Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
复制标题
DOI：
10.1016/s1470-2045(16)30562-9
复制
发表时间：
2016-12
期刊：
影响因子：
51.1
通讯作者：
Kris, Mark G.
中科院分区：
文献类型：
--
作者：
Drilon, Alexander;Rekhtman, Natasha;Arcila, Maria;Wang, Lu;Ni, Andy;Albano, Melanie;Van Voorthuysen, Martine;Somwar, Romel;Smith, Roger S.;Montecalvo, Joseph;Plodkowski, Andrew;Ginsberg, Michelle S.;Riely, Gregory J.;Rudin, Charles M.;Ladanyi, Marc;Kris, Mark G.
RET重排在1-2%的非小细胞肺癌中发现。卡博替尼是一种多激酶RET抑制剂，在肺癌患者中产生10%的应答率。为了评估卡博替尼在RET重排肺癌患者中的活性，我们在该分子亚组中进行了前瞻性2期试验。如果患者符合以下标准，我们将其纳入这项开放标签、Simon两阶段、2期试验：转移性或不可切除的肺癌携带RET重排，Karnofsky体力状态> 70%，以及可测量的疾病。卡博替尼以每天60 mg施用。主要目的是确定总缓解率（RECIST v1·1）。在接受至少一个剂量的卡博替尼并经历在基线和至少一个方案规定的随访时间点进行的成像的患者中以意向治疗方式进行该分析。次要目的是确定无进展生存期、总生存期和毒性。本方案中RET重排肺癌患者的招募已完成。本研究注册于ClinicalTrials.gov，编号NCT 01639508。用卡博替尼治疗26名RET重排肺腺癌患者。KIF 5 B-RET是16例（62%）患者中确定的主要融合类型。该研究达到了主要终点，在25例缓解可评价患者中的7例中观察到确认的部分缓解（总缓解率28% [95% CI 12-49%]）。最常见的3级治疗相关不良事件为4例患者（15%）的无症状脂肪酶升高、2例患者（8%）的丙氨酸转氨酶升高、2例患者（8%）的天冬氨酸转氨酶升高、2例患者（8%）的血小板减少症和2例患者（8%）的低磷血症。未观察到药物相关死亡。19例患者（73%）因药物相关不良事件需要降低剂量。在RET重排的肺癌患者中观察到的卡博替尼的活性将RET重排定义为肺癌患者中的可行驱动因素。需要对肿瘤生物学和新的治疗方法有更好的理解，以改善RET靶向治疗的结果。
RET rearrangements are found in 1–2% of non-small cell lung cancers. Cabozantinib is a multikinase RET inhibitor that produced a 10% response rate in unselected patients with lung cancers. To evaluate the activity of cabozantinib in patients with RET-rearranged lung cancers, we conducted a prospective phase 2 trial in this molecular subgroup. We enrolled patients in this open-label, Simon two-stage, phase 2 trial if they met the following criteria: metastatic or unresectable lung cancer harboring a RET rearrangement, Karnofsky performance status of >70%, and measurable disease. Cabozantinib was administered at 60 mg daily. The primary objective was to determine the overall response rate (RECIST v1·1). This analysis was performed in an intent to treat fashion in patients who received at least one dose of cabozantinib and underwent imaging performed at baseline and at least one protocol-specified follow up time point. The secondary objectives were to determine progression-free survival, overall survival, and toxicity. The accrual of RET-rearranged lung cancer patients to this protocol has been completed. This study was registered with ClinicalTrials.gov, number NCT01639508. Twenty six patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint with confirmed partial responses observed in seven of 25 response-evaluable patients (overall response rate 28% [95% CI 12–49%]). The most common grade 3 treatment-related adverse events were asymptomatic lipase elevation in four patients (15%), increased alanine aminotransferase in two patients (8%), increased aspartate aminotransferase in two patients (8%), thrombocytopenia in two patients (8%), and hypophosphatemia in two patients (8%). No drug-related deaths were observed. Nineteen patients (73%) required dose reduction due to drug-related adverse events. The observed activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed targeted therapy.