肿瘤浸润淋巴细胞治疗或伊匹单抗治疗晚期黑色素瘤。
Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.
机构信息
From the Division of Medical Oncology (M.W.R., M.H.G.F., M.K., J.S.W.B., J.V.T., C.U.B., A.M.-E., S.K., S.W., J.B.A.G.H.), the BioTherapeutics Unit, Hospital Pharmacy (J.H. van den Berg, C.N., M.Z., S.S.), the Divisions of Pharmacy and Pharmacology (B.N., J.H. Beijnen), Molecular Oncology and Immunology (I.J., T.N.S., J.B.A.G.H.), Biometrics (R.K., L.D.V.W., M. van Dijk, L.G.G.-O., L.H.M.V., A.T.A., H.T.), Psychosocial Research and Epidemiology (R.M.T.H., V.P.R., W.H.H.), Radiology (F.L.), and Surgical Oncology (A.C.J.A., W.J.H., M.W.J.M.W.), Netherlands Cancer Institute, the Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory (M.H., C.V.), and the Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam (A.J.M.E.), Amsterdam, the Department of Healthcare Innovation and Evaluation, Julius Center for Health Sciences and Primary Care (R.M.T.H.), the Department of Medical Oncology, University Medical Center Utrecht, Utrecht University (K.P.M.S.), Trial and Data Center, Princess Maxima Center for Pediatric Oncology (H.T.), and Oncode Institute (T.N.S.), Utrecht, the Department of Health Technology and Services Research, University of Twente (V.P.R.), and the Department of Medical Oncology, Medical Spectrum Twente (D.P.), Enschede, the Department of Medical Oncology, Erasmus Medical Center, Rotterdam (A.A.M.V.), the Department of Medical Oncology, University Medical Center Groningen, Groningen (G.A.P.H.), the Department of Medical Oncology, Amphia Hospital, Breda (M.A.M.S.-B.), the Department of Medical Oncology, Maastricht University Medical Center, Maastricht (M.J.B.A.), the Department of Medical Oncology, Isala, Zwolle (J.-W.B.G.), the Department of Medical Oncology, Máxima Medical Center, Eindhoven (G.V.), the Departments of Medical Oncology (E.K.), Biomedical Data Sciences (M.W.J.M.W.), Hematology (T.N.S.), and Clinical Oncology (J.B.A.G.H.), Leiden University Medical Center, Leiden, the Department of Medical Oncology, Radboud University Medical Center, Nijmegen (M.J.B.-S.), the Department of Medical Oncology, Medical Center Leeuwarden, Leeuwarden (W.E.F.), and the Department of Medical Oncology, Zuyderland Medical Center, Sittard-Geleen (F.W.P.J.B.) - all in the Netherlands; the Department of Oncology, National Center for Cancer Immune Therapy (T.H.B., Ö.M., J.S.G., I.M.N., T.J.M., R.B.H., E.E., M. Donia, I.M.S.), and the Department of Plastic Surgery (L.R.H.), Copenhagen University Hospital, Herlev, Denmark; and Melanoma Institute Australia, the Faculty of Medicine and Health, University of Sydney, and Royal Prince Alfred Hospital - all in Sydney (A.C.J.A.).
出版信息
N Engl J Med. 2022 Dec 8;387(23):2113-2125. doi: 10.1056/NEJMoa2210233.
BACKGROUND
Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.
METHODS
In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×10 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.
RESULTS
A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.
CONCLUSIONS
In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).
背景
免疫检查点抑制剂和靶向治疗显著改善了晚期黑色素瘤患者的预后，但约一半的患者不会获得持久的获益。肿瘤浸润淋巴细胞（TIL）过继细胞疗法的 1-2 期临床试验显示出有希望的反应，但缺乏 3 期临床试验数据来确定 TIL 在治疗晚期黑色素瘤中的作用。
方法
在这项 3 期、多中心、开放标签试验中，我们以 1:1 的比例随机分配无法切除的 IIIC 或 IV 期黑色素瘤患者接受 TIL 或抗细胞毒性 T 淋巴细胞抗原 4 治疗（ipilimumab 按 3mg/公斤体重）。输注至少 5×10 TIL 前进行非清髓性、淋巴耗竭化疗（环磷酰胺加氟达拉滨），然后用高剂量白细胞介素-2 治疗。主要终点是无进展生存期。
结果
共有 168 名患者（86%的患者对程序性死亡 1 治疗有抗药性）被分配接受 TIL（84 名患者）或 ipilimumab（84 名患者）。在意向治疗人群中，TIL 组的中位无进展生存期为 7.2 个月（95%CI，4.2 至 13.1），ipilimumab 组为 3.1 个月（95%CI，3.0 至 4.3）（进展或死亡的风险比，0.50；95%CI，0.35 至 0.72；P<0.001）；分别有 49%（95%CI，38 至 60）和 21%（95%CI，13 至 32）的患者有客观反应。TIL 组的中位总生存期为 25.8 个月（95%CI，18.2 至未达到），ipilimumab 组为 18.9 个月（95%CI，13.8 至 32.6）。所有接受 TIL 治疗的患者和 57%接受 ipilimumab 治疗的患者均发生 3 级或更高级别的治疗相关不良事件；在 TIL 组中，这些事件主要是化疗相关的骨髓抑制。
结论
在晚期黑色素瘤患者中，接受 TIL 治疗的患者无进展生存期明显长于接受 ipilimumab 治疗的患者。（由荷兰癌症协会等资助；ClinicalTrials.gov 编号，NCT02278887。）
Zotero 插件