程序性死亡蛋白-1抑制剂治疗晚期肺癌出现垂体免疫不良反应3例

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients:A report of 3 cases

程序性死亡蛋白-1(programmed cell death protein 1,PD-1)及其配体-1(PD-1 ligand 1,PD-L1)的抑制剂广泛用于肺癌治疗,但引起的免疫相关不良反应(immune related adverse events,irAEs)值得关注。垂体irAEs包括垂体炎和垂体功能减退,常见于细胞毒T淋巴细胞相关抗原-4抑制剂治疗后,而较少见于PD-1/PD-L1抑制剂治疗后。孤立性促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)缺乏是垂体irAEs的一种特殊亚型,不伴垂体其他功能紊乱和垂体肿大。本研究报告3例晚期肺癌患者,PD-1抑制剂治疗后出现孤立性ACTH缺乏及其他irAEs。病例1是68岁男性患者,先确诊PD-L1高表达的肺腺癌,采用帕博利珠单抗(pembrolizumab)单药治疗,期间出现免疫性肝炎,经高剂量甲基泼尼松龙[0.5~1.0 mg/(kg·d)]治疗后缓解;间隔11个月又确诊原发性胃癌,故在帕博利珠单抗基础上增加阿帕替尼(apatinib)治疗;帕博利珠单抗治疗共17次后,患者的肺癌和胃癌均未进展,但出现严重恶心和无力,此时甲基泼尼松龙已停药10个月,血液生化检查提示重度低钠血症(121 mmol/L,参考值137~147 mmol/L,下同),8:00 a.m.皮质醇(<1μg/dL,参考值5~25μg/dL,下同)和ACTH(2.2 ng/L,参考值7.2~63.3 ng/L,下同)降低,但甲状腺功能、性激素和泌乳素均正常。病例2是66岁男性肺腺癌患者,参加新型PD-1抑制剂HX008联合化疗的Ⅱ期临床研究(登记号:CTR20202387)。治疗5个月(共7次用药)后,患者的肺癌达到部分缓解,但恶心和呕吐却突然加重,伴轻度呼吸困难和双下肢无力,其血液生化检查提示轻度低钠血症(135 mmol/L),8:00 a.m.皮质醇(4.3μg/dL)和ACTH(1.5 ng/L)降低,但甲状腺功能正常;同时肺CT显示中度免疫性肺炎。病例3是63岁男性肺鳞状细胞癌患者,一线使用信迪利单抗(sintilimab)联合化疗,肺癌最佳疗效为部分缓解,仅出现轻度免疫性皮疹;治疗5周期后,肺癌进展,此后6个月未使用免疫治疗;再次免疫治疗前,常规评估发现8:00 a.m.血皮质醇降低(1.5μg/dL),ACTH正常(8.0 ng/L),但无肾上腺皮质功能减退症状,使用替雷利珠单抗(tislelizumab)联合化疗2周期后出现肺部感染伴持续低热、中度无力和重度低钠血症(116 mmol/L),此时,8:00 a.m.血皮质醇为3.1μg/dL,ACTH为7.2 ng/L,甲状腺功能、性激素和泌乳素均正常。这3例患者均无头痛和视力障碍,脑磁共振成像均未见垂体肿大或垂体柄增粗,且无动态变化。患者均接受了泼尼松(2.5~5 mg/d)激素替代治疗,相关症状缓解后均恢复PD-1抑制剂治疗。病例2较特殊,其因同时伴有中度免疫性肺炎而采用高剂量泼尼松[1 mg/(kg·d)]治疗,并逐渐减量至生理替代剂量,8:00 a.m.血皮质醇和ACTH恢复并维持正常,但其他两例患者的垂体功能减退均未恢复。本组病例提示,PD-1抑制剂诱发的垂体irAEs可表现为孤立性ACTH缺乏,其发病时间跨度大,临床表现不特异,恢复模式也不同。因此,对PD-1抑制剂治疗的患者,尤其是疗效好的患者,要定期监测垂体相关内分泌激素水平,警惕垂体irAEs。

Programmed cell death protein 1(PD-1)and its ligand 1(PD-L1)have been widely used in lung cancer treatment,but their immune-related adverse events(irAEs)require intensive attention.Pituitary irAEs,including hypophysitis and hypopituitarism,are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors,but rarely by PD-1/PD-L1 inhibitors.Isolated adrenocorticotropic hormone(ACTH)deficiency(IAD)is a special subtype of pituitary irAEs,without any other pituitary hormone dysfunction,and with no enlargement of pituitary gland,either.Here,we described three patients with advanced lung cancer who developed IAD and other irAEs,after PD-1 inhibitor treatment.Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1.He was treated with pembrolizumab monotherapy,and developed immune-related hepatitis,which was cured by high-dose methylprednisolone[0.5-1.0 mg/(kg·d)].Eleven months later,the patient was diagnosed with primary gastric adenocarcinoma,and was treated with apatinib,in addition to pembrolizumab.After 17 doses of pembrolizumab,he developed severe nausea and asthenia,when methylprednisolone had been stopped for 10 months.His blood tests showed severe hyponatremia(121 mmol/L,reference 137-147 mmol/L,the same below),low levels of 8:00 a.m.cortisol(<1μg/dL,reference 5-25μg/dL,the same below)and ACTH(2.2 ng/L,reference 7.2-63.3 ng/L,the same below),and normal thyroid function,sex hormone and prolactin.Meanwhile,both his lung cancer and gastric cancer remained under good control.Case 2 was a 66-year-old male with metastatic lung adenocarcinoma,who was treated with a new PD-1 inhibitor,HX008,combined with chemotherapy(clinical trial number:CTR20202387).After 5 months of treatment(7 doses in total),his cancer exhibited partial response,but his nausea and vomiting suddenly exacerbated,with mild dyspnea and weakness in his lower limbs.His blood tests showed mild hyponatremia(135 mmol/L),low levels of 8:00 a.m.cortisol(4.3μg/dL)and ACTH(1.5 ng/L),and normal thyroid function.His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously.Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma.He was treated with first-line sintilimab combined with chemotherapy,which resulted in partial response,with mild immune-related rash.His cancer progressed after 5 cycles of treatment,and sintilimab was discontinued.Six months later,he developed asymptomatic hypoadrenocorticism,with low level of cortisol(1.5μg/dL)at 8:00 a.m.and unresponsive ACTH(8.0 ng/L).After being rechallenged with another PD-1 inhibitor,teslelizumab,combined with chemotherapy,he had pulmonary infection,persistent low-grade fever,moderate asthenia,and severe hyponatremia(116 mmol/L).Meanwhile,his blood levels of 8:00 a.m.cortisol and ACTH were 3.1μg/dL and 7.2 ng/L,respectively,with normal thyroid function,sex hormone and prolactin.All of the three patients had no headache or visual disturbance.Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening,and no dynamic changes.They were all on hormone replacement therapy(HRT)with prednisone(2.5-5.0 mg/d),and resumed the PD-1 inhibitor treatment when symptoms relieved.In particular,Case 2 started with high-dose prednisone[1 mg/(kg·d)]because of simultaneous immune-related pneumonitis,and then tapered it to the HRT dose.His cortisol and ACTH levels returned to and stayed normal.However,the other two patients’hypopituitarism did not recover.In summary,these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD,with a large time span of onset,non-specific clinical presentation,and different recovery patterns.Clinicians should monitor patients’pituitary hormone regularly,during and at least 6 months after PD-1 inhibitor treatment,especially in patients with good oncological response to the treatment.