Leighl Natasha B, Rizvi Naiyer A, de Lima Lopes Gilberto, Arpornwirat Wichit, Rudin Charles M, Chiappori Alberto A, Ahn Myung-Ju, Chow Laura Q M, Bazhenova Lyudmila, Dechaphunkul Arunee, Sunpaweravong Patrapim, Eaton Keith, Chen Jihong, Medley Sonja, Poondru Srinivasu, Singh Margaret, Steinberg Joyce, Juergens Rosalyn A, Gadgeel Shirish M
Cancer Clinical Research Unit, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Hematology and Oncology, Columbia University Medical Center, New York, NY.
Clin Lung Cancer. 2017 Jan;18(1):34-42.e2. doi: 10.1016/j.cllc.2016.07.007. Epub 2016 Aug 8.
First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes.
We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival.
After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results.
Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.
对于具有表皮生长因子受体（EGFR）激活突变的晚期非小细胞肺癌患者，一线使用EGFR酪氨酸激酶抑制剂治疗与化疗相比可改善预后，但大多数患者会产生耐药性。通过1型胰岛素样生长因子1受体（IGF-1R）的代偿性信号传导可能导致耐药；对IGF-1R和EGFR进行双重阻断可能会改善预后。
我们开展了一项随机、双盲、安慰剂对照的II期研究，在未经化疗的EGFR突变阳性晚期非小细胞肺癌患者中，比较双重IGF-1R和胰岛素受体酪氨酸激酶抑制剂林西替尼联合厄洛替尼与安慰剂联合厄洛替尼的疗效。患者接受林西替尼每日两次，每次150mg，或安慰剂加厄洛替尼每日一次，每次150mg，持续21天为一个周期。主要终点是无进展生存期。
在88例患者（每组44例）随机分组后，由于林西替尼组疗效较差，试验提前揭盲。林西替尼组与安慰剂组的中位无进展生存期分别为8.4个月和12.4个月（风险比，1.37；P = 0.29）。总缓解率（47.7%对75.0%；P = 0.02）和疾病控制率（77.3%对95.5%；P = 0.03）也较低。虽然大多数不良事件≤2级，但林西替尼联合厄洛替尼导致不良事件增加，进而使厄洛替尼的暴露量减少（中位天数，228天对305天）。药代动力学和药效学结果未提示存在药物相互作用。
与单独使用厄洛替尼相比，厄洛替尼联合林西替尼导致预后较差。在肺癌中进一步开展IGF-1R抑制剂的临床研发之前，需要进一步了解信号通路以及能够预测疗效的生物标志物。
