92]。治疗前平均肿瘤生长率为 3.78mm/月[CI 2.61-4.95]，治疗期间为 0.8mm/月[CI -0.2-1.88]（p<0.02）。27 名患者（63%）发生严重 3-4 级 AE，包括肝炎（25%）、高血糖（21%）、情绪障碍（12%）和皮肤毒性（12%），在临时或永久停药或降低剂量后，AE 结果良好。
buparlisib 在晚期 FTC 和 PDTC 中未显示出显著疗效。然而，肿瘤生长率的降低可能表明致癌途径和/或逃逸机制不完全抑制。这应导致评估联合治疗，联合使用 PI3K 和丝裂原活化蛋白激酶通路的抑制剂。
