Lessons learned: Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC.Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients.
Background: Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC.
Methods: In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m2 intravenously or 2.3 mg/m2 orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0-2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression.
Results: Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5-3.6) and 1.2 (95% CI, 1.1-1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2-7.6) and 3.4 (95% CI, 1.8-5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib.
Conclusion: Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.
作者总结
经验
• 小细胞肺癌(SCLC)患者靶向治疗的选择非常有限, 迄今尚无一种制剂被看好有充足的潜力进入III期临床试验。
• Linsitinib是强效的胰岛素生长因子1受体酪氨酸激酶抑制剂, 可能对SCLC具有治疗活性。
• 本文的阴性结果在一定程度上可能是由SCLC缺乏可靠的预测性生物标记物所致,尽管linsitinib在未经选择的复发性SCLC患者中是安全的, 但并未显示出临床活性。
摘要
背景. 复发性小细胞肺癌(SCLC)的治疗仍然不尽人意。胰岛素生长因子1受体(IGF-1R)信号通路在SCLC的生长、存活及化疗耐药中发挥作用。Linsitinib是强效的IGF-1R酪氨酸激酶抑制剂, 可能对SCLC具有治疗活性。
方法. 本项II期研究中, 8例符合入选条件的患者按1:2比例随机接受拓扑替康(1.5 mg/m2静脉注射或2.3 mg/m2口服, 每日1次×5天, 共4周期)或linsitinib(150 mg口服, 每日2次直至发生疾病进展)治疗。主要终点为无进展生存(PFS)。研究入选了铂类治疗敏感或抵抗、体能状态(PS)评分0∼2分、具有足够骨髓和肝肾功能的复发性SCLC患者。研究排除了合并糖尿病、肝硬化, 以及服用胰岛素促泌剂的患者。拓扑替康组患者在发生疾病进展后, 允许交叉至linsitinib组。
结果. 15例患者接受拓扑替康治疗(8例耐药, 3例PS为2分), 29例患者接受linsitinib治疗(16例耐药, 5例PS为2分)。拓扑替康组有2例患者达到部分缓解。仅有拓扑替康组4/15例患者、linsitinib组1/29例患者达到疾病稳定。中位PFS分别为拓扑替康组3.0个月[95%置信区间(CI): 1.5∼3.6], linsitinib组1.2个月(95% CI:1.1∼1.4, P=0.000 1)。拓扑替康组和linsitinib组中位总生存分别为5.3个月(95% CI:2.2∼7.6)和3.4个月(95% CI:1.8∼5.6, P=0.71)。3/4级不良事件(发生率>5%)于拓扑替康组为贫血、血小板减少、中性粒细胞减少/白细胞减少、腹泻、疲乏、脱水以及低钾血症, 于linsitinib组为血小板减少、疲乏、丙氨酸氨基转移酶/天冬氨酸氨基转移酶水平升高。
结论. Linsitinib用于治疗未经选择的复发性SCLC患者是安全的, 但未显示出临床活性。The Oncologist 2016;21:1163–1164e
Trial registration: ClinicalTrials.gov NCT01533181.
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