Heppt Markus V, Heinzerling Lucie, Kähler Katharina C, Forschner Andrea, Kirchberger Michael C, Loquai Carmen, Meissner Markus, Meier Friedegund, Terheyden Patrick, Schell Beatrice, Herbst Rudolf, Göppner Daniela, Kiecker Felix, Rafei-Shamsabadi David, Haferkamp Sebastian, Huber Margit A, Utikal Jochen, Ziemer Mirjana, Bumeder Irmgard, Pfeiffer Christiane, Schäd Susanne G, Schmid-Tannwald Christoph, Tietze Julia K, Eigentler Thomas K, Berking Carola
Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany.
Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054 Erlangen, Germany.
Eur J Cancer. 2017 Sep;82:56-65. doi: 10.1016/j.ejca.2017.05.038. Epub 2017 Jun 22.
Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date.
Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression.
Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001).
Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis.
葡萄膜黑色素瘤（UM）是一种具有高转移扩散潜力的眼部恶性肿瘤。与皮肤黑色素瘤不同，免疫疗法在UM患者中尚未显示出令人信服的疗效。联合免疫检查点阻断，即抑制程序性细胞死亡蛋白1（PD-1）检查点和细胞毒性T淋巴细胞相关抗原4（CTLA-4）检查点，迄今为止尚未对UM进行系统评估。
从20个德国皮肤癌中心纳入接受PD-1抑制剂单药治疗或联合PD-1抑制剂与伊匹木单抗（一种抗CTLA-4单克隆抗体）治疗的转移性UM患者。分析96例患者的记录以评估治疗结果。通过多变量Cox回归和二元逻辑回归确定与总生存期（OS）或治疗反应相关的临床和血液参数。
86例患者仅接受了PD-1抑制剂治疗（帕博利珠单抗治疗54例，纳武利尤单抗治疗32例），经中心确认的缓解率为4.7%。帕博利珠单抗治疗患者的中位OS为14个月，纳武利尤单抗治疗患者为10个月（p = 0.765）。15例患者接受了联合免疫检查点阻断治疗，2例观察到部分缓解。该组未达到中位OS。多变量Cox回归确定东部肿瘤协作组（ECOG）体能状态（p = 0.002）、血清乳酸脱氢酶（LDH）水平升高（p = 0.002）、C反应蛋白（CRP）水平升高（p = 0.001）以及相对嗜酸性粒细胞计数（REC）<1.5%（p = 0.002）为生存不良的独立危险因素。CRP和LDH水平升高且REC<1.5%的患者疾病进展和死亡风险最高（p = 0.001）。
血液标志物可预测接受免疫检查点阻断治疗的转移性UM患者的生存情况。正常的血清LDH和CRP水平以及高REC可能有助于识别预后较好的患者。
