Two cases of late-onset secondary adrenal insufficiency after discontinuation of nivolumab
Authors: K. Otsubo, K. Nakatomi, R. Furukawa, K. Ashida, Y. Yoneshima, Y. Nakanishi, I. Okamoto
Journal: Annals of Oncology (2017)

Nivolumab, a monoclonal antibody to the immune-checkpoint protein PD-1 (programmed cell death-1) has been approved for the treatment of several tumors. On the basis of the results of randomized phase III trials, nivolumab is now administered as a standard therapy for patients with advanced, previously treated non-small-cell lung cancer (NSCLC) [1.Borghaei H. Paz-Ares L. Horn L. et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6773) Google Scholar,2.Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6236) Google Scholar]. Given that nivolumab promotes the response of effector T cells to tumor and self-antigens, it can elicit immune-related adverse events. We now report two cases of secondary adrenal insufficiency that developed several months after discontinuation of nivolumab treatment in patients with advanced NSCLC. Case 1: A 68-year-old woman with postoperative recurrence of lung adenocarcinoma was treated with three lines of chemotherapy before initiation of nivolumab treatment as a result of disease progression. After the second administration of nivolumab, the patient developed fever with a body temperature of 38.1 °C and hypoxia on exertion, with computed tomography revealing pulmonary consolidation around metastatic lesions. Methylprednisolone (1000 mg/day, d.i.v.) was administered for 3 days, and her symptoms resolved immediately. Although nivolumab was discontinued at this time, the pulmonary metastatic lesions gradually decreased in size without any additional treatment. Four months after nivolumab withdrawal, the patient developed fatigue and appetite loss, and laboratory data revealed eosinophilia (23.8%; reference range, 1.0–4.0) (Figure 1A) as well as low levels of cortisol (0.5 µg/dl; reference range, 6.24–18) and adrenocorticotropic hormone (ACTH) (2.4 pg/dl; reference range, 7.2–63.3). No enlargement of the pituitary gland was apparent by magnetic resonance imaging. On the basis of these findings, the patient was diagnosed with nivolumab-induced secondary adrenal insufficiency. She received two cycles of methylprednisolone pulse therapy (1000 mg/day, d.i.v. for 3 days) followed by oral hydrocortisone (15 mg/day), resulting in amelioration of her symptoms and eosinophilia. Case 2: A 66-year-old man was diagnosed with stage IV lung adenocarcinoma (cT4N1M1a). He was treated with four cycles of carboplatin-pemetrexed as the first-line therapy. After disease progression, he received 11 cycles of nivolumab as the second-line therapy until subsequent disease progression. Six months after the last administration of nivolumab, the patient developed fatigue and diarrhea. Laboratory data revealed eosinophilia (38.6%) (Figure 1B) and low levels of cortisol (1.0 µg/dl) and ACTH (<1.0 pg/dl). No enlargement of the pituitary gland was detected by magnetic resonance imaging. The patient was diagnosed with nivolumab-induced secondary adrenal insufficiency and received i.v. hydrocortisone (200 mg/day for 2 days and 100 mg/day for 2 days) followed by oral hydrocortisone (40 mg/day). His symptoms and eosinophilia ameliorated, and hydrocortisone was successfully tapered. Immune-checkpoint inhibitors are associated with several immune-mediated adverse effects including adrenal insufficiency, the frequency of which induced by antibodies to PD-1 is reported to be 0% to 2.9% for patients with NSCLC. Common characteristics of adrenal insufficiency include fatigue, weight loss, nausea, and hyponatremia. Relative eosinophilia has also been found to be a marker of adrenal insufficiency. Adrenal insufficiency is classified as primary if the adrenal glands are impaired or secondary if due to a disorder of the hypothalamic-pituitary axis, with ACTH levels being high in the former case and low or inappropriately normal for a low cortisol concentration in the latter. Treatment of both primary and secondary adrenal insufficiency is based on glucocorticoid replacement. Pharmacodynamics analysis of nivolumab revealed a sustained high occupancy of PD-1 molecules on circulating T cells over 2 months after a single infusion [3.Brahmer J.R. Drake C.G. Wollner I. et al.Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.J Clin Oncol. 2010; 28: 3167-3175Crossref PubMed Scopus (2311) Google Scholar], indicating that nivolumab is able to block PD-1-mediated signaling even when it is undetectable in serum. T-cell memory for tumor antigens may also be reactivated by immune-checkpoint inhibitors, with the resulting antitumor effect being maintained for several months. Indeed, a long-term antitumor action was observed in patients with NSCLC or malignant melanoma after discontinuation of nivolumab [4.Topalian S.L. Sznol M. McDermott D.F. et al.Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.J Clin Oncol. 2014; 32: 1020-1030Crossref PubMed Scopus (1771) Google Scholar,5.Gettinger S.N. Horn L. Gandhi L. et al.Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer.J Clin Oncol. 2015; 33: 2004-2012Crossref PubMed Scopus (933) Google Scholar], suggesting that immune-related adverse events might also occur even after nivolumab withdrawal. As far as we are aware, the present study is the first to report cases of late-onset secondary adrenal insufficiency occurring several months after nivolumab discontinuation. Physicians should thus be aware of the risk for late-onset adrenal insufficiency induced by immune-checkpoint inhibitors, and patients should be monitored carefully even after discontinuation of these agents. None declared.