Ou Sai-Hong Ignatius, Solomon Benjamin J, Besse Benjamin, Bearz Alessandra, Lin Chia-Chi, Chiari Rita, Camidge D Ross, Lin Jessica J, Abbattista Antonello, Toffalorio Francesca, Soo Ross A
Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
J Thorac Oncol. 2025 Apr;20(4):513-520. doi: 10.1016/j.jtho.2024.11.021. Epub 2024 Nov 22.
Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present the overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive NSCLC from the final analyses of the pivotal phase 2 study.
Adults with ALK-positive NSCLC, enrolled in expansion cohorts (EXPs) on the basis of prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was the objective response rate; secondary endpoints included OS and safety.
Thirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression after crizotinib ± chemotherapy), 28 in EXP3B (disease progression after one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression after ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression after ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% confidence interval [CI]: NR-NR) in EXP1, NR (95% CI: 51.5-NR) in EXP2-3A, 37.4 months (95% CI: 12.3-NR) in EXP3B, 19.2 months (95% CI: 15.4-30.2) in EXP4-5, and 20.7 months (95% CI: 16.1-30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 patients (28%), temporary treatment discontinuation in 158 patients (57%), and permanent discontinuation in 35 patients (13%).
After a minimum follow-up of five years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.
gov NCT01970865.
洛拉替尼是一种强效的、可穿透血脑屏障的第三代间变性淋巴瘤激酶（ALK）和ROS1酪氨酸激酶抑制剂，对ALK耐药突变具有广泛的覆盖范围。我们通过关键2期研究的最终分析，展示了洛拉替尼在晚期ALK阳性非小细胞肺癌（NSCLC）患者中的总生存期（OS）和长期安全性。
ALK阳性NSCLC成人患者，根据既往治疗情况入组扩展队列（EXP1 - 5），接受洛拉替尼100 mg口服，每日一次，每21天为一个连续周期。主要终点为客观缓解率；次要终点包括OS和安全性。
EXP1入组30例患者（初治），EXP2 - 3A入组59例患者（克唑替尼±化疗后疾病进展），EXP3B入组28例患者（一种第二代ALK酪氨酸激酶抑制剂[TKI]±化疗后疾病进展），EXP4 - 5入组111例患者（≥2种ALK TKI±化疗后疾病进展），EXP3B - 5入组139例患者（≥1种ALK TKI±化疗后疾病进展）。EXP1的中位OS未达到（NR）（95%置信区间[CI]：NR - NR），EXP2 - 3A的中位OS为NR（95% CI：51.5 - NR），EXP3B的中位OS为37.4个月（95% CI：12.3 - NR），EXP4 - 5的中位OS为19.2个月（95% CI：15.4 - 30.2），EXP3B - 5的中位OS为20.7个月（95% CI：16.1 - 30.3）。77例患者（28%）报告了导致剂量减少的全因不良事件，158例患者（57%）出现临时治疗中断，35例患者（13%）出现永久停药。
经过至少五年的随访，全球2期研究的最终分析证实，洛拉替尼在初治和既往治疗的ALK阳性NSCLC患者中具有显著活性、延长的OS以及总体一致的安全性结果。
美国国立医学图书馆临床试验注册中心NCT01970865。
