1 Yale University School of Medicine and Yale Cancer Center, New Haven, CT.
J Clin Oncol. 2019 Jan 1;37(1):52-60. doi: 10.1200/JCO.18.00204. Epub 2018 Nov 8.
Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070).
We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1.
Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not.
Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti-programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.
帕博利珠单抗在黑色素瘤中具有活性，但在未经治疗的脑转移患者中的活性尚未得到充分证实。我们报告了在一项 II 期临床试验（ClinicalTrials.gov 标识符：NCT02085070）中接受新的或进展性脑转移治疗的接受帕博利珠单抗治疗的患者的长期随访结果。
我们纳入了 23 名患有黑色素瘤且有一个或多个无症状、未经治疗的 5-20mm 脑转移灶且无需使用皮质类固醇的患者；70%的患者有既往全身治疗史。帕博利珠单抗的治疗时间最长为 24 个月。脑转移瘤的反应（主要终点）通过改良的实体瘤反应评估标准（RECIST）进行评估。对预处理肿瘤进行 T 细胞浸润和程序性死亡配体 1 的分析。
6 名患者（26%）出现脑转移瘤反应。8 名患者（35%）未达到方案评估扫描时间，由于进展或需要放疗而无法对脑转移瘤的反应进行评估。脑转移和全身反应是一致的，所有患者在 24 个月时仍在继续。中位无进展生存期和总生存期分别为 2 个月和 17 个月。11 名患者（48%）在 24 个月时存活。这包括 3 名无法评估的患者。其中 1 例患者出现脑出血，2 例患者因瘤周水肿出现症状需要放射外科治疗，但所有 3 例患者在 24 个月后仍继续使用商业版的帕博利珠单抗。没有 24 个月的幸存者接受了后续 BRAF 抑制剂治疗。65%的患者出现神经相关不良事件；除 1 例外，所有不良事件均为 1 级或 2 级。3 例患者发生癫痫，用抗癫痫药物治疗。大多数应答者的预处理肿瘤 CD8 细胞密度和程序性死亡配体 1 表达较高，而所有无应答者则没有。
帕博利珠单抗治疗黑色素瘤脑转移瘤具有可接受的毒性和持久的应答。需要多学科治疗来优化脑转移瘤患者的管理，包括考虑对大病灶或有症状的病灶进行放疗，而这些在本试验中是被排除的。2 年生存率与未发生脑转移且接受抗程序性细胞死亡 1 药物治疗的患者相似。脑内和脑外反应的一致性支持使用帕博利珠单抗治疗小的、无症状的脑转移瘤。
