Department of Medical Oncology, Westmead and Blacktown Hospital, New South Wales, New South Wales, Australia.
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
J Immunother Cancer. 2021 May;9(5). doi: 10.1136/jitc-2020-002121.
Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases.
We performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients.
Of the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23-83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab.Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren's syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet's syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare.The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005).
In patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.
免疫疗法的临床试验排除了患有自身免疫性疾病的患者。虽然回顾性研究已经检查了单药 ipilimumab 和抗 PD1 抗体在自身免疫性疾病患者中的安全性和有效性，但尚无关于联合治疗的数据，而联合治疗的毒性风险显著更高。我们旨在确定联合免疫疗法治疗患有晚期黑色素瘤和预先存在的自身免疫性疾病的患者的安全性和疗效。
我们对 2015 年 3 月至 2020 年 2 月期间在 10 个国际中心接受 ipilimumab 和抗 PD1 联合治疗的晚期黑色素瘤和预先存在自身免疫性疾病的患者进行了回顾性研究。对患者的自身免疫性疾病、治疗、毒性和结局数据进行了检查。
在接受 ipilimumab 和抗 PD1 治疗的 55 名患者中，中位年龄为 63 岁（范围 23-83）。46 例患者接受了 ipilimumab 和 nivolumab 治疗，9 例患者接受了 ipilimumab 和 pembrolizumab 治疗。18 例（33%）患者自身免疫性疾病发作，其中 7 例类风湿关节炎患者中有 4 例，6 例银屑病患者中有 3 例，10 例炎症性肠病患者中有 5 例，19 例甲状腺炎患者中有 3 例，1 例干燥综合征患者中有 1 例，1 例多发性肌炎患者中有 1 例，1 例贝赫切特综合征患者中有 1 例伴有银屑病。由于疾病发作，8 例（44%）患者停止了联合治疗。37 例（67%）患者出现与免疫相关的不良事件（irAE），20 例（36%）患者因 irAE 停止联合免疫治疗。没有与治疗相关的死亡。接受免疫抑制治疗的患者（OR 4.59；p=0.03）发生疾病发作的风险更高。总缓解率为 55%，其中 77%的缓解仍在继续。无进展生存期和总生存期的中位数分别为 10 个月和 24 个月。基线时接受免疫抑制治疗的患者的总生存期为 11 个月（95%CI 3.42 至 18.58），而未接受免疫抑制治疗的患者为 31 个月（95%CI 20.89 至 41.11，p=0.005）。
在患有预先存在的自身免疫性疾病、未接受免疫抑制治疗和晚期黑色素瘤的患者中，ipilimumab 和抗 PD1 的联合治疗与先前报道的试验相比具有相似的疗效。预先存在的自身免疫性疾病有发作的风险，特别是在炎症性肠病和风湿性疾病患者以及基线时接受免疫抑制治疗的患者中。
