Gadgeel Shirish M, Shaw Alice T, Govindan Ramaswamy, Gandhi Leena, Socinski Mark A, Camidge D Ross, De Petris Luigi, Kim Dong-Wan, Chiappori Alberto, Moro-Sibilot Denis L, Duruisseaux Michael, Crino Lucio, De Pas Tommaso, Dansin Eric, Tessmer Antje, Yang James Chih-Hsin, Han Ji-Youn, Bordogna Walter, Golding Sophie, Zeaiter Ali, Ou Sai-Hong Ignatius
Shirish M. Gadgeel, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Alice T. Shaw, Massachusetts General Hospital; Leena Gandhi, Dana-Farber Cancer Institute, Boston, MA; Ramaswamy Govindan, Washington University School of Medicine, St Louis, MO; Mark A. Socinski, University of Pittsburgh, Pittsburgh, PA; D. Ross Camidge, University of Colorado Cancer Center, Denver, CO; Alberto Chiappori, Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Sai-Hong Ignatius Ou, University of California at Irvine, Orange, CA; Luigi De Petris, Karolinska Institutet, Stockholm, Sweden; Dong-Wan Kim, Seoul National University Hospital, Seoul; Ji-Youn Han, Lung Cancer Centre, National Cancer Centre, Goyang, South Korea; Denis L. Moro-Sibilot, Service de Pneumologie; Michael Duruisseaux, Centre Hospitalier Universitaire de Grenoble, Grenoble; Eric Dansin, Centre Oscar Lambret, Lille, France; Lucio Crino, Santa Maria della Misericordia Hospital, Perugia; Tommaso De Pas, European Institute of Oncology, Milan, Italy; Antje Tessmer, Evangelische Lungenklinik Berlin, Berlin, Germany; James Chih-Hsin Yang, Graduate Institute of Oncology and Cancer Research Centre, National Taiwan University, Taipei, Taiwan; and Walter Bordogna, Sophie Golding, and Ali Zeaiter, F. Hoffmann-La Roche, Basel, Switzerland.
J Clin Oncol. 2016 Dec;34(34):4079-4085. doi: 10.1200/JCO.2016.68.4639. Epub 2016 Oct 31.
Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC.
目的 在I期和II期研究中，阿来替尼已显示出在中枢神经系统（CNS）中的活性。为了进一步评估这种活性，我们汇总了两项单臂II期研究（NP28761和NP28673；ClinicalTrials.gov标识符分别为NCT01871805和NCT01801111）中ALK阳性非小细胞肺癌（NSCLC）患者的疗效和安全性数据。
患者与方法 两项研究均纳入了先前接受过克唑替尼治疗的ALK阳性NSCLC患者；所有患者均接受阿来替尼每日两次，每次600mg的治疗。两项研究的主要终点均为独立审查委员会（IRC）评估的客观缓解率（ORR；根据实体瘤疗效评价标准[RECIST]1.1版）。其他终点（均由IRC评估）包括CNS ORR（CORR）、CNS疾病控制率（CDCR）和CNS缓解持续时间（CDOR）。
结果 136例患者有基线CNS转移（占整个研究人群的60%）；50例患者（37%）在基线时有可测量的CNS疾病。95例患者（70%）曾接受过CNS放疗；55例患者在开始阿来替尼治疗前6个月以上完成了CNS放疗。中位随访时间为12.4个月（范围0.9至19.7个月）。对于有基线可测量CNS疾病的患者，IRC CORR为64.0%（95%CI，49.2%至77.1%），CDCR为90.0%（95%CI，78.2%至96.7%），中位CDOR为10.8个月（95%CI，7.6至14.1个月）。对于有可测量和/或不可测量基线CNS疾病的患者，IRC CORR为42.6%（95%CI，34.2%至51.4%），CDCR为85.3%（95%CI，78.2%至90.8%），中位CDOR为11.1个月（95%CI，10.3个月至不可评估）。对于曾接受放疗的患者（n = 95），CORR为35.8%（95%CI，26.2%至46.3%），对于未接受过放疗的患者（n = 41），CORR为58.5%（95%CI，42.1%至73.7%）。如先前报道，无论基线CNS疾病情况如何，阿来替尼耐受性良好。
结论 在克唑替尼难治的ALK阳性NSCLC中，阿来替尼除了具有全身活性外，还显示出对CNS转移的良好疗效。
