镥[177Lu]奥曲肽治疗中肠神经内分泌肿瘤的3期试验
Phase 3 Trial of Lu-Dotatate for Midgut Neuroendocrine Tumors.
作者信息
Strosberg Jonathan, El-Haddad Ghassan, Wolin Edward, Hendifar Andrew, Yao James, Chasen Beth, Mittra Erik, Kunz Pamela L, Kulke Matthew H, Jacene Heather, Bushnell David, O'Dorisio Thomas M, Baum Richard P, Kulkarni Harshad R, Caplin Martyn, Lebtahi Rachida, Hobday Timothy, Delpassand Ebrahim, Van Cutsem Eric, Benson Al, Srirajaskanthan Rajaventhan, Pavel Marianne, Mora Jaime, Berlin Jordan, Grande Enrique, Reed Nicholas, Seregni Ettore, Öberg Kjell, Lopera Sierra Maribel, Santoro Paola, Thevenet Thomas, Erion Jack L, Ruszniewski Philippe, Kwekkeboom Dik, Krenning Eric
机构信息
From the Moffitt Cancer Center, Tampa, FL (J.S., G.E.-H.); Markey Cancer Center, University of Kentucky, Lexington (E.W.); Cedars Sinai Medical Center, Los Angeles (A.H.), and Stanford University School of Medicine, Stanford (E.M., P.L.K.) - both in California; University of Texas M.D. Anderson Cancer Center (J.Y., B.C.) and Excel Diagnostics Imaging Clinic (E.D.), Houston; Dana-Farber Cancer Institute, Boston (M.H.K., H.J.); University of Iowa, Iowa City (D.B., T.M.O.); Zentralklinik, Bad Berka (R.P.B., H.R.K.), and Charité-Universitätsmedizin, Berlin (M.P.) - both in Germany; Royal Free Hospital (M.C.) and King's College Hospital NHS Foundation Trust (R.S.), London, and Beatson Oncology Centre, Glasgow (N.R.) - all in the United Kingdom; Hôpital Beaujon, Clichy (R.L., P.R.), and Advanced Accelerator Applications, St. Genis-Pouilly (T.T.) - both in France; Mayo Clinic College of Medicine, Rochester, MN (T.H.); University Hospitals and KU Leuven, Leuven, Belgium (E.V.C.); Robert H. Lurie Comprehensive Cancer Center, Chicago (A.B.); Hospital Universitari de Bellvitge, Barcelona (J.M.), and Hospital Universitario Ramón y Cajal, Madrid (E.G.) - both in Spain; Vanderbilt University Medical Center, Nashville (J.B.); Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan (E.S.); University Hospital, Uppsala University, Uppsala, Sweden (K.O.); Advanced Accelerator Applications USA, New York (M.L.S., P.S., J.L.E.); and Erasmus Medical Center, Rotterdam, the Netherlands (D.K., E.K.).
出版信息
N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427.
BACKGROUND
Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors.
METHODS
We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here.
RESULTS
At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame.
CONCLUSIONS
Treatment with Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
背景
一线生长抑素类似物治疗期间病情进展的晚期中肠神经内分泌肿瘤患者的治疗选择有限。本随机对照试验评估了镥-177（Lu）-奥曲肽对晚期、进展性、生长抑素受体阳性中肠神经内分泌肿瘤患者的疗效和安全性。
方法
我们将229例高分化转移性中肠神经内分泌肿瘤患者随机分为两组，一组接受Lu-奥曲肽（116例），每8周静脉输注一次，剂量为7.4 GBq（共4次输注），并接受包括长效奥曲肽（LAR）在内的最佳支持治疗，LAR肌肉注射剂量为30 mg（Lu-奥曲肽组）；另一组单独接受长效奥曲肽治疗（113例），每4周肌肉注射一次，剂量为60 mg（对照组）。主要终点为无进展生存期。次要终点包括客观缓解率、总生存期、安全性和副作用情况。总生存期的最终分析将按方案规定在未来进行；这里报告了预先设定的总生存期期中分析结果。
结果
在进行主要分析的数据截止日期时，Lu-奥曲肽组第20个月时的无进展生存率估计为65.2%（95%置信区间[CI]，50.0至76.8），对照组为10.8%（95%CI，3.5至23.0）。Lu-奥曲肽组的缓解率为18%，对照组为3%（P<0.001）。在计划的总生存期期中分析中，Lu-奥曲肽组有14例死亡，对照组有26例死亡（P=0.004）。Lu-奥曲肽组分别有1%、2%和9%的患者发生3级或4级中性粒细胞减少、血小板减少和淋巴细胞减少，而对照组无患者发生，在观察期内未发现肾毒性证据。
结论
对于晚期中肠神经内分泌肿瘤患者，与高剂量长效奥曲肽相比，Lu-奥曲肽治疗可显著延长无进展生存期并显著提高缓解率。在期中分析中可见总生存期获益的初步证据；计划中的最终分析将予以确认。Lu-奥曲肽组不到10%的患者发生了具有临床意义的骨髓抑制。（由Advanced Accelerator Applications资助；NETTER-1临床试验注册号，NCT01578239；欧盟临床试验注册号2011-005049-11。）
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