Department of Medical Oncology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Ann Oncol. 2017 Apr 1;28(4):862-867. doi: 10.1093/annonc/mdw692.
Combination of T cell checkpoint blockade by CTLA-4- and PD-1-blockade is one of the most promising therapies in patients with advanced melanoma. It induces superior response rates when compared with single-agent therapy, but at the cost of a high percentage of grade 3 and 4 adverse events (AEs). This combination therapy was until July 2016 not available in the Netherlands, which prompted several physicians to treat patients with less than standard numbers of courses of ipilimumab followed directly by nivolumab or pembrolizumab.
In this retrospective analysis, patients were included who were treated with two courses (day 0 and 21) anti-CTLA-4 (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22 with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on treatment-related AEs were collected from electronic patient records and scored according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans.
Forty advanced melanoma patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median follow-up (FU) was 51 weeks (range: 4-63 weeks) with a minimum FU of 26 weeks. Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best overall response rate (BORR) was 55% (95% CI 39-70) and disease control rate was 75% (95% CI 59-87). Ongoing responses were observed in 82% of responding patients.
Treatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results warrant further investigation in a prospective randomized controlled clinical trial.
细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）和程序性死亡受体 1（PD-1）联合阻断是晚期黑色素瘤患者最有前途的治疗方法之一。与单药治疗相比，它诱导了更高的缓解率，但也以高比例的 3 级和 4 级不良事件（AE）为代价。这种联合治疗方法直到 2016 年 7 月在荷兰都不可用，这促使一些医生在标准疗程的伊匹单抗治疗后，直接使用纳武单抗或帕博利珠单抗治疗患者。
在这项回顾性分析中，纳入了接受两疗程（第 0 天和 21 天）抗 CTLA-4（伊匹单抗 3mg/kg，每 3 周 1 次）治疗的患者，随后直接接受抗 PD-1（从第 22 天开始，纳武单抗 3mg/kg，每 2 周 1 次或帕博利珠单抗 2mg/kg，每 3 周 1 次）治疗。从电子病历中收集与治疗相关的 AE 数据，并根据 CTCAE 4.03 标准进行评分。使用 RECIST 1.1 对 CT 扫描和 EORTC 标准对 PET 扫描进行总体反应评估。
40 名晚期黑色素瘤患者可纳入（帕博利珠单抗 29/40 例，纳武单抗 11/40 例）。中位随访（FU）时间为 51 周（范围：4-63 周），最小 FU 时间为 26 周。38%的患者发生 3 级和 4 级治疗相关 AE。最佳总缓解率（BORR）为 55%（95%CI 39-70），疾病控制率为 75%（95%CI 59-87）。在有反应的患者中，82%的患者观察到持续反应。
与 CTLA-4 和 PD-1 联合治疗相比，短期 CTLA-4 阻断治疗后直接进行 PD-1 阻断治疗可能具有相似的疗效，但潜在毒性较低。这些结果需要在一项前瞻性随机对照临床试验中进一步研究。
