Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy.
Department of Experimental and Clinical Oncology, Melanoma Cancer Unit, Veneto Oncology Institute-IRCCS, Padua, Italy.
Clin Cancer Res. 2021 Sep 1;27(17):4737-4745. doi: 10.1158/1078-0432.CCR-21-1046. Epub 2021 Jun 10.
Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases.
This phase III study recruited patients 18 years of age and older with wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS).
From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths.
Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.
二期临床试验显示，在黑色素瘤脑转移患者中，伊匹单抗联合福莫司汀和伊匹单抗联合纳武单抗具有令人鼓舞的活性。我们报告了 NIBIT-M2 研究的主要分析和 4 年随访结果，这是第一项比较这些方案与福莫司汀治疗伴有脑转移的黑色素瘤患者的 III 期临床试验。
这项 III 期研究纳入了来自 9 个中心的年龄在 18 岁及以上、野生型或突变型黑色素瘤、有活动、未经治疗、无症状脑转移的患者，以 1:1:1 的比例随机分配至福莫司汀组、伊匹单抗联合福莫司汀组和伊匹单抗联合纳武单抗组。主要终点是总生存期（OS）。
2013 年 1 月至 2018 年 9 月，27、26 和 27 例患者分别接受了福莫司汀、伊匹单抗联合福莫司汀和伊匹单抗联合纳武单抗治疗。福莫司汀组的中位 OS 为 8.5 个月（95%CI，4.8-12.2），伊匹单抗联合福莫司汀组为 8.2 个月（95%CI，2.2-14.3）（与福莫司汀相比，HR 为 1.09；95%CI，0.59-1.99； = 0.78），伊匹单抗联合纳武单抗组为 29.2 个月（95%CI，0-65.1）（与福莫司汀相比，HR 为 0.44；95%CI，0.22-0.87； = 0.017）。伊匹单抗联合纳武单抗组的 4 年生存率明显高于福莫司汀组[（41.0%；95%CI，20.6-61.4）vs. 10.9%（95%CI，0-24.4； = 0.015）]，伊匹单抗联合福莫司汀组为 10.3%（95%CI，0-22.6）。在福莫司汀组、伊匹单抗联合福莫司汀组和伊匹单抗联合纳武单抗组中，分别有 11 例（48%）、18 例（69%）和 8 例（30%）患者发生与治疗相关的 3 级或 4 级不良事件，无治疗相关死亡。
与福莫司汀相比，伊匹单抗联合纳武单抗可显著改善无症状脑转移黑色素瘤患者的总生存期和长期生存。
