Osorio J C, Ni A, Chaft J E, Pollina R, Kasler M K, Stephens D, Rodriguez C, Cambridge L, Rizvi H, Wolchok J D, Merghoub T, Rudin C M, Fish S, Hellmann M D
Department of Medicine, Weill Cornell Medical College, New York, USA
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA.
Ann Oncol. 2017 Mar 1;28(3):583-589. doi: 10.1093/annonc/mdw640.
Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.
Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.
Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04).
Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.
程序性细胞死亡蛋白1（PD-1）阻断疗法已在多种恶性肿瘤中显示出持久疗效并延长了生存期。尽管可能会发生免疫相关不良事件（irAE），但该治疗总体耐受性良好。自身免疫性甲状腺功能障碍是最常见的irAE之一，但此前尚未对其临床、机制和免疫学特征进行评估。
纳入了在纪念斯隆凯特琳癌症中心作为KEYNOTE-001（NCT01295827）一部分接受帕博利珠单抗治疗的晚期非小细胞肺癌（NSCLC）患者（n = 51）。从首次治疗前开始，在每次研究访视时前瞻性评估甲状腺功能测试和抗甲状腺抗体。评估甲状腺功能障碍的发生频率、与抗甲状腺抗体的关联、临床病程以及与帕博利珠单抗治疗的无进展生存期和总生存期的关系。
在接受治疗的51例患者中，3例在基线时为甲状腺功能减退，48例不是。48例患者中有10例（21%，95%置信区间[CI] 10%至35%）发生了需要甲状腺替代治疗的甲状腺功能障碍。发生甲状腺功能障碍的10例患者中有8例存在抗甲状腺抗体，而未发生甲状腺功能障碍的38例患者中有3例存在抗甲状腺抗体（80%对8%，P < 0.0001）。甲状腺功能障碍在帕博利珠单抗治疗过程中出现较早（中位时间为42天），大多数患者（10例中有6例）在甲状腺功能减退发作前经历了短暂的甲状腺功能亢进；未出现持续性甲状腺功能亢进。甲状腺功能亢进和甲状腺功能减退大多无症状。发生甲状腺功能障碍的受试者接受帕博利珠单抗治疗后的总生存期显著更长（风险比，0.29；95% CI 0.09 - 0.94；P = 0.04）。
帕博利珠单抗治疗NSCLC期间甲状腺功能障碍很常见，其特征为发病早，常先有短暂的甲状腺功能亢进，与抗甲状腺抗体密切相关，并且可能与改善的预后相关。在T细胞导向治疗中存在抗体介导的毒性提示PD-1生物学在调节体液免疫方面的影响未得到充分认识。
