BACKGROUND Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. METHODS We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. RESULTS We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). CONCLUSIONS The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.

中文翻译：

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立体定向放射外科与免疫检查点抑制或靶向治疗相结合的黑色素瘤脑转移患者的回顾性研究。

背景技术越来越多的证据表明，立体定向放射外科（SRS）与同时免疫疗法或靶向疗法在黑色素瘤脑转移瘤（BM）患者中具有协同作用。我们旨在分析在SRS之前或之后的9周内开始的免疫检查点抑制剂（ICI）或BRAF / MEK抑制剂对总体生存（OS）的影响。我们还评估了患者和疾病特征的预后价值，将其作为接受SRS治疗的患者OS的预测指标。方法我们确定了2011年至2018年间经SRS治疗的皮肤或未知原发性黑色素瘤的BM患者。结果我们纳入了84例患者。中位OS为12个月（95％CI为9-20个月）。中位随访时间为30个月（95％CI 28-49）。新诊断为BM的28例患者开始了抗PD-1 +/- CTLA-4治疗（n = 18），在SRS之前或之后的9周内，使用ipilimumab单药治疗（n = 10）或BRAF +/- MEK抑制剂（n = 11）。与伊匹木单抗单药治疗相比，接受抗PD-1 +/- CTLA-4 mAb的患者表现出更好的生存率（OS 24 vs. 7.5个月； HR 0.32，95％0.12-0.83，p = 0.02）和BRAF +/- MEK抑制剂（分别为OS 24和7个月; HR 0.11，95％0.04-0.34，p = 0.0001）。与接受双重BRAF / MEK抑制（BMi）治疗的患者亚组相比，该益处仍然很明显（n = 5）。在多变量Cox回归分析中，年龄> 65岁，同步BM，> 2个转移部位，> 4 BM和ECOG> 1与较差的预后相关。在SRS的9周内使用抗PD-1 +/- CTLA-4 mAb进行治疗可改善预后。BM诊断时血清乳酸脱氢酶（LDH）水平≥2xULN的存在与OS降低相关（HR 1.60，95％CI 1.03-2.50; p = 0.04）。结论抗PD-1 +/- CTLA-4 mAbs与SRS并用与新诊断BM的黑色素瘤患者的生存期延长有关。除中枢神经系统肿瘤负担外，全身性疾病的扩展在接受SRS治疗的患者中保留了其预后价值。血清LDH水平升高是这些患者预后不良的预兆。全身疾病的扩展在接受SRS治疗的患者中保留了其预后价值。血清LDH水平升高是这些患者预后不良的预兆。全身疾病的扩展在接受SRS治疗的患者中保留了其预后价值。血清LDH水平升高是这些患者预后不良的预兆。