新辅助纳武利尤单抗和伊匹单抗治疗可切除 III 期黑色素瘤。

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

机构信息

From the Departments of Medical Oncology (C.U.B., M.W.L., L.L.H., J.M.L., S.M.P., J.B.A.G.H., K.A.T.N., J.V.T., S.W., A.M.-E., I.L.M.R.), Pathology (B.A.W.), Biometrics (M.L.-Y., A.T.A., L.G.G.-O.), Surgical Oncology (W.J.H., A.M.J.K., A.C.J.A.), Head and Neck Surgery (W.M.C.K., C.L.Z.), Radiology (B.A.S.), and Molecular Oncology and Immunology (J.B.A.G.H.), Netherlands Cancer Institute, and the Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Cancer Center Amsterdam (A.J.M.E.), Amsterdam, the Departments of Medical Oncology (C.U.B., J.B.A.G.H., F.M.S., E.K.) and Otorhinolaryngology Head and Neck Surgery (C.L.Z.), Leiden University Medical Center, Leiden, the Departments of Medical Oncology (K.A.T.N., R.C.S., A.A.M.V.), Surgical Oncology (D.J.G., R.C.S.), and Radiology and Nuclear Medicine (A.A.M.V.), Erasmus Medical Center, Rotterdam, the Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht (S.B.V., K.P.M.S.), the Department of Medical Oncology, Medical Center Leeuwarden, Leeuwarden (R.R.), the Department of Medical Oncology, Zuyderland Medical Center, Sittard-Geleen (F.W.P.J.B.), the Department of Medical Oncology, Medisch Spectrum Twente, Enschede (D.P.), the Department of Medical Oncology, Maxima Medical Center, Veldhoven (G.V.), the Department of Medical Oncology, Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, Maastricht (M.J.B.A.), the Department of Medical Oncology, Amphia Hospital, Breda (M.A.M.S.B.), the Department of Medical Oncology, Radboud University Medical Center, Nijmegen (M.J.B.-S.), the Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen (G.A.P.H.), and Isala Oncology Center, Isala Hospital, Zwolle (J.-W.B.G.) - all in the Netherlands; the Department of Hematology and Medical Oncology, University Clinic Regensburg, Regensburg, Germany (C.U.B.); Melanoma Institute Australia (R.A.S., A.M.M., R.P.M.S., N.G.M., M.G., S.N.L., A.S., T.E.P., K.F.S., R.V.R., S.C., J.S., M.A.R., A.C.J.A., M.S.C., G.V.L.), the Faculty of Medicine and Health (R.A.S., A.M.M., R.P.M.S., N.G.M., S.N.L., A.S., T.E.P., K.F.S., S.C., J.S., M.A.R., A.C.J.A., G.V.L.), and Charles Perkins Centre (R.A.S., G.V.L.), University of Sydney, the Departments of Tissue Pathology and Diagnostic Oncology (R.A.S., R.V.R.) and Melanoma and Surgical Oncology (R.P.M.S., T.E.P., K.F.S., S.C., J.S., M.A.R., A.C.J.A.), Royal Prince Alfred Hospital, NSW Health Pathology (R.A.S., R.V.R.), the Departments of Medical Oncology (A.M.M., G.V.L.) and Breast and Melanoma Surgery (A.S.), Royal North Shore and Mater Hospitals, and the Department of Radiology, Mater Hospital (R.K.), Sydney, Royal Prince Alfred Hospital, Institute of Academic Surgery, Camperdown, NSW (A.C.J.A.), the Division of Cancer Surgery, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (D.E.G.), the Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC (L.S., S.S.), Lake Macquarie Oncology, Lake Macquarie Private Hospital, the Department of Medical Oncology, Calvary Mater Hospital, and the Department of Medicine, School of Medicine and Public Health, University of Newcastle, Newcastle, NSW (A.W.), the Department of Medical Oncology, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), the Department of Medical Oncology, Fiona Stanley Hospital, Perth, WA (M.K.), the Department of Medical Oncology, Alfred Health, Melbourne, and the Department of Medicine, School of Translational Medicine, Monash University, Melbourne, VIC (M.C.A.), and the Department of Medical Oncology, Westmead Hospital and Blacktown, Sydney (M.S.C.) - all in Australia; the Melanoma Clinic, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (J.B.A.G.H.); the Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (J.P., P.R.); the Department of Medical Oncology, Centre Léon Bérard, Lyon (M.A.-A.), Université Paris Cité, Assistance Publique-Hôpitaux de Paris (AP-HP) Dermato-Oncology and Clinical Investigation Center, Cancer Institute AP-HP, Nord Paris Cité, INSERM Unité 976, Saint Louis Hospital, Paris (C.L.), and the Department of Medical Oncology, Gustave Roussy and Paris-Saclay University, Villejuif (C.R.) - all in France; the Department of Surgical Oncology, Angeles Clinic and Research Institute, Los Angeles (M.B.F.); and the Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy (P.A.A.).

出版信息

N Engl J Med. 2024 Nov 7;391(18):1696-1708. doi: 10.1056/NEJMoa2402604. Epub 2024 Jun 2.

DOI:10.1056/NEJMoa2402604

PMID:38828984

Abstract

BACKGROUND

In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy.

METHODS

In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival.

RESULTS

A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group.

CONCLUSIONS

Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

摘要

背景

在可切除的、宏观 III 期黑色素瘤患者的 1-2 期试验中，新辅助免疫疗法比辅助免疫疗法更有效。

方法

在这项 3 期试验中，我们将可切除的、宏观 III 期黑色素瘤患者随机分为两组，分别接受两周期新辅助伊匹单抗联合纳武利尤单抗治疗，然后手术，或手术，然后接受 12 周期辅助纳武利尤单抗治疗。仅在新辅助组中，对有部分缓解或无反应的患者进行辅助治疗。主要终点是无事件生存。

结果

共有 423 名患者接受了随机分组。在中位随访 9.9 个月时，新辅助组的 12 个月无事件生存率估计为 83.7%（99.9%置信区间[CI]，73.8 至 94.8），而辅助组为 57.2%（99.9%CI，45.1 至 72.7）。限制平均生存时间差异为 8.00 个月（99.9%CI，4.94 至 11.05；P<0.001；进展、复发或死亡的风险比为 0.32；99.9%CI，0.15 至 0.66）。在新辅助组中，59.0%的患者有主要病理缓解，8.0%有部分缓解，26.4%无反应（>50%存活肿瘤残留），2.4%有进展；4.2%的患者尚未进行手术或手术被省略。在新辅助组中，有主要病理缓解的患者 12 个月无复发生存率为 95.1%，部分缓解的患者为 76.1%，无反应的患者为 57.0%。与全身治疗相关的 3 级或更高级别的不良事件发生在新辅助组的 29.7%的患者和辅助组的 14.7%的患者中。

结论

在可切除的、宏观 III 期黑色素瘤患者中，与手术和反应驱动的辅助治疗后接受伊匹单抗联合纳武利尤单抗新辅助治疗相比，手术和辅助纳武利尤单抗治疗后无事件生存时间更长。（由 Bristol Myers Squibb 等资助；NADINA ClinicalTrials.gov 编号，NCT04949113）。