Background: This case describes severe transaminitis resulting 21 days after administration of the first dose of nivolumab 480 mg for non-small cell lung cancer (NSCLC) adenocarcinoma. The patient was an 81-year-old male whose disease had progressed after 3 cycles of carboplatin/pemetrexed. Molecular tumor marker testing did not reveal any actionable mutations prior to treatment.
Case Report : The patient initially presented with headaches, worsening shortness of breath and Grade 4 transaminitis (AST/ALT > 10x ULN). During hospitalization, he was treated with PO prednisone and IV methylprednisolone with a decrease in transaminases. Due to ongoing psychoses and worsening myopathies, the steroid doses were reduced. On day 14 of hospitalization, mycophenolate mofetil (MMF) 500 mg PO BID was initiated due to steroid refractory transaminitis. The patient was put on infection prophylaxis with sulfamethoxazole/trimethoprim and fluconazole at the time of MMF initiation. Valacyclovir was initiated when MMF was increased to 1,000 mg PO BID after three days without a response to lower doses. Ultimately the patient expired from cardiac failure 18 days after
hospitalization.
Discussion: Nivolumab recently received US Food and Drug Administration approval for every 4-week dosing based on pharmacokinetic data. Without clinical evidence, it was concluded that this increased dosing would not differ in safety or efficacy from previously approved doses, despite steady-state peak and average time concentrations predicted to be higher than the every 2-week dosing regimen. Both the National Comprehensive Cancer Network and American Society of Clinical Oncology recommend initiation of MMF for steroid refractory irAE transaminitis. These recommendations are based on case reports in patients receiving ipilimumab or nivolumab. The specific dosing and timing of initiation is not well elucidated. Additionally, there are case reports of use of antithymocyte globulin for management of irAEs.
Conclusions: Administration of 480-mg nivolumab may lead to more rapid onset of severe transaminitis. Administration of this dosing should be delayed until a patient demonstrates tolerability to the 240-mg dosing. High-dose steroids, in combination with MMF may provide more rapid clinical improvement. All patients on increased doses of immunosuppressive agents should receive opportunistic infection prophylaxis.
