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Case history

image A 57-year-old man presented with haematuria and was diagnosed with locally advanced clear cell renal cell carcinoma (RCC) of the right kidney. He underwent radical nephrectomy, but 6 months later a surveillance CT scan of thorax, abdomen and pelvis revealed enlarged aortocaval lymph node and lung metastases. Multidisciplinary team review confirmed inoperable metastatic RCC. He was asymptomatic and had a WHO performance status score of 0 and no comorbidities. He was offered systemic anticancer therapy in a randomized phase III trial comparing the combination of ipilimumab plus nivolumab with sunitinib in advanced, untreated RCC. He was randomized to receive ipilimumab 1 mg/kg plus nivolumab 3 mg/kg intravenously every 3 weeks for four doses (induction phase), followed by nivolumab 3 mg/kg every 2 weeks (maintenance phase). He tolerated the first three doses of ipilimumab/nivolumab well but was admitted to hospital with abdominal pain, lethargy and headache 2 days prior to the fourth dose. Clinical examination of organ systems was normal and his haemodynamic parameters were stable.

He had deranged liver functions tests: alanine aminotransferase 7.41 μkat/l (range 0.17–0.68 μkat/l), aspartate aminotransferase 5.26 μkat/l (range 0.17–0.51 μkat/l), alkaline phosphatase 4.66 μkat/l (range 0.5–2.0 μkat/l), normal bilirubin, thyroid stimulating hormone 0.15 mIU/l (range 0.35–5.0 mIU/l), free thyroxine 5.1 pmol/l (range 9–21 pmol/l) and testosterone 4.8 nmol/l (range 10–36 nmol/l). Liver screen including coagulation, ultrasound, anti-nuclear antibodies, viral serology for hepatitis, immunoglobulins, caeruloplasmin, alpha-fetoprotein and coeliac serology was normal. MRI of brain and pituitary ruled out intracranial metastases or pituitary abnormalities.

The patient was diagnosed with immune checkpoint inhibitor (ICPI)-related hepatotoxicity and pituitary dysfunction. Treatment with corticosteroids normalized his liver function tests, but he required long-term replacement of thyroxine and testosterone.

What is the role of ICPIs in metastatic RCC?

What is the optimal dose of ipilimumab in combination with nivolumab?

What is the underlying mechanism of immune-related adverse events (irAEs)?

What is the clinical presentation and management of immune-related hepatitis?

What is the clinical presentation and management of immune-related endocrinopathies?

How should the patient's irAEs be managed?

What is the role of ICPIs in metastatic RCC?

RCC is an immunologically sensitive tumour. Older immunotherapy drugs such as interferon and high-dose interleukin produce a durable clinical response in some patients. The current era of immune checkpoint targeting of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand, programmed death-ligand 1 (PD-L1), has expanded the therapeutic options for inoperable and metastatic RCC.

On the basis of the results of the CheckMate 025 trial,1 nivolumab, a monoclonal antibody against PD-1, was approved by the US Food and Drug Administration in individuals with RCC who had undergone prior treatment. CheckMate 025 demonstrated a 5 month improvement in overall survival (OS) in patients treated with nivolumab 3 mg/kg compared with everolimus (25.0 vs 19.6 months; HR for death 0.73; 98.5% CI 0.57, 0.93; p=0.002). The objective response rate ...

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