Case Series: Tofacitinib Is Effective in Treating Refractory Immune Checkpoint Inhibitor Hepatitis
Key findings
- The authors present the first peer-reviewed reports of using a Janus kinase (JAK) inhibitor to treat refractory hepatitis associated with immune checkpoint inhibitors (ICIs)
- After receiving ipilimumab and nivolumab, three patients with metastatic melanoma developed ICI-hepatitis that was refractory to high-dose glucocorticoids, tacrolimus, and mycophenolate mofetil
- All patients responded rapidly to tofacitinib 10 mg twice daily administered in the hospital
- Oncologic outcomes varied, and as JAK signaling is crucial for antitumor responses, research is needed to determine which patients with autoimmune side effects will benefit most from JAK inhibition
Toxicities of immune checkpoint inhibitors (ICIs), including hepatitis, can be dose-limiting or even fatal. Unfortunately, options are limited for patients with ICI-hepatitis who don't respond to systemic glucocorticoids and antimetabolite immunosuppressive medications, the mainstay of treatment.
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Ryan J. Sullivan, MD, an oncologist at Mass General Cancer Center, Michael L. Dougan, MD, PhD, a physician in the Mass General Division of Gastroenterology and director of the GI Center for Cancer Complications at the Mass General Cancer Center, and colleagues are the first to describe three patients with glucocorticoid-refractory ICI-hepatitis who responded well to tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3.
In Clinical Gastroenterology and Hepatology, they explain that these were the only three patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis between August 2022 and September 2023.
Patient 1
Presentation—A 63-year-old man with metastatic melanoma, previously treated with pembrolizumab, was found to have progressive disease in the liver. One month after beginning ipilimumab and nivolumab, he presented with biopsy-confirmed ICI-hepatitis refractory to high-dose glucocorticoids, mycophenolate mofetil (MMF), and tacrolimus.
Response to tofacitinib—Inpatient treatment with tofacitinib, 10 mg twice daily in combination with continued glucocorticoids, was associated with normalized liver function tests.
Oncologic outcomes—Imaging revealed progression of melanoma in the liver, scalp, and neck 10 months after the last doses of ipilimumab and nivolumab and eight months after the last dose of tofacitinib. The patient restarted nivolumab and was switched to relatlimab without recurrence of hepatitis.
Patient 2
Presentation—A 46-year-old woman with metastatic melanoma previously treated with pembrolizumab underwent treatment with ipilimumab and nivolumab for progressive disease in the adrenal glands. Three months later, she developed biopsy-confirmed ICI-hepatitis, which was initially glucocorticoid-responsive. However, when prednisone was tapered, her liver function tests worsened, and she was admitted for treatment with tacrolimus and MMF in addition to increased doses of glucocorticoids.
Response to tofacitinib—Because the hepatitis continued to be refractory, tofacitinib 10 mg twice daily was started. The patient's hepatitis resolved rapidly.
Oncologic outcomes—Unfortunately, imaging two months later demonstrated worsening melanoma, and the patient passed away shortly afterward.
Patient 3
Presentation—A 61-year-old woman with locally advanced melanoma, initially treated with surgical resection and one year of adjuvant nivolumab, was found to have a recurrence in the endometrium, brain, bowel, and multistation lymph nodes. Following hysterectomy and resection and radiation of brain metastases, she received ipilimumab and nivolumab. Three months later, she developed severe ICI-hepatitis refractory to high-dose glucocorticoids, tacrolimus, and MMF.
Response to tofacitinib—Once the patient was started on tofacitinib, 10 mg twice daily, her liver function tests normalized rapidly. Tofacitinib was stopped after six weeks, partly because of a delay in insurance coverage. One week later, the hepatitis returned, although to a lesser degree. The patient was restarted on tofacitinib 10 mg twice daily, again with resolution of hepatitis.
Oncologic outcomes—Subsequent imaging revealed no metastatic disease in the thorax, abdomen, or pelvis but demonstrated progressive disease in the brain. The patient received additional radiation to the brain and then was transitioned to BRAF-targeted therapy.
A Conundrum
JAK inhibitors have also proven effective in managing refractory ICI-colitis and ICI-myocarditis, but JAK1 signaling is crucial for antitumor responses. Research is needed to determine which patients with autoimmune side effects will benefit most from JAK inhibition while maintaining durable antitumor immunity.
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