德国埃森大学医院Dirk Schadendorf团队研究了辅助性纳武单抗联合伊匹单抗以及单独辅助性纳武单抗，治疗切除的无疾病证据的IV期黑色素瘤患者的疗效。相关论文于2022年9月10日发表在《柳叶刀》杂志上。

先前的IMMUNED试验显示，在切除或放疗后无疾病证据的IV期黑色素瘤患者中，辅助性纳武单抗联合伊匹单抗以及单独辅助性纳武单抗治疗后无复发生存率显著提高。研究组报告了最终分析，包括总体生存数据。

IMMUNED试验是一项由研究者赞助的、双盲、安慰剂对照、三臂、临床2期试验，在德国20个学术医疗中心进行。研究组招募年龄为18-80岁、患有IV期黑色素瘤、手术或放疗后无疾病迹象的患者。

将患者按1:1:1随机分组，分别接受纳武单抗加伊匹单抗（纳武单抗1 mg/kg加伊匹单抗3 mg/kg，每3周4次，随后每2周一次纳武单抗3 mg/kg）、单独纳武单抗（纳武单抗3 mg/kg，每2周一次）或匹配的安慰剂治疗，为期1年。主要终点是意向治疗人群的无复发生存率。次要终点是复发时间、总生存期、无进展生存期或无复发生存期2（安慰剂组中的患者在经历疾病复发后转为纳武单抗治疗）和安全终点。

2015年9月2日至2018年11月20日，共有175名患者被纳入该研究，167名患者被随机分配，其中纳武单抗加伊匹单抗组56例，纳武单抗加伊匹单抗匹配安慰剂组59例，双安慰剂对照组52例。中位随访49.2个月后，纳武单抗加伊匹单抗组的4年无复发生存率为64.2%，纳武单抗组为31.4%，安慰剂组为15.0%。

纳武单抗加伊匹单抗组与安慰剂组的复发风险比（HR）为0.25，纳武单抗组和安慰剂组的风险比为0.60，组间差异均显著。任何治疗组均未达到中位总生存期。纳武单抗加伊匹单抗组的总体生存率显著优于安慰剂组（HR为0.41），但单独纳武单抗与安慰剂组无显著差异（HR为0.75）。纳武单抗加伊匹单抗组的4年总生存率为83.8%，纳武单抗组为72.6%，安慰剂组为63.1%。

安慰剂组患者在经历疾病复发后改用纳武单抗治疗的中位无进展生存期或无复发生存期2未达到（95%置信区间21.2个月未达到）。与研究组之前的报告相比，3-4级治疗相关不良事件的发生率基本上保持不变，纳武单抗加伊匹单抗组中发生率为71%，单独纳武单抗组中发生率29%。无治疗相关死亡。

研究结果表明，与安慰剂相比，两种有效方案在无复发风险的IV期黑色素瘤患者中继续显示出显著改善的无复发生存率。与安慰剂相比，接受纳武单抗加伊匹单抗治疗的患者总体生存率显著提高。

在复发后，安慰剂组患者中使用后续抗PD-1治疗的比例较高，并且很可能影响单独使用纳武单抗与安慰剂的总体生存率比较。与安慰剂相比，纳武单抗加伊匹单抗治疗的无复发和总体生存益处加强了已开始治疗的无疾病证据的IV期黑色素瘤患者的临床实践变化。

附：英文原文

Title: Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial

Author: Elisabeth Livingstone, Lisa Zimmer, Jessica C Hassel, Michael Fluck, Thomas K Eigentler, Carmen Loquai, Sebastian Haferkamp, Ralf Gutzmer, Friedegund Meier, Peter Mohr, Axel Hauschild, Bastian Schilling, Christian Menzer, Felix Kiecker, Edgar Dippel, Alexander Roesch, Mirjana Ziemer, Beate Conrad, Silvia Krner, Christine Windemuth-Kieselbach, Leonora Schwarz, Claus Garbe, Jürgen C Becker, Dirk Schadendorf, Elisabeth Livingstone, Lisa Zimmer, Jessica C Hassel, Michael Fluck, Thomas K Eigentler, Carmen Loquai, Sebastian Haferkamp, Ralf Gutzmer, Friedegund Meier, Peter Mohr, Axel Hauschild, Bastian Schilling, Christian Menzer, Felix Kiecker, Edgar Dippel, Alexander Roesch, Mirjana Ziemer, Beate Conrad, Silvia Krner, Jan-Christoph Simon, Rudolf A Herbst, Carola Berking, Jochen Utikal, Sabine Sell, Uwe M Martens, Patrick Terheyden, Rudolf Stadler, Christine Windemuth-Kieselbach, Leonora Schwarz, Claus Garbe, Jürgen C Becker, Dirk Schadendorf

Issue&Volume: 2022-09-10

Abstract:

Background

The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data.

Methods

IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete.

Findings

Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9–58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2–75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7–43·8) in the nivolumab alone group, and 15·0% (6·7–26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13–0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36–1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17–0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36–1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8–91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4–83·2) in the nivolumab alone group, and 63·1% (46·9–75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3–4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57–82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17–42) of patients receiving nivolumab alone. There were no treatment-related deaths.

Interpretation

Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease.

DOI: 10.1016/S0140-6736(22)01654-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01654-3/fulltext