From the University of Colorado Cancer Center, Aurora (D.R.C.); Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine (H.R.K.), Samsung Medical Center (M.-J.A.), and Seoul National University Hospital (D.-W.K.), Seoul, National Cancer Center, Goyang (J.-Y.H.), Seoul National University Bundang Hospital, Seongnam (J.-S.L.), and Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju (K.H.L.) - all in South Korea; National Taiwan University Hospital (J.C.-H.Y.) and the Faculty of Medicine, School of Medicine, National Yang-Ming University (G.-C.C.), Taipei, and the Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung (G.-C.C.) - all in Taiwan; the Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna (M.J.H.); Queen Elizabeth Hospital, Kowloon, Hong Kong (J.Y.-C.L.); Azienda Ospedaliera S. Giuseppe Moscati, Avellino (C.G.), the Scientific Institute of Romagna for the Study and Treatment of Cancer, Meldola (A.D.), Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS Struttura Operativa Complessa Oncologia Medica A, Aviano (A.B.), Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples (A.M.), and the Medical Oncology Unit, University Hospital of Parma, Parma (M.T.) - all in Italy; Complejo Hospitalario Universitario de A Coruña, Coruña (R.G.C.), and Vall d'Hebron University Hospital, Barcelona (E.F.) - both in Spain; the Department of Hematology and Oncology, University Department of Internal Medicine-Oncology, Pius-Hospital Medical Campus, University of Oldenburg, Oldenburg, Germany (F.G.); the Department of Medical Oncology, Christie NHS Foundation Trust, and Division of Cancer Sciences, University of Manchester, Manchester (R.C.), and Guy's and St. Thomas' NHS Foundation Trust (S.G.) and Royal Marsden Hospital and the National Heart and Lung Institute, Imperial College London (S.P.), London - all in the United Kingdom; Virginia Cancer Specialists Research Institute and US Oncology Research, The Woodlands, TX (A.S.); Yale Cancer Center, New Haven, CT (S.N.G.); and Millennium Pharmaceuticals, Cambridge, MA (N.G., J.H., D.K.).
N Engl J Med. 2018 Nov 22;379(21):2027-2039. doi: 10.1056/NEJMoa1810171. Epub 2018 Sep 25.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.
In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred.
A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted.
Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).
布加替尼是一种下一代间变性淋巴瘤激酶（ALK）抑制剂，在对克唑替尼耐药的ALK 阳性非小细胞肺癌（NSCLC）患者中具有强大的疗效。布加替尼与克唑替尼相比，在未接受过 ALK 抑制剂的晚期 ALK 阳性 NSCLC 患者中的疗效尚不清楚。
在一项开放标签、3 期试验中，我们按 1:1 的比例随机分配未接受过 ALK 抑制剂的晚期 ALK 阳性 NSCLC 患者，接受每日一次 180 mg 布加替尼（先进行 7 天 90 mg 的导入期）或每日两次 250 mg 克唑替尼。主要终点是通过盲法独立中心评估的无进展生存期。次要终点包括客观缓解率和颅内缓解率。当预计有 50%的疾病进展或死亡事件（198 个中的 198 个）发生时，进行第一次中期分析。
共有 275 名患者进行了随机分组；137 名患者被分配至布加替尼组，138 名患者被分配至克唑替尼组。在第一次中期分析（99 个事件）时，布加替尼组的中位随访时间为 11.0 个月，克唑替尼组为 9.3 个月。与克唑替尼相比，布加替尼的无进展生存期更高（估计 12 个月无进展生存率，67%[95%置信区间（CI），56 至 75]与 43%[95%CI，32 至 53]；疾病进展或死亡的风险比，0.49[95%CI，0.33 至 0.74]；对数秩检验 P<0.001）。布加替尼的确认客观缓解率为 71%（95%CI，62 至 78），克唑替尼为 60%（95%CI，51 至 68）；有可测量病灶的患者颅内反应的确认率分别为 78%（95%CI，52 至 94）和 29%（95%CI，11 至 52）。未发现新的安全性问题。
在未接受过 ALK 抑制剂的 ALK 阳性 NSCLC 患者中，与克唑替尼相比，接受布加替尼治疗的患者无进展生存期显著延长。（由 Ariad 制药公司资助；ALTA-1L ClinicalTrials.gov 编号，NCT02737501）。
