Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.
Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.
复制标题
DOI：
10.1056/nejmoa2005653
复制
发表时间：
2020-08-27
期刊：
影响因子：
--
通讯作者：
Subbiah V
中科院分区：
文献类型：
--
作者：
Drilon A;Oxnard GR;Tan DSW;Loong HHF;Johnson M;Gainor J;McCoach CE;Gautschi O;Besse B;Cho BC;Peled N;Weiss J;Kim YJ;Ohe Y;Nishio M;Park K;Patel J;Seto T;Sakamoto T;Rosen E;Shah MH;Barlesi F;Cassier PA;Bazhenova L;De Braud F;Garralda E;Velcheti V;Satouchi M;Ohashi K;Pennell NA;Reckamp KL;Dy GK;Wolf J;Solomon B;Falchook G;Ebata K;Nguyen M;Nair B;Zhu EY;Yang L;Huang X;Olek E;Rothenberg SM;Goto K;Subbiah V
RET融合是1%至2%的非小细胞肺癌（NSCLC）的致癌驱动因素。在RET融合阳性NSCLC患者中，选择性RET抑制的疗效和安全性尚不清楚。我们在selpercatinib 1-2期试验中分别招募了既往接受过含铂化疗和既往未接受过治疗的晚期RET融合阳性NSCLC患者。主要终点是由独立审查委员会确定的客观缓解（完全或部分缓解）。次要终点包括缓解持续时间、无进展生存期和安全性。在前105例连续入组的RET融合阳性NSCLC患者中，既往至少接受过含铂化疗，客观缓解的百分比为64%（95%置信区间[CI]，54 - 73）。中位缓解持续时间为17.5个月（95% CI，12.0至无法评估），63%的缓解在中位随访12.1个月时仍在持续。在39例既往未接受过治疗的患者中，客观缓解的百分比为85%（95% CI，70 - 94），90%的缓解在6个月时仍在持续。在入组时有可测量中枢神经系统转移的11例患者中，客观颅内缓解的百分比为91%（95% CI，59 - 100）。最常见的3级或3级以上不良事件为高血压（14%的患者）、丙氨酸转氨酶水平升高（12%）、天冬氨酸转氨酶水平升高（10%）、低钠血症（6%）和淋巴细胞减少症（6%）。531例患者中共有12例（2%）因药物相关不良事件停用selpercatinib。Selpercatinib具有持久的疗效，包括颅内活性，在既往接受过含铂化疗和既往未接受过治疗的RET融合阳性NSCLC患者中主要具有轻度毒性作用。（由Loxo Oncology等资助; LIBRETTO-001 ClinicalTrials.gov编号，NCT 03157128。）
RET fusions are oncogenic drivers in 1 to 2% of non–small-cell lung cancers (NSCLCs). In patients with RET fusion–positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. We enrolled patients with advanced RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1–2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. In the first 105 consecutively enrolled patients with RET fusion–positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.)